Systems, methods, and devices for generating nitric oxide

Abstract

Disclosed herein is a system for delivering nitric oxide to a subject, the system comprising: (a) a nitric oxide injection line configured to inject a first gas at an injection point into a respiratory conduit containing respiratory gas, the first gas comprising a first amount of nitric oxide; (b) a sampling line configured to sample a second gas comprising a second amount of nitric oxide and respiratory gas at a sampling location between the injection point of the first gas and the subject; and (c) 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 the second amount of nitric oxide in the sampling line.

Description

Detailed Description of the Invention

[0001] [Technical field] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 418,426, filed October 21, 2022, and U.S. Provisional Patent Application No. 63 / 418,430, filed October 21, 2022, the contents of which are incorporated herein by reference in their entireties.

[0002] Some aspects described herein relate to medical devices, and more particularly to systems and methods for generating and delivering gases, including nitric oxide. [Background technology]

[0003] Some aspects described herein relate to the production of nitric oxide (NO), which is then typically delivered to a patient in a medical setting.

[0004] Nitric oxide is a vasodilator indicated for improving oxygen delivery and reducing the need for extracorporeal membrane oxygenation, particularly in term and near-term neonates with hypoxemic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in combination with ventilatory support. Low concentrations of inhaled nitric oxide can also prevent, reverse, or limit the progression of disorders, including, but not limited to, acute pulmonary vasoconstriction, traumatic injury, aspiration or inhalation injury, intrapulmonary fat embolism, acidosis, pneumonia, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, acute pulmonary hypertension after cardiac surgery, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reaction, sepsis, asthma, and asthmatic conditions, 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.

[0005] Generally, nitric oxide can be inhaled or otherwise delivered to an individual's lungs. Providing a therapeutic dose of nitric oxide can treat patients suffering from disorders or physiological conditions that may be mediated by inhaled nitric oxide, or can supplement or minimize the need for conventional treatment for such disorders or physiological conditions. A significant challenge in nitric oxide delivery is that the presence of trace amounts of oxygen (O) in nitric oxide-containing gases can oxidize nitric oxide to produce nitrogen dioxide (NO). Unlike nitric oxide, nitrogen dioxide, which forms nitrates and nitrites in the lungs, is highly toxic at low parts per million levels. Accordingly, some embodiments described herein relate to systems and methods for generating nitric oxide on demand that reduce the period during which nitric oxide is exposed to oxygen.

[0006] To ensure continuous delivery, some known nitric oxide delivery devices require the user to follow a series of steps to hand over nitric oxide delivery from a first delivery system to a second delivery system when the first delivery system approaches depletion. Some embodiments described herein describe systems and methods that improve the continuity of nitric oxide delivery.

[0007] Some known nitric oxide delivery devices are orientation sensitive and can malfunction if moved or tilted. Thus, a need exists for systems and apparatus that are resistant to orientation-related malfunctions. This need, and all other needs, are addressed, at least in part, by the present disclosure. [Summary of the Invention]

[0008] The present disclosure is directed to a system for delivering nitric oxide to a subject, the system comprising: (a) a nitric oxide injection line configured to inject a first gas at an injection point into a respiratory conduit containing respiratory gas, the first gas comprising a first amount of nitric oxide; (b) a sampling line configured to sample a second gas comprising a second amount of nitric oxide and respiratory gas at a sampling location between the injection point of the first gas and the subject; and (c) 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 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 setpoint amount.

[0009] Also disclosed herein is a setup comprising a system described in any one of the examples herein integrated with a ventilator, an anesthetic gas delivery system, a bidirectional flow system, an intrapulmonary percussion ventilator system, a high-flow oxygen delivery system, or any combination thereof.

[0010] Additional advantages will be set forth in part in the following specification, and in part will be obvious from the specification, or may be learned by practice of the aspects described hereinafter. 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 is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a schematic, illustrative view of a console according to one embodiment. [Figure 2] FIG. 1 is a flow diagram of a method for producing nitric oxide according to one embodiment. [Figure 3] FIG. 1 is a schematic, illustrative view of a cassette, according to one embodiment. [Figure 4] FIG. 1 is a perspective view of a cassette, according to one embodiment. [Figure 5] FIG. 5 is a cross-sectional view of the cassette illustrated in FIG. 4. [Figure 6] FIG. 6 is a top view of the cassette illustrated in FIGS. 4 and 5. [Figure 7] 1 is a perspective view of a liquid container assembly according to one embodiment. [Figure 8] FIG. 8 is a cross-sectional view of the liquid container assembly illustrated in FIG. 7. [Figure 9] 8 is another cross-sectional view of the liquid container assembly illustrated in FIG. 7. [Figure 10A] 8A and 8B are perspective views of the liquid container assembly illustrated in FIG. 7 in different orientations, according to one embodiment. [Figure 10B] 8A and 8B are perspective views of the liquid container assembly illustrated in FIG. 7 in different orientations, according to one embodiment. [Figure 10C] 8A and 8B are perspective views of the liquid container assembly illustrated in FIG. 7 in different orientations, according to one embodiment. [Figure 10D] 8A and 8B are perspective views of the liquid container assembly illustrated in FIG. 7 in different orientations, according to one embodiment. [Figure 10E] 8A and 8B are perspective views of the liquid container assembly illustrated in FIG. 7 in different orientations, according to one embodiment. [Figure 10F] 8A and 8B are perspective views of the liquid container assembly illustrated in FIG. 7 in different orientations, according to one embodiment. [Figure 10G] 8A and 8B are perspective views of the liquid container assembly illustrated in FIG. 7 in different orientations, according to one embodiment. [Figure 11A] FIG. 1 is an exploded view of a cartridge assembly, according to one aspect. [Figure 11B] FIG. 11B is a perspective view of the cartridge assembly of FIG. 11A. [Figure 12]1 depicts experimental data showing a positive correlation between cartridge media moisture content and nitrogen dioxide conversion capacity. [Figure 13A] 1 depicts an exemplary schematic diagram of a system according to one aspect. [Figure 13B] 1 depicts a flow diagram of an exemplary system operation. [Figure 14] 1 depicts an exemplary setup according to one aspect. DETAILED DESCRIPTION OF THE INVENTION

[0012] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. The present invention may be more readily understood by reference to the following detailed description, examples, drawings, and claims, as well as the accompanying text. However, before the present articles, systems, and / or methods are disclosed and described, it is to be understood that the present invention is not limited to specific or exemplary aspects of the disclosed articles, systems, and / or methods, unless otherwise specified, and that such aspects can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0013] The following description of the present invention is provided as an enabling teaching of the invention in its best, currently known mode. In light of this, those skilled in the art will recognize and appreciate that many changes can be made to the various aspects of the invention described herein and still obtain the beneficial results of the present invention. It will also be apparent that some desirable advantages of the present invention can be obtained by selecting some features of the invention without utilizing other features. Thus, those skilled in the art will recognize that many modifications and adaptations to the present invention are possible and may even be desirable in certain circumstances and are a part of the present invention. Accordingly, the following description is again offered as illustrative of the principles of the present invention, and not in limitation.

[0014] definition 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 in which the event or circumstance occurs and instances in which it does not occur.

[0015] It will be appreciated that certain features of the disclosure that are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0016] As used in this 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 cassette" includes two or more such cassettes and not just one; reference to "a console" includes two or more such consoles and not just one; and so on.

[0017] Throughout the description and claims of this specification, the word "comprise," as well as other forms of this word, such as "comprising" and "comprises," are open, non-limiting terms, meaning "including, but not limited to," and are not intended to exclude, for example, other additives, segments, integers, or steps. Furthermore, the terms "comprise," "comprising," and "comprises," with respect to various aspects, elements, and features of the disclosed invention, should also be understood to include the more limited aspects of "consisting essentially of" and "consisting of."

[0018] Unless otherwise defined, 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 claims that follow, reference will be made to several terms that are defined herein.

[0019] The terms "for example" and "such as," and their grammatical equivalents, unless otherwise stated, are understood to be accompanied by the phrase "without limitation." It is further understood that these phrases are used for descriptive purposes only. It is further understood that the term "exemplary," as used herein, means "example," and is not intended to convey an indication of a preferred or ideal embodiment.

[0020] As used herein, the expressions "ambient temperature" and "room temperature" are art-recognized and generally refer to temperatures from about 20°C to about 35°C.

[0021] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Furthermore, when numerical ranges of varying scope are set forth herein, it is contemplated that any combination of these values ​​inclusive of the recited values ​​may be used. Furthermore, ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value.

[0022] Similarly, when values ​​are expressed as approximations, 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 of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. Unless otherwise stated, the term "about" will mean within 5% (e.g., within 2% or 1%) of the particular value modified by the term "about."

[0023] Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numerical values ​​within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, 6, and any integers and subincrements therebetween. This applies regardless of the size of the range.

[0024] In still further aspects, when a particular value is disclosed between two endpoints, it is understood that these endpoints can also be included.

[0025] In still further aspects, when ranges are given and example values ​​are provided, it should be understood that any range can be formed between any example values ​​within the broadest range.

[0026] References in this specification and the concluding claims to parts by weight of a particular element or component in a composition indicate the weight relationship between the element or component and any other element or component in the composition or item for which the parts by weight are expressed. Thus, in a composition 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 are present in such ratio regardless of whether additional components are included in the composition.

[0027] Weight percent (wt %) of a component is based on the total weight of the formulation or composition in which the component is included, unless specifically stated to the contrary.

[0028] When an element is referred to as being "connected" or "coupled" to another element, it will be understood that it may be directly connected or coupled to another element, or that 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 present. Other words used to describe relationships between elements or layers should be interpreted similarly (e.g., "between" vs. "directly between," "adjacent" vs. "directly adjacent," "on" vs. "directly on").

[0029] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0030] It will be understood that terms such as "first," "second," and the like 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 used only 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 could be referred to as a second element, component, region, layer, or section without departing from the teachings of the exemplary embodiments.

[0031] As used herein, the term "substantially" means that the subsequently described event or circumstance occurs entirely, or that the subsequently described event or circumstance occurs generally, typically, or approximately.

[0032] Still further, the term "substantially" can, in some embodiments, refer to at least about 90%, at least about 95%, at least about 99%, or about 100% of a stated property, ingredient, composition, or other condition used to characterize or otherwise quantify a quantity.

[0033] In other aspects, as used herein, the term "substantially free" is intended to refer to a composition that is substantially absent, or when used in the context of a component of a composition, an amount of less than about 1% by weight, e.g., less than about 0.5% by weight, less than about 0.1% by weight, less than about 0.05% by weight, or less than about 0.01% by weight of the recited material, based on the total weight of the composition.

[0034] Spatial terms such as "beneath," "below," "lower," "above," "upper," "bottom," and "top" may be used herein for ease of description to describe the relationship of one element or feature to another element(s) or feature(s), as illustrated in the figures. It will be understood that spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is turned over, an element described as "below" or "directly below" another element or feature would be oriented "above" the other element or feature. Thus, the term "below" can encompass both an orientation above and below. A device may be oriented differently (rotated 90 degrees or at another orientation), and the spatially relative descriptors used herein will be interpreted accordingly.

[0035] 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 a memory. The memory of the computing device is also referred to as a non-transitory computer-readable medium, which can include instructions or computer code for performing various computer-implemented operations. The computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not itself include a transient, propagating signal (e.g., a propagating electromagnetic wave that carries information in a transmission medium such as space or a cable). The medium and computer code (also referred to as code) may be designed and constructed for a specific purpose(s). Examples of non-transitory computer-readable media include, but are not limited to, magnetic storage media such as hard disks, floppy disks, and magnetic tape; optical storage media such as compact disks / digital video disks (CDs / DVDs), compact disk read-only memory (CD-ROMs), and holographic devices; magneto-optical storage media such as optical disks; carrier wave signal processing modules; read-only memory (ROM); random access memory (RAM); and / or the like. One or more processors can be communicatively coupled to the memory and operable to execute code stored on the non-transitory processor-readable media. Examples of processors include general-purpose processors (e.g., CPUs), graphical processing units, field programmable gate arrays (FPGAs), application-specific integrated circuits (ASICs), digital signal processors (DSPs), programmable logic devices (PLDs), etc. Examples of computer code include, but are not limited to, microcode or microinstructions, machine instructions such as those generated by a compiler, code used to generate web services, and files containing higher-level instructions executed by a computer using an interpreter.For example, aspects may be implemented using an imperative programming language (e.g., C, Fortran, etc.), a functional programming language (Haskell, Erlang, etc.), a logic programming language (e.g., Prolog), an object-oriented programming language (e.g., Java, C++, etc.), or other suitable programming language and / or development tools. Additional examples of computer code include, but are not limited to, control signals, encryption code, and compression code.

[0036] Although aspects of the present invention may be described and claimed in particular statutory classes, such as system statutory classes, this is for convenience only, and one of ordinary skill in the art will understand that each aspect of the present invention may be described and claimed in any statutory class. Unless expressly stated otherwise, it is in no way intended that any method or aspect set forth herein be construed as requiring its steps to be performed in a particular order. Accordingly, no order is intended to be inferred from method claims in any respect unless the claims or specification specifically state that the steps are to be limited to a particular order. This holds for any possible implicit basis for interpretation, including the obvious meaning derived from the arrangement of steps or operational flow, grammatical structure or punctuation, or logical matters regarding the number or type of aspects described in the specification.

[0037] The present invention may be understood more readily by reference to the following detailed description of certain embodiments and examples included therein, as well as the drawings and accompanying description.

[0038] device In certain aspects, disclosed herein are consoles. It should be understood that the consoles disclosed herein can be used for medical purposes, more specifically, for delivering nitric oxide to a subject. In aspects disclosed herein, the console can include various compartments and elements configured to deliver a desired amount of nitric oxide to a subject.

[0039] In one aspect, disclosed herein is a console comprising at least one air inlet, a first receptacle configured to accommodate a first source of nitric oxide, and a second receptacle configured to accommodate a second source of nitric oxide. In other words, the console disclosed herein is configured to accommodate at least two sources capable of providing a desired amount of nitric oxide.

[0040] In still further aspects, the console comprises a controller configured to selectively couple at least one air inlet to one of the first receptacle or the second receptacle to deliver nitric oxide from the first source or the second source. In still further aspects, the console comprises an outlet coupled to the first receptacle and / or the second receptacle and configured to deliver nitric oxide to the subject.

[0041] It is understood that the source of nitric oxide can be any source known in the art. For example, the source of nitric oxide can be pressurized nitric oxide in a tank. In such an embodiment, the receptacle can be adapted to house the tank itself or a nitric oxide delivery element in communication with the tank and providing the desired amount of nitric oxide as needed.

[0042] Additionally, in still further embodiments, nitric oxide can be formed in situ. In such embodiments, the first and second sources can include materials configured to form nitric oxide on demand. For example, without limitation, the first and second nitric oxide sources can include air or a nitrite solution and an electrical device that enables the formation of nitric oxide through a spark.

[0043] In some embodiments, the first nitric oxide source and the second nitric oxide source can include nitrogen dioxide. In yet other exemplary and non-limiting embodiments, the first nitric oxide source and the second nitric oxide source can include liquid dinitrogen tetroxide. In this exemplary embodiment, the liquid dinitrogen tetroxide can be contained in a reservoir (e.g., a first reservoir and a second reservoir for the first nitric oxide source and the second nitric oxide source, respectively). The reservoir(s) can be located within a cassette(s). The liquid nitrogen dioxide can be a source of gaseous nitrogen dioxide that can be converted to nitric oxide within the cassette. In still further embodiments, the first nitric oxide source comprises a first cassette configured to form nitric oxide, and / or the second nitric oxide source comprises a second cassette configured to generate nitric oxide. In a still further aspect, the at least one air inlet is coupled to a first receptacle, and when 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 receptacle to the second receptacle, thereby delivering nitric oxide from the second source.

[0044] In a still yet further aspect, the controller is configured to monitor the state of charge of the first nitric oxide source and / or the second nitric oxide source.

[0045] An exemplary, non-limiting console is shown in Figure 1, which is a schematic, illustrative diagram of a console 50, according to one embodiment. The console 50 is an on-demand delivery system for nitric oxide. As shown in Figure 1, the console 50 includes a controller 60, one or more air inlets 70, an air outlet 80, and one or more receptacles 90 configured to receive a cassette(s) 100.

[0046] The controller 60 in the console 50 can be operable to deliver nitric oxide at a controlled flow rate and / or concentration. In such embodiments, the controller disclosed herein is configured to control the rate at which nitric oxide is delivered to the subject. In still yet further embodiments, the controller is also configured to deliver nitric oxide at a desired concentration.

[0047] For example, controller 60 may include one or more processors, memory, and / or control circuitry operable, for example, to selectively activate individual cassettes 100 and / or control flow rate through console 50. In such embodiments, controller 60 is configured to control the rate of nitric oxide generation within the first cassette and / or the second cassette. For example, controller 60 may be operable to control one or more pumps to draw air through one or more air inlets 70, selectively control flow through one or more cassettes 100, control the temperature of liquid dinitrogen tetroxide within cassette(s) 100, control the rate at which nitrogen dioxide is produced within cassette(s) 100, control the rate at which nitric oxide is produced within cassette(s) 100, control the concentration and / or flow rate at which nitric oxide exits cassette(s) 100, and control the concentration and / or flow rate at which nitric oxide-containing gas exits console 50 (e.g., through one or more air outlets 80) for delivery to the patient. The controller 60 may include one or more user interfaces or controls so that nitric oxide can be delivered on demand and / or so that a user can interface with the controller 60 to select, for example, a flow rate and / or a nitric oxide flow concentration.

[0048] A cassette 100 can be inserted into each of one or more receptacles 90 and configured to generate nitric oxide when activated. Each cassette 100 can be a single-use, disposable component that stores liquid dinitrogen tetroxide (N2O4). N2O4 can be converted to gaseous nitrogen dioxide (NO2), and each cassette can be activated to convert NO2 to nitric oxide (NO).

[0049] In some embodiments, the console 50 can be designed and / or configured to accommodate two or more receptacles 90 and two or more cassettes 100. Each receptacle 90 is configured to receive one cassette 100. The controller 60 can be capable of automatically changing from a first receptacle / cassette to a second receptacle / cassette when the first cassette approaches depletion. As also noted, the controller 60 can be operable to selectively deliver nitric oxide from any of the cassettes 100, monitor the fill status of each cassette 100, and / or transition from delivering nitric oxide from a first cassette to a second cassette when, for example, the first cassette approaches empty. This simplifies the usability of the delivery console 50 by eliminating the operator step required to control the transition between two separate consoles when the first cassette approaches depletion and extends the time of nitric oxide delivery.

[0050] In some aspects, the console 50 may be designed and / or configured to accommodate only one air inlet 70. If the console 50 accommodates two or more receptacles 90 and two or more cassettes 100, the controller 60 may be capable of selectively coupling the air inlet 70 to one of the receptacle(s) 90 such that the console 50 can automatically transition from producing nitric oxide using one of the cassette(s) 100. For example, the controller 60 may be capable of automatically changing from coupling the air inlet 70 to a first receptacle / cassette to coupling the air inlet 70 to a second receptacle / cassette when the first cassette approaches depletion.

[0051] In some embodiments, the console 50 can be designed and / or configured to accommodate two or more air inlets 70. For example, the console can include two or more air inlets such that a first receptacle and a second receptacle are separately coupled to at least one air inlet.

[0052] In such an embodiment, each air inlet 70 is separately coupled to one of two or more receptacles 90 and one of two or more cassettes 100. The controller 60 may enable selective activation of the air inlets 70 coupled to one of the receptacles and one of the cassettes such that the console 50 can automatically transition from generating nitric oxide using one of the cassette(s) 100. For example, the controller 60 may enable automatic change from activating a first air inlet 70 coupled to a first receptacle / cassette to activating a second air inlet 70 coupled to a second receptacle / cassette when the first cassette approaches depletion. In other words, the controller is configured to selectively activate at least one air inlet in a first receptacle or a second receptacle based on the fill status 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 state of charge of liquid dinitrogen tetroxide used as a source of nitric oxide.

[0053] 2 is a flow diagram for generating nitric oxide according to an exemplary embodiment disclosed herein. The method 200 of FIG. 2 can be implemented, for example, using the controller 60 of the console 50 in FIG.

[0054] As shown in FIG. 2, method 200 begins at 201 by directing air from at least one air inlet (e.g., air inlet(s) 70 in FIG. 1 ) through a first cassette (e.g., cassette(s) 100 in FIG. 1 ) that generates nitric oxide gas. For example, a controller (e.g., controller 60 in FIG. 1 ) can control the air inlet (e.g., air inlet 70 in FIG. 1 ) to direct air through the first cassette (e.g., cassette(s) 100 in FIG. 1 ). The controller can be further operable to control the rate at which nitric oxide is generated by the cassette, e.g., by controlling the temperature of a reservoir containing dinitrogen tetroxide, and / or the concentration at which the nitric oxide is delivered, e.g., by controlling the flow rate of a carrier gas from the air inlet to the air outlet.

[0055] At 202, the method continues to detect the nitrogen tetroxide fill status of the first cassette. A controller (e.g., controller 60 in FIG. 1 ) monitors and detects the nitrogen tetroxide fill status of the first cassette (e.g., cassette(s) 100 in FIG. 1 ) while the first cassette produces nitric oxide. The nitrogen tetroxide fill status is used to determine the appropriate time to stop dosing using the first cassette and start dosing using the second cassette when the first cassette approaches depletion. This method improves utilization of the cassette nitrogen tetroxide source material to reduce remaining material (e.g., nitrogen tetroxide, nitrogen dioxide) at the end of dosing for each cassette while maintaining continuous nitric oxide dosing delivery. The nitrogen tetroxide fill status can be detected, for example, by monitoring the temperature and / or pressure of a liquid container assembly (e.g., liquid container assembly 3000, discussed in more detail below). As the amount of nitrogen tetroxide in the liquid container assembly decreases (i.e., approaches depletion), the temperature required to achieve the internal pressure to produce a given amount / concentration of nitric oxide may increase. A feedback control mechanism can measure the amount / concentration of nitric oxide produced by the cassette and adjust the temperature setpoint of the liquid container assembly to maintain a set level and / or produce a target amount / concentration. The controller can determine that the cassette is approaching depletion based on the temperature and / or pressure within the liquid container assembly and / or the rate at which the cassette is producing nitric oxide.

[0056] At 203, the method continues to automatically reroute air from at least one air inlet (e.g., air inlet(s) 70 in FIG. 1 ) through a second cassette (e.g., cassette(s) 100 in FIG. 1 ) that generates nitric oxide based on detecting that the state of fill of the first cassette is below a threshold. For example, when a controller (e.g., controller 60 in FIG. 1 ) detects that the state of fill of the first cassette (e.g., cassette(s) 100 in FIG. 1 ) is below a predetermined threshold, the controller automatically reroutes air from the air inlet (e.g., air inlet(s) 70 in FIG. 1 ) through the second cassette (e.g., cassette(s) 100 in FIG. 1 ) to ensure continuity of the generated air flow. The first cassette is different from the second cassette. In some cases, at 203, the method can further include activating the second cassette, for example, by breaking or rupturing a container (e.g., an ampoule) containing the liquid dinitrogen tetroxide.

[0057] The control algorithm for generating nitric oxide can also switch from controlling the first cassette to controlling the second cassette. In some embodiments, the switch can be gradual. In still further embodiments, 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. For example, the second cassette can be ramped up (e.g., by increasing the temperature of a liquid reservoir in the second cassette to generate a target level of nitric oxide) while the first cassette maintains a steady supply of nitric oxide via the air outlet. During the ramp-up phase, the nitric oxide generated from the second cassette can be vented to room air or inactivated. When the second cassette reaches the target level, a valve can disconnect the first cassette from the air outlet and connect the second cassette to the air outlet. Any residual nitric oxide generated by the disconnected first cassette can be vented to room air and / or inactivated. In other embodiments, the switch from the first cassette to the second cassette can be gradual.

[0058] For example, the control algorithm can gradually increase the concentration of nitric oxide produced by the second cassette (e.g., by increasing the temperature of the liquid container of the second cassette) while decreasing the concentration of nitric oxide produced by the first cassette (e.g., by reducing the temperature of the liquid container of the first cassette). During the transition period, both the first cassette and the second cassette can be coupled to air outlets to contribute to the supply of nitric oxide. In other words, embodiments are also disclosed in which at least one air inlet is simultaneously coupled to both the first receptacle and the second receptacle at least once.

[0059] In some embodiments, for example, a system contains only one air inlet (e.g., air inlet(s) 70 in FIG. 1 ), while the system contains two or more cassettes (e.g., cassette(s) 100 in FIG. 1 ). A controller (e.g., controller 60 in FIG. 1 ) can be capable of directing air from the air inlet through a first cassette (e.g., cassette(s) 100 in FIG. 1 ) that produces nitric oxide gas by coupling the air inlet to the first cassette. The controller can monitor and detect the fill status of the first cassette while the first cassette is producing nitric oxide. When the controller detects that the fill status of the first cassette is below a threshold, the controller can automatically reroute air from the air inlet through a second cassette (e.g., cassette(s) 100 in FIG. 1 ) that produces nitric oxide gas by coupling the air inlet to the second cassette to ensure continuity of airflow.

[0060] In some embodiments, for example, a system contains two or more air inlets (e.g., air inlet(s) 70 in FIG. 1 ), while the system contains two or more cassettes (e.g., cassette(s) 100 in FIG. 1 ). Each air inlet is separately coupled to one of the two or more cassettes. A controller (e.g., controller 60 in FIG. 1 ) can route air from a first air inlet (e.g., air inlet(s) 70 in FIG. 1 ) through a first cassette (e.g., cassette(s) 100 in FIG. 1 ), which generates nitric oxide gas by activating the first air inlet. The controller can monitor and detect the fill status of the first cassette while the first cassette is generating nitric oxide. When the controller detects that the fill state of the first cassette is below a threshold, the controller can automatically reroute air from the second air inlet through a second cassette (e.g., cassette(s) 100 in FIG. 1 ) that produces nitric oxide gas by switching to and activating the second air inlet to ensure continuity of airflow.

[0061] FIG. 3 is a schematic, illustrative diagram of cassette 100, according to an embodiment. U.S. Pat. No. 8,887,720, the disclosure of which is incorporated herein by reference in its entirety, describes known reservoir assemblies and cartridges suitable for use with cassette 100. Cassette 100 includes cartridge assembly 200 and liquid container (LV) assembly 300. LV assembly 300 includes reservoir 310, restrictor 320, and heater 330. Reservoir 310 can contain liquid nitrogen tetroxide. Upon activation (e.g., by console 50), heater 330 increases the temperature of the liquid nitrogen tetroxide, producing nitrogen dioxide. The nitrogen dioxide can exit reservoir 310 through restrictor 320. Heater 330 and restrictor 320 together can provide a controlled release of nitrogen dioxide. After passing through the restrictor, the nitrogen dioxide can flow to cartridge assembly 200, which can be operable to convert the nitrogen dioxide to nitric oxide, for example, through a chemical reaction. The chemical reaction can be, for example, a reaction between the nitrogen dioxide and an antioxidant coated on a water-retaining surface-active material. In some implementations, the antioxidant can be ascorbic acid, and the surface-active material can be silica gel. In yet other embodiments, the nitric oxide can be formed from the nitrogen dioxide in the presence of a certain amount of water, without the presence of an antioxidant. The generated nitric oxide is then delivered to the patient through console 50.

[0062] FIG. 4 is a perspective view of cassette 1000, according to an embodiment. Cassette 1000 includes a cartridge assembly 2000 and a liquid container (LV) assembly 3000. LV assembly 3000 can contain liquid nitrogen tetroxide. During operation, the liquid nitrogen tetroxide can be heated to produce nitrogen dioxide. The nitrogen dioxide can flow into cartridge assembly 2000 for further conversion. Cartridge assembly 2000 can be operable to convert nitrogen dioxide to nitric oxide, for example, through a chemical reaction. The chemical reaction can be a reaction between nitrogen dioxide and an antioxidant coated on a water-retaining surface-active material. In some implementations, the antioxidant can be ascorbic acid, and the surface-active material can be silica gel.

[0063] In another embodiment, the antioxidant can be water. The generated nitric oxide is then delivered to the patient through the console. FIG. 5 is a cross-sectional view of the cassette 1000 illustrated in FIG. 4. FIG. 6 is a top view of the cassette 1000 illustrated in FIGS. 4 and 5. As shown in FIG. 5, the cartridge assembly 2000 includes a cartridge housing 2100, a cartridge inlet frit 2110, a cartridge media 2200, a cartridge edge connector 2500, a compression stopper 2300, a cartridge outlet frit 2120, a cartridge housing lid 2400, and an output gas port 2600. The cartridge assembly 2000 is configured to convert nitrogen dioxide to nitric oxide through a chemical reaction. The chemical reaction can be a reaction between nitrogen dioxide and an antioxidant coated on a water-retaining surface-active material. The cartridge media 2200 contained in the cartridge assembly 2000 can be an antioxidant coated on a surface-active material. In some implementations, the antioxidant can be ascorbic acid and the surface-active material can be silica gel. It is further understood that water can be used as an antioxidant. In still further embodiments, other known antioxidants can be used, such as vitamin C, vitamin E, alpha-tocopherol, gamma-tocopherol, or any combination thereof.

[0064] The cartridge inlet frit 2110 and the cartridge outlet frit 2120 are configured to retain the cartridge media 2200 inside the cartridge housing 2100 and provide a uniform flow of air into and out of the cartridge through the frits. The compression stopper 2300 is configured to retain the cartridge media 2200 inside the cartridge housing 2100 by compression. The compression stopper 2300 can be fabricated from an elastomer or any other suitable material that allows the compression stopper 2300 to fit into the cartridge housing 2100 and / or compress the cartridge media 2200. The compression stopper 2300 can be chemically non-reactive with the cartridge media 2200, antioxidants, nitrogen dioxide, and / or nitric oxide. The cartridge housing lid 2400 is configured to seal and close the cartridge housing 2100 such that the cartridge media 2200 contained therein is protected and isolated from room air. The output gas port 2600 is configured to output the generated nitric oxide at a controlled rate for delivery to the patient.

[0065] The cassette edge connector 2500 is configured to electrically and / or communicatively connect the cassette 1000 to a control unit capable of controlling the delivery of nitric oxide. As shown in FIG. 6 , the control unit can be a cassette printed circuit board assembly 4000. In some embodiments, the cassette printed circuit board 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 cassettes 1000, control the temperature of the liquid nitrogen tetroxide in the cassette(s) 1000, control the rate at which nitrogen dioxide is generated in the cassette(s) 1000, control the rate at which nitric oxide is generated in the cassette(s) 1000, and control the concentration and / or flow rate at which nitric oxide exits the cassette(s) 1000 through the output gas port 2600. In some implementations, the cassette printed circuit board assembly 4000 can be connected to a single heater element and configured to control the temperature of the nitrogen tetroxide in the cassette 1000. In operation, the cassette printed circuit board assembly 4000 can control a single heater element to heat the temperature at an elevated level. The liquid container heater 3510 can be a single cartridge heater, as shown in FIG. 6. The liquid container heater 3510 can be thermally coupled to the reservoir by the restrictor body 3210 (as best shown in FIG. 6) inside the liquid container assembly 3000. In some implementations, multiple heaters can be used in the liquid container assembly 3000 to increase and / or control the temperature of the dinitrogen tetroxide.

[0066] In some implementations, cassette printed circuit board assembly 4000 can receive / send signals from a console (e.g., console 50 in FIG. 1 ) and implement instructions received from the console. For example, cassette printed circuit board assembly 4000 can activate liquid container heater 3510 on liquid container assembly (3000) in response to instructions received from the console and / or sending a signal from thermistor 3500 back to the console so that the console can monitor the temperature within cassette 1000. In such implementations, the console can control one or more pumps that draw air through air gas port 3700 and flow through one or more cassettes 1000.

[0067] Temperature is monitored and / or controlled with a single thermistor 3500, as shown in FIG. 6. The thermistor 3500 is attached to the top surface of the liquid container assembly 3000 via a spade tab hole connection secured with screws (not shown), as shown in FIG. 6. Compared to a wired heater coil heating element, the single heater element liquid container heater 3510 has improved mechanical strength and durability, which reduces the likelihood of wire / coil breakage failure. The process of securing the liquid container heater 3510 and thermistor 3500 to the liquid container assembly 3000 is substantially simplified compared to the process of securing a wired heater coil heating element as implemented in some known cassettes. In some embodiments, multiple thermistors are used to monitor and / or control temperature and can be attached to the liquid container assembly 3000.

[0068] The input air tube 3600 and input air gas port 3700 are configured to direct input air into the cassette 1000, as shown in FIG. 5. The nitrogen dioxide-containing gas tube 3800 is configured to direct the generated nitrogen dioxide to the cartridge assembly 2000 for further conversion to nitric oxide, as shown in FIG. 6. The actuation pin opening 3415 accommodates a pin for actuation of the cassette 1000, which will be discussed in detail in the description of FIG. 8. The T-fitting 3416, as shown in FIG. 6, is coupled to a restrictor (e.g., capillary restrictor tube 3211, as shown in FIG. 9) to direct the nitrogen dioxide generated in the liquid container assembly from the input air gas port 3700, through the input air tube 3600, into the carrier gas (e.g., air) flowing over the nitrogen dioxide-containing gas tube 3800 and cartridge assembly 2000.

[0069] 5, the deactivation chamber 4100 is configured to encase the liquid container assembly 3000 to prevent accidental release of nitrogen dioxide and / or nitrogen tetroxide from the cassette 1000. A deactivation chamber top gasket and clamp 4200 and a deactivation chamber bottom gasket 4300 are configured to connect the deactivation chamber 4100 to the liquid container assembly 3000. The deactivation chamber top gasket and clamp 4200 and the deactivation chamber bottom gasket 4300 may be made of an elastic material. In the event that the ampoule 3150 is ruptured when the cassette 1000 is not being used to generate nitric oxide (e.g., if dropped during transport), the nitrogen tetroxide and / or nitrogen dioxide contained in the cassette 1000 can be vented to the deactivation chamber 4100 through the deactivation vent path 4400. The color indicator 4500 can change color to alert the user that nitrogen dioxide is being vented into the deactivation chamber 4100 .

[0070] Figure 7 is a perspective view of a liquid container assembly 3000, according to an embodiment. Figure 8 is a cross-sectional view of the liquid container assembly 3000 illustrated in Figure 7. Figure 9 is another cross-sectional view of the liquid container assembly 3000 illustrated in Figure 7. As mentioned above, the liquid container (LV) assembly 3000 is configured to store liquid dinitrogen tetroxide. The liquid dinitrogen tetroxide can be heated to produce nitrogen dioxide.

[0071] Still further disclosed herein is an apparatus comprising: a frangible container containing dinitrogen tetroxide; a reservoir, the frangible container disposed within the reservoir and configured to contain the dinitrogen tetroxide when the frangible container is broken; and an outlet, disposed on a wall of the reservoir, the frangible container, the reservoir, and the outlet collectively configured such that when the frangible container is broken, the level of dinitrogen tetroxide in the reservoir does not reach the outlet, regardless of the orientation of the container.

[0072] Such an exemplary embodiment is also shown in FIG. 8. As shown in FIG. 8, LV assembly 3000 includes ampoule 3150 (e.g., a frangible container). Ampoule 3150 is configured to store liquid dinitrogen tetroxide. LV assembly 3000 includes an actuation mechanism capable of breaking ampoule 3150 to release the liquid dinitrogen tetroxide into a reservoir within LV assembly 3000. The actuation mechanism includes actuation wedge 3121, actuation wedge spring 3122, actuation sleeve 3123, ePTFE pad 3124, actuation sleeve (bottom) 3414, actuation pin 4313, actuation pin O-ring 3412, actuation pin spring 3411, and LV housing 3400.

[0073] Prior to actuation / breakage, the ampoule 3150 is laterally secured in place using an expanded PTFE foam pad (ePTFE pad 3124) under the bottom end of the ampoule 3150 and a low-contact-force conical spring (actuation wedge spring 3122) on the actuation top end of the ampoule 3150. The ePTFE pad 3124 and actuation wedge spring 3122 dampen mechanical shock on the ends of the ampoule 3150. The ampoule 3150 is also supported around its circumference for the lower half of its length using an aluminum sleeve (actuation sleeve 3123), which has minimal clearance between the inner diameter of the actuation sleeve 3123 and the outer diameter of the ampoule 3150, minimizing potential shock from side impacts. These features improve the mechanical durability of the ampoule 3150.

[0074] Breaking / actuation of the ampoule 3150 is accomplished using an actuation wedge 3121. The leading edge of the actuation wedge 3121 applies a lateral force to the unsupported free end of the ampoule 3150 when it contacts during actuation. The lateral force bends the ampoule 3150 relative to the cylindrical actuation sleeve 3123, which maintains the position of the ampoule 3150 concentrically disposed with the LVM housing 3400 and supports it along approximately half of its length. The lateral bending force strains the wall of the ampoule 3150 at the midpoint of its length, which fractures the ampoule 3150. During actuation and before breakage, the larger diameter inside the LVM housing 3400 forms a gas seal with the U-cup seal 3410. Before and after use, the actuation pin 3413 is in the retracted position. In the retracted position, the inner smaller diameter portion of the LVM housing 3400 maintains an open vent gas path (inert vent path 4400 shown in FIG. 5) between the inside of the LV assembly 3000 and the inert chamber 4100 (shown in FIG. 5). The inert chamber 4100 can contain an absorbent medium, such as a soda-lime chemical absorbent medium, which can be suitable for neutralizing dinitrogen tetroxide and / or nitrogen dioxide, preventing toxic gases from being released from the LV assembly.

[0075] An actuation sleeve (bottom) 3414, an actuation pin 3413, an actuation pin O-ring 3412, and an actuation pin spring 3411 are also part of the actuation mechanism. The actuation sleeve 3414 is configured to protect the actuation pin 3413 and hold it in place before or after actuation. The actuation pin 3413 and actuation pin spring 3411 are disposed within an actuation pin opening 3415, as shown in FIG. 5 . The actuation pin 3413 and actuation pin spring 3411 are configured to actuate the LV assembly 3000 by applying a constant force to the actuation wedge 3121 and actuation wedge spring 3122. The actuation pin O-ring 3412 is configured to seal the LV assembly 3000 and prevent liquid / gas leakage.

[0076] Upon actuation, liquid nitrogen tetroxide is released from ampoule 3100 into the reservoir. Further, actuation can seal inactivation vent path 4400. The reservoir can be heated by a heater to generate nitrogen dioxide and control the pressure within the reservoir. The nitrogen dioxide can exit LV assembly 3000 through a restrictor. By controlling the pressure (which is a function of temperature), the nitrogen dioxide can be released through the restrictor at a controlled rate. After passing through the restrictor, the nitrogen dioxide can flow with a carrier gas supplied by the console to cartridge assembly 2000, which can be operable to convert the nitrogen dioxide to nitric oxide. As shown in FIGS. 8 and 9, LV assembly 3000 contains restrictor body 3210 and capillary restrictor tube 3211. A single liquid reservoir heater 3510 (as shown in FIG. 6) is loaded into a hole in the restrictor body 3210 adjacent to the capillary restrictor tube 3211 to heat the liquid dinitrogen tetroxide to produce nitrogen dioxide. The proximity of the liquid reservoir heater 3510 to the capillary restrictor tube 3211 is positioned to keep the temperature of the restrictor body 3210 high compared to the temperature of the LV assembly 3000, which reduces the possibility of liquid condensation and clogging of the capillary restrictor tube 3211. In some embodiments, multiple heaters can be used in the LV assembly 3000 to heat the temperature of the dinitrogen tetroxide.

[0077] The body of the liquid container assembly 3000 can be manufactured using aluminum, which reduces machining and material costs. In fact, most of the LV assembly 3000 components can be manufactured using aluminum for the same reasons. Aluminum provides high thermal conductivity and heat transfer for heat generated at the restrictor body 3210 end of the LV assembly 3000. The restrictor body 3210 is desirably constructed of a material with a higher heat capacity than the body of the liquid container assembly 3000, such as stainless steel, which can provide relatively better heat retention during cool-down (e.g., during periods when the cartridge heater is turned off), keeping the capillary restrictor tube 3211 warmer than the reservoir and further inhibiting condensation.

[0078] As mentioned above, temperature can be monitored and / or controlled using a single thermistor 3500 attached to the top surface of the restrictor body 3210 via a threaded spade tab hole connection. A single thermistor 3500 has improved mechanical strength and durability, reducing the likelihood of wire break failure. In some embodiments, multiple thermistors can be used and attached to the liquid container assembly 3000 to monitor temperature.

[0079] The LV assembly 3000 also includes an insulating polymer sleeve 3110 to insulate the LV assembly 3000 and reduce heat loss. The insulating sleeve 3110 is applied around the outer surface of the LV assembly 3000 during assembly. This insulating sleeve 3110 creates a small air gap between the outer surface of the LV assembly 3000 and the surrounding absorbent medium within the deactivation chamber 4100 (as shown in FIG. 5). This air gap provides an insulating layer that reduces the rate of heat loss to the surrounding medium and reduces heating time to the target temperature by approximately two-fold compared to heating without the insulating sleeve at the same input power. The T-fitting 3416 is the same as that shown in FIG. 6 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 vent set screw 3214 are configured to join the pipes (e.g., capillary restrictor tube 3211 and T-fitting 3416) and allow the release of nitric oxide flow.

[0080] In yet a further aspect, the device includes a separator disposed at the outlet that is positioned above the nitrogen tetroxide regardless of the orientation of the container or external vibrations applied to the container. For example, LV assembly 3000 includes gas inlet frit (or separator) 3212 coupled to capillary restrictor tube 3211 and T-fitting 3416. Gas inlet frit 3212, capillary restrictor tube 3211, and T-fitting 3416 collectively define a flow path through which nitrogen dioxide exits LV assembly 3000. As best seen in FIGS. 9 and 10B , gas inlet frit 3212 is positioned on a pedestal that is coaxial with and disposed within LV assembly 3000. In this manner, gas inlet frit 3212 can be positioned above the level of the nitrogen tetroxide in the reservoir regardless of the orientation of LV assembly 3000. This feature improves the performance of the LV assembly 3000 for a wider range of use conditions, such as when the patient or cassette may be moved during use, such as in hospital patient transport or other ambulatory / portable use applications. For example, the location of the gas inlet frit 3212 allows the liquid container assembly to operate in any orientation without liquid contacting the gas inlet frit 3212, which could clog the gas path and inhibit nitrogen dioxide from exiting the liquid container assembly 3000. This allows the cassette 1000 to be transported or placed in a console, which may be in a vehicle, such as an ambulance or helicopter. Such a console can be used without risk of nitric oxide interruption due to changes in orientation or vibration.

[0081] 10A-10G are side views of the liquid container assembly illustrated in FIG. 7 in different orientations. As mentioned above, the gas inlet frit 3212 is positioned so that the liquid fill height does not reach the frit inlet position in any orientation of the LV assembly 3000. Several examples of liquid levels in extreme orientations are shown in FIGS. 10A-10E. FIGS. 10A and 10B show the liquid nitrogen tetroxide fill level in an upright orientation at room temperature. FIG. 10C shows the liquid nitrogen tetroxide fill level in a 5-degree tilted orientation at room temperature. FIGS. 10D and 10E show the liquid nitrogen tetroxide fill level in a 90-degree rotated orientation at room temperature. FIGS. 10F and 10G show the liquid nitrogen tetroxide fill level in an upside-down orientation at room temperature. As shown in Figures 10A-10G, in any of the extreme orientations of the LV assembly 3000, the liquid fill height does not reach the frit suction position, thus preventing or reducing the possibility of liquid clogging the gas path during use or transport.

[0082] FIG. 11B is a perspective view of cartridge assembly 2000, according to an embodiment. FIG. 11A is an exploded view of cartridge assembly 2000 of FIG. 11A. Cartridge assembly 2000 includes cartridge housing 2100. Cartridge housing 2100 is filled with porous media 2200 that has been infiltrated with an antioxidant. Stopper 2300, which may be constructed of rubber or other suitable elastomeric material, can pack and contain porous media 2200 and antioxidant within cartridge housing 2100 under compression. Lid 2400 can be threaded or otherwise coupled to cartridge housing 2100. As best shown in FIGS. 4 and 5, cartridge assembly 2100 can be placed within cassette 1000, discussed above.

[0083] The cartridge assembly 2000 can be fluidly coupled to the liquid container assembly 3000 via the capillary restrictor tube 3211, the T-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 cassette 1000 into the T-fitting 3416. By controlling the temperature of the reservoir of the nitrogen tetroxide-containing liquid container assembly 3000, the rate at which the nitrogen dioxide flows into the T-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.

[0084] Cartridge medium 2200 can be silica gel or other suitable high surface area wettable material. Cartridge medium 2200 can be wetted with an antioxidant, such as an aqueous solution of ascorbic acid. In some embodiments, cartridge medium 2200 can be wetted with water. Nitrogen dioxide can react with water bound to cartridge medium 2200 to produce nitric oxide following the following reaction: a. 6NO2 (gas) + 3H2O (liquid) → 3HNO3 (liquid) + 3HNO2 (liquid) Equation 1a b.3HNO2 (liquid) → HNO3 (liquid) + 2NO (gas) + H2O (liquid) Equation 1b

[0085] The ascorbic acid-wet cartridge medium 2200 (or other suitable antioxidant-containing cartridge) can be functionally similar to the medium described in U.S. Pat. No. 8,607,785, the entire disclosure of which is incorporated herein by reference. The cartridge assembly 2100 differs from known cartridges in some aspects in that, with the exception of water and antioxidants, the cartridge medium is substantially entirely (greater than 95%) active derivatized silica gel. As also noted, the cartridge medium can be substantially devoid (less than 5%) of inactive ingredients, such as ultra-high molecular weight polyethylene binder material, which in some known cartridges was sintered with silica to produce a solid media unit. Such solid media units did not fit into known cartridge housings and therefore did not maximize space within the housing. In contrast, the cartridge medium 2200 is a flowable granular material. The stopper 2300 can keep the cartridge medium 2200 in a compressed state, allowing the cartridge medium 2200 to fit into the cartridge housing 2100, maximizing use of available volume and eliminating the need for a binder to produce the solid media unit. Furthermore, unlike known media units that require multiple coating and drying steps on various individual components and subcomponents, cartridge media 2200 is more suitable for mass manufacturing because cartridge media 2200 can be wetted with antioxidant solution or water in large quantities, which can then be added to cartridge housings in an assembly line-like process from bulk containers.

[0086] In some cases, cartridge 2100 may not include ascorbic acid or other antioxidants, which may degrade over time and instead rely on stable water to improve shelf life. Additionally or alternatively, cartridge 2100 may be designed with the availability of water to reduce nitrogen dioxide in mind, such that cartridge 2100 may be operable to generate nitric oxide based on 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.

[0087] Additionally, cartridge medium 2200 may have a higher density and / or a higher water content than known cartridges. For example, some known cartridges have cartridge media with water contents between 1 and 10.6%. As shown in FIG. 12, experimental data reveals a positive correlation between the water content of cartridge medium 2200 and nitrogen dioxide conversion capacity. Increased NO conversion capacity results from the reaction between NO and water to produce NO (as discussed above), resulting in increased NO conversion capacity. In some embodiments, cartridge medium 2200 can have a water content of at least 20%. For example, the water content can be 20% to 60% by weight, 20% to 40% by weight, or 20% to 35% by weight. Such high water concentrations, especially those above 20% by weight, were not feasible with known cartridges because the presence of inert binder materials reduced the relative proportion of surfactants available to absorb water.

[0088] The cartridge medium 2200 can be wetted with a solution containing one or more suitable antioxidants. Because the generated nitric oxide may be intended for inhalation, it is desirable that the cartridge medium 2200 and / or the material with which it is wetted be non-toxic and / or food-safe. Therefore, in such embodiments, catalysts and / or antioxidants containing heavy metals or other materials that may contaminate the nitric oxide may be inappropriate. One suitable antioxidant is ascorbic acid. Various embodiments of the cartridge medium 2200 can be wetted with a solution containing 0-32% ascorbic acid by weight, with exemplary values ​​of 1%, 5%, 10%, 15%, 20%, 25%, and 30% by weight. It should be understood that the ascorbic acid can be present in any amount falling between any two of the above values, or it can be present in any range that can be formed by any two values ​​falling within the broadest range. For example, ascorbic acid can be present in an amount of 1% to 32% by weight, or 5% to 32% by weight, or 15% to 32% by weight, or 1% to 15% by weight, or 10% to 15% by weight, etc. It may be desirable for the antioxidant concentration to be at or below its room temperature solubility limit, because at higher concentrations, the antioxidant may precipitate before the cartridge medium 2200 is uniformly saturated, which may result in inconsistent nitric oxide conversion kinetics. However, it should be understood that it may be possible to further increase the antioxidant concentration by heating the antioxidant solution before wetting the cartridge medium 2200.

[0089] system Currently known NO concentration (amount)-based control methods have serious drawbacks. For example, they may be unable to determine the optimal initial infusion concentration at the start of administration because the initial NO concentration is zero and the flow delivered by a respiratory assist device, such as a ventilator, is initially unknown. Known systems typically require the user to provide a ventilator flow rate in the low, medium, or high range once a dose set point is input before administration begins. The user-provided ventilator flow rate information defines the typical initial infusion parameters and rate of change for feedback control information within the algorithm, which is used to maintain the dose without excessive overshoot of the target dose and to optimize the time to reach the target dose.

[0090] Furthermore, the speed of feedback control, an NO concentration-based control method, can be limited by the time response of the NO gas sensor to changes in NO concentration and the time it takes for changes in the initial NO injection control to propagate from the source to the sampling system. Depending on the flow mode of a respiratory assist device, such as a ventilator, the feedback control time interval can vary from less than 30 seconds to more than 60 seconds. The speed of change in system parameters is limited by the time of the change in information. For this reason, the system response to changes in ventilator system operation will be slower compared to systems that use faster-changing parameters to control dose.

[0091] Other known nitric oxide delivery systems use ventilator flow measured at the nitric oxide infusion site as the primary input parameter to determine the infusion flow from the delivery system at a fixed nitric oxide source concentration. This method is particularly well suited to the speed of system control associated with changes in ventilator system flow. Also, under normal operating conditions where all ventilator flow passes through the NO injector module once, this control method achieves acceptable NO concentration accuracy (within + / - 20% of the dose).

[0092] The precision of such systems may be insufficient for several important medical applications that require a highly controlled presence of nitric oxide. The systems disclosed herein enable the achievement of this goal.

[0093] In some embodiments, a system for delivering nitric oxide to a subject is disclosed, the system comprising a nitric oxide infusion line configured to inject a first gas at an injection point into a respiratory conduit containing a respiratory gas. In such exemplary and non-limiting embodiments, the first gas comprises a first quantity of nitric oxide. It should be understood that the injection point can be located anywhere along the respiratory conduit. In some embodiments, the injection point abuts a portion of the respiratory conduit proximate a respiratory assist device. It should be understood that the respiratory assist device can be any device capable of providing a stable amount of respiratory gas to a patient at a desired rate and concentration. In certain embodiments, the respiratory assist device is a ventilator. In still further embodiments, the ventilator can be a face mask-type ventilator. In yet other embodiments, the ventilator can be a mechanical ventilator. In still further embodiments, the mechanical ventilator can be a negative pressure ventilator and / or a positive pressure ventilator. In still other embodiments, other types of ventilators can also be used to deliver respiratory gas to a patient. For example, other types of ventilators may include tracheostomy ventilators.

[0094] In still yet further aspects, the breathing gas may include air and / or oxygen-enriched air.

[0095] In still further aspects, the disclosed systems include a sampling line configured to sample a second gas. In such aspects, the second gas includes a second amount of nitric oxide and a respiratory gas. It should be understood that sampling of the second gas can occur 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.

[0096] It should be appreciated that in still further aspects, the breathing assist device can include a respiratory conduit configured to deliver fresh respiratory gas to the subject, as well as an expiratory conduit configured to remove exhaled gas from the subject. In some aspects, the exhaled gas is vented to the ambient atmosphere, while in other aspects, the exhaled gas can be collected, scrubbed to remove carbon dioxide and other harmful gases, and optionally recirculated. In still further aspects, the respiratory conduit and expiratory conduit can be attached to a face mask or tubing that is inserted directly into the subject. In certain aspects, the sampling location can be a distance of about 6 to about 12 inches from where the respiratory conduit and expiratory conduit connect to the face mask or respiratory tubing. In still other aspects, the distance can be about 6 inches to about 12 inches, with exemplary values ​​of about 7 inches, about 8 inches, about 9 inches, about 10 inches, and about 11 inches. It should be appreciated that the distance can be anywhere between two of the above disclosed values. Furthermore, in still further aspects, the sampling location can be at a distance that can fall within any range formed by any of the above values. For example, but not limited to, the sampling location can be at a distance of between about 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.

[0097] In yet another aspect, the system may further comprise 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.

[0098] In such exemplary but non-limiting embodiments, the source configured to provide a third gas having a third amount of nitric oxide can be any source configured to provide or form nitric oxide. In certain embodiments, any of the nitric oxide sources disclosed herein can be utilized. In certain embodiments, the nitric oxide source can be a tank of nitric oxide. In other embodiments, the nitric oxide source can be a system that allows for the formation of nitric oxide through a spark. In still other embodiments, the nitric oxide source can be one or more cassettes configured to form nitric oxide through a chemical reaction, as described above.

[0099] In still further aspects, the nitric oxide setpoint controller is configured to set a nitric oxide setpoint amount or target amount of nitric oxide to be delivered to the subject. It should be understood that the terms "target amount" and "nitric oxide setpoint" can be used interchangeably herein. The target (or setpoint) amount is determined based on the subject's medical condition and in accordance with a physician's prescription. In certain aspects, the target amount can be set manually by a caregiver or the subject. It should be understood that the setpoint can be defined in any terms. For example, in some aspects, the nitric oxide setpoint is a flow rate of nitric oxide that correlates to a first amount of nitric oxide. In yet other aspects, the nitric oxide setpoint is a concentration of nitric oxide that correlates to the first amount of nitric oxide. It should be understood that in certain aspects, the system can include a setpoint controller that can allow the target amount to be defined both in terms of a nitric oxide flow rate and in terms of a concentration of nitric oxide.

[0100] It should be understood that the concentration (or amount) of nitric oxide can be determined in ppm. In still further aspects, the systems disclosed herein are capable of delivering any desired amount of nitric oxide to a subject. In certain embodiments, the amount of nitric oxide delivered to a subject can be greater than 0 ppm to about 10,000 ppm, including exemplary values ​​of about 100 ppb, about 200 ppb, about 500 ppb, about 1 ppm, about 5 ppm, about 10 ppm, about 20 ppm, about 40 ppm, about 50 ppm, about 100 ppm, about 250 ppm, about 500 ppm, about 1,000 ppm, about 1,250 ppm, about 1,500 ppm, about 1,750 ppm, about 2,000 ppm, about 2,250 ppm, about 2,500 ppm, about 2,750 ppm, about 3,000 ppm, about 3,250 ppm, about 3,500 ppm, about 3,750 ppm, and about 4,000 ppm. It should be understood that the actual amount of nitric oxide delivered to a subject can have any value between any two of the disclosed values ​​above, or can fall within any range formed by any value within the broadest range. In some examples, the nitric oxide delivered to a subject can range from about 0.1 ppm to 100 ppm, e.g., for selective pulmonary vasodilation. In some examples, the nitric oxide delivered to a subject can range from about 100 ppm to 300 ppm, e.g., for antimicrobial applications.

[0101] Additionally, in other embodiments, the target value can be determined in flow units and can be between about 0.5 microliters / minute and about 2 milliliters / minute of NO.

[0102] In still further embodiments, the first gas infused into the respiratory conduit can include a carrier gas. In such embodiments, it should be understood that the carrier gas is a gas that carries a quantity (in this case, the first quantity) of nitric oxide to the subject. In certain embodiments, the carrier gas can be passed through a source of nitric oxide, regardless of the method of forming or delivering the nitric oxide, and collect the nitric oxide therewith. Furthermore, in other embodiments, for example, when the source of nitric oxide is a tank containing nitric oxide, such a tank can also include a carrier gas. In certain embodiments, the carrier gas can include a quantity of an inert gas, such as nitrogen, or can include air or oxygen-enriched air.

[0103] In yet a further aspect, the first gas can be injected with a respiratory gas to form a second gas, which can include a second amount of nitric oxide, a respiratory gas, and optionally a carrier gas.

[0104] An exemplary system 5000 is shown in FIG. 13A. The respiratory assist device 5100 has two conduits: a respiratory conduit 5300 and an expiratory conduit 5400. A user can establish a target amount of nitric oxide to be delivered in a nitric oxide setpoint controller 5010, which communicates with a feedback loop controller 5020, which in turn communicates with a nitric oxide source 5030. The nitric oxide source either generates nitric oxide or delivers nitric oxide in a third amount. It should be understood that at least once during nitric oxide delivery to the subject, the first amount of nitric oxide is the same as the third amount of nitric oxide. For example, during a first infusion, the controller 5020 communicates with the nitric oxide source 5030 to deliver an amount of nitric oxide to the respiratory conduit 5600 at a delivery point 5500, at which point the third amount of nitric oxide is equal to the first amount of nitric oxide.

[0105] The respiratory conduit 5300 carries the respiratory gas and a second gas 5035 comprising a second amount of nitric oxide. The expiratory conduit 5400 carries gas exhaled by the subject. In some embodiments, the exhaled gas is vented to the atmosphere. In yet other embodiments, the exhaled gas is collected, scrubbed of harmful gases such as carbon dioxide, and recirculated into the respiratory conduit.

[0106] In still further embodiments, the sampling line 5055 can be operated by a pump 5040. The sampling line samples the second amount of nitric oxide, for example, at location 5600 of the respiratory conduit 5300. It should be understood that this schematic is merely exemplary and the sampling location can be anywhere, as disclosed above. The sampling line 5055, operated by the pump 5040, transports the second gas via line 5065 to at least one sensor 5060. In such embodiments, 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. The NO sensor 5060 communicates with a feedback loop controller 5020. Upon receiving information regarding the second amount of nitric oxide in the sampling line, the feedback loop controller 5020 can communicate with the nitric oxide setpoint controller 5010 to compare the second amount of nitric oxide to a target amount. In embodiments where the second amount of nitric oxide is different from the nitric oxide setpoint 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 setpoint amount.

[0107] In still further aspects, as disclosed above, nitric oxide can be formed in situ. It can be formed by a chemical reaction using a spark or liquid dinitrogen tetroxide. In aspects where nitric oxide is used from liquid dinitrogen tetroxide, the source can be any of those disclosed above. In still further aspects, as disclosed above, the amount of nitric oxide formed by the source can be controlled by the temperature and pressure applied to the source.

[0108] An exemplary, non-limiting flow diagram 6000 of the operation of the system disclosed herein is shown in FIG. 13B. First, a user can establish a target amount of NO in 6010, which is communicated to a feedback loop controller 6020 (1). The feedback loop controller communicates with an NO source 6030 (2), and a first amount 6040 of NO is infused into a respiratory conduit (not shown) (3). A sampling line measures a second amount of NO 6050 (4) and communicates it to the feedback loop controller 6020 (5). If the target amount of NO in 6010 differs from the second amount 6050, the controller 6020 communicates with the source 6030 to form a third amount of NO 6060 (9) to correct for the overall amount of NO reaching the subject. This amount is infused into the system and measured again at (10). The loop can continue in this manner as long as the subject is receiving NO.

[0109] In still further embodiments, the system can further comprise one or more additional sensors 5070. In such embodiments, the one or more additional sensors are in communication with the feedback loop controller (5072). In still further embodiments, the one or more additional sensors comprise an oxygen sensor and / or a nitrogen dioxide sensor. In yet other embodiments, 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.

[0110] In still further aspects, the system can further comprise an auxiliary sensor 5080 positioned adjacent the injection point and configured to measure the flow rate of the respiratory gas, the auxiliary sensor in communication with the feedback loop controller 5095. In such aspects, when the flow rate of the respiratory gas differs from the flow rate correlated to the nitric oxide setpoint amount, the feedback loop controller corrects the flow rate of the third gas.

[0111] For example, in such embodiments, an auxiliary sensor such as flow sensor 5080 is connected to the output of a breathing assist device, such as a ventilator. In such embodiments, this sensor can provide a direct measurement of ventilator dilution flow. If an auxiliary flow sensor is used, it provides ventilator flow information to the system that is used in conjunction with the NO dose set point to define the target NO amount and the first (infusion) amount of NO. The flow sensor can also be used to detect changes in ventilator flow, allowing the system to respond more quickly to changes in ventilator flow than when using only the measured NO concentration in the circuit.

[0112] Systems that rely solely on flow sensors without sampling the amount of nitric oxide near the subject can be inadequate when the entire ventilator flow does not pass through the NO injection. For example, such systems can be problematic when NO needs to be delivered to a subject during anesthesia. Anesthesia can be an extensive procedure, and therefore it is desirable to recirculate exhaled gas and, therefore, anesthetic compounds back to the subject. Anesthetic gas machines typically recirculate exhaled gas to minimize the use of expensive anesthetic drugs. When residual NO is present in the recirculated gas, the additional NO injection required to maintain the target concentration should be reduced compared to typical use cases without recirculation. Ventilator flow-based control methods assume a zero starting concentration of NO in the patient gas and do not account for residual NO in the recirculated gas. As a result, the amount of NO injected may be overestimated because the actual amount of NO in the respiratory conduit is higher than the target. This condition can continue to increase over time, leading to NO and NO2 concentrations in the ventilator circuit that do not meet FDA guidance requirements when recirculation occurs. As a result, NO delivery systems that use ventilator flow-based control have not been validated for use with circulatory anesthesia delivery systems.

[0113] Some ventilator systems (e.g., intrapulmonary percussive ventilation (IPV) systems) introduce respiratory gas downstream of the first gas injection. For this reason, the respiratory gas flow measurement at the point of NO injection does not represent the complete respiratory gas flow to the patient. If the first amount of NO (injected) is determined based on the flow measurement at the injection point, it may result in the NO concentration obtained by the subject being lower than the desired set dose.

[0114] In bidirectional flow modes of delivery, the accuracy of ventilator circuit flow measurements is also reduced when both directions of flow are included in the control of dose. This form of error with bidirectional flow devices results in over-delivery of NO and ventilator circuit NO concentrations that do not meet FDA guidance requirements.

[0115] The systems disclosed herein, which are configured to measure the second amount of NO delivered to a subject and correct it if necessary by measuring the flow rate of respiratory gas, can enable accurate delivery of NO amounts in anesthetic gas delivery systems, bidirectional flow systems (e.g., BiPAP, Phasitron), systems that introduce additional flow after the injection module (e.g., Intrapulmonary Percussion Ventilator), and the like.

[0116] In still further aspects, 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 include a first amount of the pharmaceutically active ingredient.

[0117] In still further embodiments, the system can also measure gases exhaled by the subject. In some embodiments, the exhalation conduit includes a fourth gas exhaled by the subject, the fourth gas being vented to the ambient environment. In still yet further embodiments, the exhalation conduit can include a fourth gas exhaled by the subject, and the system is configured to recirculate at least a portion of the fourth gas into the respiratory conduit, the at least a portion of the fourth gas being substantially free of carbon dioxide. It should be understood that the fourth gas can be treated to remove carbon dioxide before being recirculated to the respiratory conduit.

[0118] In embodiments in which the fourth gas is recirculated, such gas may comprise a fourth amount of nitric oxide. The fourth gas enters the respiratory conduit with the respiratory gas and the first gas to form a second gas that can be sampled at the sampling point. In such embodiments, the second gas may comprise at least a portion of the fourth gas. It should be understood that in such exemplary, non-limiting embodiments, the second amount of nitric oxide comprises at least the first amount of nitric oxide and a fourth amount of nitric oxide.

[0119] If the respiratory gas contains a first amount of the pharmaceutically active ingredient, and if exhaled gas is collected, the exhaled gas (or a fourth gas) may contain a second amount of the pharmaceutically active ingredient. In such embodiments, it should be understood that the second amount of the pharmaceutically active ingredient is less than the first amount of the pharmaceutically active ingredient.

[0120] When the system is used for anesthesia, the pharmaceutically active ingredient comprises an anesthetic agent.

[0121] In still further aspects, the systems disclosed herein are configured to deliver respiratory gas at rates between about 0.1 L / min and about 200 L / min, 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 systems can deliver any amount of respiratory gas that falls between any two of the aforementioned values, or between any range that any two of the aforementioned values ​​can form. For example, the system can deliver breathing gas at rates 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, etc.

[0122] Also disclosed herein is a setup comprising any of the disclosed systems integrated with a ventilator, an anesthetic gas delivery system, a bidirectional flow system, an intrapulmonary percussion ventilator system, a high-flow oxygen delivery system, or any combination thereof.

[0123] FIG. 14 shows an exemplary, non-limiting schematic diagram of the setup disclosed herein in one embodiment.

[0124] method Still further disclosed herein is a method of delivering nitric oxide to a subject. In such an embodiment, the method includes directing air from at least one air inlet through a first cassette that generates nitric oxide gas, detecting a state of charge of the first cassette, and automatically rerouting the air from the at least one air inlet through a second cassette that generates nitric oxide if the state of charge of the first cassette is near or below a threshold value.

[0125] Any of the cassettes disclosed above can be used in this method. In certain aspects, the first cassette is disposed in a first receptacle and the second cassette is disposed in a second, separate receptacle. In yet other aspects, the first cassette and the second cassette are in electrical communication with a controller. Again, it should be understood that any of the controllers disclosed above can be used in the described method.

[0126] In still further aspects, the controller is configured to automatically reroute the air. In yet still further aspects, the controller is configured to simultaneously connect both receptacles to the air inlet as needed. In still further aspects, as disclosed above, the controller used in the described methods is configured to control the rate of production of nitric oxide gas in the first cassette and / or the second cassette.

[0127] While various embodiments have been described above, it should be understood that they have been presented by way of example only and not limitation. Further, while various embodiments have been described as having particular combinations of features and / or components, other embodiments may in some cases have combinations of any feature and / or component from any embodiment, as well as additional features and / or components, where appropriate.

[0128] Where the above methods indicate certain events occurring in a particular order, the order of certain events may be changed. Additionally, certain events may be performed simultaneously in parallel processing, where possible, rather than just performed sequentially as described above. While various aspects have been described as having particular combinations of features and / or components, other aspects may in some cases include any combination of features and / or components from any aspect, where appropriate.

[0129] Exemplary Embodiments Example 1. A console comprising: at least one air inlet; a first receptacle configured to accommodate a first source of nitric oxide; a second receptacle 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 receptacle or the second receptacle to deliver nitric oxide from the first source or the second source; and an outlet coupled to the first receptacle and / or the second receptacle and configured to deliver nitric oxide to a subject. Example 2. A console as described in the examples herein, particularly Example 1, wherein the first nitric oxide source comprises a first cassette configured to form nitric oxide and / or the second nitric oxide source comprises a second cassette configured to generate nitric oxide. Example 3. A console as described in any of the examples herein, specifically Examples 1 or 2, wherein at least one air inlet is coupled to a first receptacle, and when 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 receptacle to a second receptacle, thereby delivering nitric oxide from the second source. Example 4. A console as described in any one of the examples herein, specifically Examples 1-3, wherein at least one air inlet is simultaneously coupled to the first receptacle and the second receptacle at least once. Example 5. The console described in any one of the examples herein, specifically Examples 1-4, wherein the controller is configured to monitor the charge status of the first nitric oxide source and / or the second nitric oxide source. Example 6. A console as described in any one of the examples herein, specifically Examples 1-5, wherein the console includes two or more air inlets such that the first receptacle and the second receptacle are separately coupled to at least one air inlet. Example 7. A console as described in any of the examples herein, specifically Example 6, wherein the controller is configured to selectively activate at least one air inlet in the first receptacle or the second receptacle based on the fill status of the first nitric oxide source and / or the second nitric oxide source. Example 8. The console of any one of the examples herein, particularly Examples 1-7, wherein the controller is configured to control the rate of nitric oxide delivered to the subject. Example 9. The console described in any one of the examples herein, specifically Examples 2-8, wherein the controller is configured to control the rate of nitric oxide generation in the first cassette and / or the second cassette. Example 10. A console described in any one of the Examples herein, specifically Examples 2-9, wherein the first cassette and / or the second cassette comprise a first reservoir and a second reservoir, respectively, the first reservoir and the second reservoir containing dinitrogen tetroxide, and the first cassette and / or the second cassette is configured to convert the dinitrogen tetroxide to nitric oxide. Example 11. The console described in any of the examples herein, particularly Example 10, wherein the controller is configured to control the charge of dinitrogen tetroxide. Example 12. The console described in any one of the examples herein, specifically Examples 3-11, wherein the controller is configured to incrementally increase the concentration of nitric oxide from a second source while still delivering nitric oxide from the first source. Example 13. The console described in any one of the examples herein, specifically Examples 3-12, wherein the remaining nitric oxide in the first nitric oxide source is vented after at least one air inlet is switched to a second receptacle. Example 14. A method comprising: routing air from at least one air inlet through a first cassette that generates nitric oxide gas; detecting a state of fill of the first cassette; and automatically rerouting the air from the at least one air inlet through a second cassette that generates nitric oxide if the state of fill of the first cassette is near or below a threshold value. Example 15. The method described in the Examples herein, specifically Example 14, wherein a first cassette is disposed within a first receptacle and a second cassette is disposed within a second, separate receptacle. Example 16. The method of any of the examples herein, specifically Example 14 or 15, wherein the first cassette and the second cassette are in electrical communication with the controller. Example 17. The method of any of the examples herein, particularly Example 16, wherein the controller is configured to automatically reroute the air. Example 18. The method of any of the examples herein, specifically Example 16 or 17, wherein the controller is configured to control the rate of production of nitric oxide gas in the first cassette and / or the second cassette. Example 19. The method described in any one of the Examples herein, specifically Examples 14-18, wherein the rerouting is gradual or immediate. Example 20. An apparatus comprising: a frangible container containing dinitrogen tetroxide; a reservoir configured to contain the dinitrogen tetroxide when the frangible container is disposed within the reservoir and when the frangible container is broken; and an outlet configured on a wall of the reservoir, the frangible container, the reservoir, and the outlet collectively configured such that when the frangible container is broken, the level of dinitrogen tetroxide in the reservoir does not reach the outlet regardless of the orientation of the container. Example 21. The apparatus described in the examples herein, specifically Example 20, wherein the apparatus comprises a separator disposed at the outlet and positioned above the dinitrogen tetroxide regardless of the orientation of the container or external vibrations applied to the container. Example 22. The apparatus of example 19 or 20, wherein the reservoir is configured to be heated to form nitrogen dioxide from dinitrogen tetroxide. Example 23. The device described in any of the examples herein, particularly Example 22, wherein the device is further configured to convert nitrogen dioxide to nitric oxide. Example 24. The apparatus of any one of the examples herein, specifically Examples 20-23, wherein the apparatus is thermally insulated. Example 25. The device of any one of the examples herein, specifically Examples 20-24, wherein the device comprises an actuation mechanism comprising an actuation wedge configured to break a frangible container. Example 26. A device described in any of the examples herein, specifically Example 24 or 25, wherein the actuation mechanism further comprises at least one actuation sleeve, the at least one actuation sleeve configured to maintain the positioning of the frangible container. Example 27. A system for delivering nitric oxide to a subject, the system comprising: (a) a nitric oxide injection line configured to inject a first gas into a respiratory conduit containing a respiratory gas at an injection point, the first gas comprising a first amount of nitric oxide; (b) a sampling line configured to sample a second gas comprising a second amount of nitric oxide and the respiratory gas at a sampling location between the injection point of the first gas and the subject; and (c) 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 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 setpoint amount. Example 28. A system described in any of the examples herein, specifically Example 27, wherein the sampling location is about 6 to about 12 inches from the connection point of the respiratory and expiratory conduits to the face mask or respiratory tube. Example 29. A system described in any of the examples herein, specifically, Example 27 or 28, wherein the sampling line is configured to be operated by a pump and deliver a predetermined amount of a second gas to at least one sensor. Example 30. The system described in any one of the examples herein, specifically Examples 27-29, wherein the respiratory gas is delivered by a respiratory assist device. Example 31. The system described in any one of the examples herein, specifically Examples 27-30, wherein the breathing gas comprises air and / or oxygen-enriched air. Example 32. The system of any one of the examples herein, particularly Examples 27-31, wherein the first gas further comprises a carrier gas. Example 33. The system described in any of the examples herein, specifically Example 32, wherein the second gas further comprises a carrier gas. Example 34. The system described in any one of the examples herein, specifically Examples 27-33, wherein at least one sensor is an NO sensor. Example 35. A system described in any one of the examples herein, specifically, Examples 27-34, wherein the feedback loop controller further communicates with one or more additional sensors. Example 36. The system described in any example herein, particularly Example 35, wherein the additional one or more sensors comprises an oxygen sensor and / or a nitrogen dioxide sensor. Example 37. The system described in any of the examples herein, specifically 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. Example 38 A system described in any one of the examples herein, specifically Examples 27-37, wherein the nitric oxide set point amount is a therapeutic target amount. Example 39. The system described in any one of the examples herein, specifically Examples 27-37, wherein the nitric oxide set point is a flow rate of nitric oxide correlated to the first amount of nitric oxide. Example 40. The system described in any one of the examples herein, specifically Examples 27-39, wherein the nitric oxide set point is a concentration of nitric oxide correlated to the first amount of nitric oxide. Example 41. The system described in any one of the examples herein, specifically, Examples 27-40, wherein when the second amount of nitric oxide differs from the nitric oxide setpoint 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 setpoint amount. Example 42. The system described in any one of the examples herein, specifically, Examples 27-41, 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. Example 43. The system described in any one of the examples herein, specifically Examples 27-42, wherein the source is configured to form nitric oxide in situ. Example 44. A system as described in the examples herein, specifically Example 43, wherein the third amount is controlled by the temperature and pressure supplied to the source. Example 45. A system described in any one of the examples herein, specifically Examples 27 to 44, wherein the system includes an auxiliary sensor positioned adjacent to the injection point and configured to measure the flow rate of respiratory gas, the auxiliary sensor being in communication with the feedback loop controller. Example 46. A system described in the examples herein, specifically Example 45, wherein the feedback loop controller corrects the flow of a third gas when the flow rate of the respiratory gas differs from the flow rate correlated to the nitric oxide set point amount. Example 47. The system described in any one of the examples herein, specifically Examples 27-46, wherein the respiratory gas further comprises a first amount of an active pharmaceutical ingredient. Example 48. A system described in any one of the examples herein, specifically Examples 27-47, wherein the exhalation conduit contains a fourth gas exhaled by the subject, and the fourth gas is vented to the ambient environment. Example 49. The system described in any one of the examples herein, specifically Examples 27-48, wherein the expiratory conduit contains a fourth gas exhaled by the subject, and 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. Example 50 The system described in any of the examples herein, specifically Example 49, wherein the fourth gas comprises a fourth amount of nitric oxide. Example 51 The system of any of the examples herein, specifically, Example 49 or 50, wherein the second gas comprises at least a portion of the fourth gas. Example 52 The system described in the examples herein, specifically Example 51, wherein the second amount of nitric oxide comprises at least the first amount of nitric oxide and a fourth amount of nitric oxide. Example 53. The system described in any one of the examples herein, specifically Examples 49-52, wherein the fourth gas comprises a second amount of the pharmaceutically active ingredient, and the second amount of the pharmaceutically active ingredient is less than the first amount of the pharmaceutically active ingredient. Example 54. The system described in any one of the examples herein, specifically Examples 49-53, wherein the pharmaceutically active ingredient comprises an anesthetic. Example 55. The system described in any one of the examples herein, specifically Examples 27-24, wherein the system is configured to deliver between 0.1 L / min and 200 L / min of respiratory gas. Example 56. A setup comprising a system described in any one of the examples herein, specifically Examples 27-55, integrated with a ventilator, an anesthetic gas delivery system, a bidirectional flow system, an intrapulmonary percussion ventilator system, a high-flow oxygen delivery system, or any combination thereof.

Claims

1. 1. A system for delivering nitric oxide to a subject, the system comprising: a) a nitric oxide injection line configured to inject a first gas at an injection point into a respiratory conduit containing a respiratory gas, the first gas comprising a first quantity of nitric oxide; b) a sampling line configured to sample a second gas comprising a second quantity of nitric oxide and the respiratory gas at a sampling location between the injection point of the first gas and a subject; c) a feedback loop controller, 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; iii) a feedback loop controller in communication with at least one sensor configured to measure the second quantity of nitric oxide in the sampling line; 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.

2. 10. The system of claim 1, wherein the sampling location is about 6 to about 12 inches from the connection point of the respiratory and expiratory conduits with a face mask or respiratory tube.

3. 3. The system of claim 1 or 2, wherein the sampling line is configured to be operated by a pump to deliver a predetermined amount of the second gas to the at least one sensor.

4. The system of any one of claims 1 to 3, wherein the breathing gas is delivered by a breathing assist device.

5. The system of any one of claims 1 to 4, wherein the breathing gas comprises air and / or oxygen-enriched air.

6. The system of any one of claims 1 to 5, wherein the first gas further comprises a carrier gas.

7. The system of claim 6 , wherein the second gas further comprises the carrier gas.

8. The system of any one of claims 1 to 7, wherein the at least one sensor is a NO sensor.

9. The system of any one of claims 1 to 8, wherein the feedback loop controller further communicates with one or more additional sensors.

10. The system of claim 9 , wherein the one or more additional sensors comprise an oxygen sensor and / or a nitrogen dioxide sensor.

11. The system of claim 10 , 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.

12. The system of any one of claims 1 to 11, wherein the nitric oxide set point amount is a therapeutic target amount.

13. The system of any preceding claim, wherein the nitric oxide set point is a flow rate of nitric oxide correlated to the first quantity of nitric oxide.

14. The system of any one of claims 1 to 13, wherein the nitric oxide set point is a concentration of nitric oxide correlated to the first amount of nitric oxide.

15. 15. The system of claim 1, wherein when the second amount of nitric oxide differs from the nitric oxide setpoint 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 setpoint amount.

16. 16. The system of any one of claims 1-15, 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.

17. The system of any one of claims 1 to 16, wherein the source is configured to form nitric oxide in situ.

18. 20. The system of claim 17, wherein the third amount is controlled by the temperature and pressure supplied to the source.

19. 19. The system of claim 1, further comprising an auxiliary sensor positioned adjacent to an injection point and configured to measure the flow rate of the breathing gas, the auxiliary sensor being in communication with the feedback loop controller.

20. 20. The system of claim 19, wherein the feedback loop controller corrects the flow of the third gas when the flow rate of the breathing gas differs from a flow rate correlated to the nitric oxide setpoint amount.

21. The system of any one of claims 1 to 20, wherein the breathing gas further comprises a first amount of an active pharmaceutical ingredient.

22. 22. The system of any one of claims 1 to 21, wherein the exhalation conduit contains a fourth gas exhaled by the subject, the fourth gas being vented to the ambient environment.

23. 23. The system of any one of claims 1 to 22, wherein an expiratory conduit contains a fourth gas exhaled by the subject, the system being configured to recirculate at least a portion of the fourth gas into the respiratory conduit, the at least a portion of the fourth gas being substantially free of carbon dioxide.

24. 24. The system of claim 23, wherein the fourth gas comprises a fourth amount of nitric oxide.

25. 25. The system of claim 23 or 24, wherein the second gas comprises at least a portion of the fourth gas.

26. 26. The system of claim 25, wherein the second amount of nitric oxide comprises at least the first amount of nitric oxide and the fourth amount of nitric oxide.

27. 27. The system of any one of claims 23 to 26, wherein the fourth gas comprises a second amount of the pharmaceutically active ingredient, the second amount of the pharmaceutically active ingredient being less than the first amount of the pharmaceutically active ingredient.

28. The system of any one of claims 23 to 27, wherein the pharmaceutically active ingredient comprises an anesthetic agent.

29. A system according to any preceding claim, wherein the system is configured to deliver between 0.1 L / min and 200 L / min of breathing gas.

30. 30. A setup comprising the system of any one of claims 1 to 29 integrated with a ventilator, an anesthetic gas delivery system, a bidirectional flow system, an intrapulmonary percussion ventilator system, a high flow oxygen delivery system, or any combination thereof.

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