Patent Description:
A number of gases have been shown to have pharmaceutical action in humans and animals. One such gas is nitric oxide (NO) that, when inhaled, acts to dilate blood vessels in the lungs, improving oxygenation of the blood and reducing pulmonary hypertension. In the field of inhalation therapy for various pulmonary conditions such as acute pulmonary vasoconstriction, hypertension and thromboembolism, or inhalation injury, treatment has included the use of the therapeutic gas NO supplied from a gas cylinder. More specifically, this gaseous NO for inhalation therapy is supplied to a patient from a high pressure gas cylinder containing NO. For example, such an approach is disclosed in <CIT> entitled "Nitric Oxide Delivery System", which is incorporated herein by reference in its entirety.

Inhaled nitric oxide (INO) therapy, generally speaking, involves delivering a concentration of NO, at a set dose, to mechanically ventilated patients. NO delivery systems of this type (wrap-around style) can sense fresh gas flow in the inspiratory limb of the mechanical ventilator, and ratio-metrically deliver NO from source cylinders into the inspiratory limb of the ventilator, via an injector module, to achieve a prescribed patient dose.

Typically speaking, the concentration of the NO source (e.g., from the source cylinders) may be about <NUM> ppm NO. As discussed above, this NO source gas at <NUM> ppm can be proportionally delivered (e.g., ratio-metrically delivered) into fresh gas flow such that the concentration of NO in the fresh gas flow is about <NUM> to <NUM> ppm.

Although INO therapy has many benefits, it has been found that when delivering NO into fresh gas flow, nitrogen dioxide (NO<NUM>), a toxic gas, can be generated by reacting with O<NUM> in fresh gas flow. More specifically, the formation of nitrogen dioxide is proportional to the square of the NO concentration multiplied by the concentration of O<NUM>.

The kinetics and rate equation for the conversion of NO to NO<NUM> is given by:.

Thus, giving a formation rate of NO<NUM> = k[NO]<NUM>[O<NUM>], where k is in units of L•mol-<NUM>•s-<NUM>, or in partial pressures for the gases.

Accordingly, the amount of NO<NUM> produced (ppm NO<NUM>) is related to the square of the NO concentration and is linear to the oxygenation concentration and time.

In light of the above, NO delivered into a ventilator breathing circuit from a low concentration NO source (e.g., <NUM> ppm, <NUM> ppm, and <NUM> ppm NO cylinders) may not result in undesirably high amounts of NO<NUM>, for example > <NUM> ppm; however, following the above kinetics, the use of NO delivered into a ventilator breathing circuit from a high concentration source (e.g., <NUM> ppm, <NUM> ppm, and <NUM>,<NUM> ppm NO cylinders) would be expected to generate an unacceptable amount of toxic NO<NUM>, for example > <NUM> ppm NO<NUM> generated when providing a <NUM> ppm NO dose with <NUM>% O<NUM>. Theoretically, for the same NO therapy dose, NO<NUM> from a <NUM> ppm source gas may have a formation rate to <NUM> times greater than an <NUM> ppm source.

Some have attempted to address this problem using varying techniques; however, these techniques may not work in specific systems, may not work when delivering high concentration NO, may not work at all, or can fail to address the actual cause of NO<NUM> generation and/or underlying factors in NO<NUM> generation not previously appreciated. Accordingly a need exists for systems and methods of reducing NO<NUM> generation that work in specific systems, address the actual cause of NO<NUM> generation and/or the underlying factors not previously appreciated.

<CIT> discloses that, during the administration of NO to a patient, NO reacts with oxygen in the respiratory gas to form NO2. Since NO2 is a toxic gas, minimizing the formation of this gas is important. A previously unknown property of NO is that an initial amount of NO2 is formed when NO and O<NUM> mix. By adding NO to respiratory gas at a number of spaced-apart mixing points, the total initial amount of NO2 formed can be reduced. In a method and a device for mixing and administering NO, the gas containing NO is supplied to a flow divider for distributing the flow and sending sub-flows to a number of various mixing points.

Patent document <CIT> is hereby acknowledged.

The present disclosure provides a device for use in combining a first gas stream comprising molecular oxygen (O2) and a second gas stream comprising nitric oxide (NO) for delivery of a combined gas stream to a patient as detailed in claim <NUM>. Advantageous features are provided in dependent claims.

Systems and methods of the present invention can be used to reduce NO<NUM> generated when, for example, being delivered into fresh gas flow in a ventilator breathing circuit. Further, systems and methods of the present invention can enable high concentration NO to be delivered into ventilator breathing circuits, via a diffusing device, without generating undesirably large amounts of NO<NUM> for example > <NUM> ppm NO<NUM> for a dose of <NUM> ppm NO with <NUM>% O<NUM>. Use of high concentration NO sources (e.g., <NUM>, <NUM>, <NUM>,<NUM> ppm NO cylinders) can provide benefits such as, but not limited to, the use of smaller NO gas cylinders, which allows increased portability and introducing smaller volumes of the high concentration gas into the ventilator gas stream, and less dilution of oxygen-enriched Fresh Gas Flow (FGF) by the NO and carrier N<NUM> gases. It has surprisingly been found that introduction of smaller NO volumes with diffusion at equivalent or higher rates can generate less NO<NUM> overall with shorter diffusion time associated with smaller gas volume. The issues addressed herein relate to at least rapidly reducing NO concentration before large concentrations of NO<NUM> can be formed.

Further features of embodiments of the present disclosure, their nature and various advantages will become more apparent upon consideration of the following detailed description, taken in conjunction with the accompanying drawings, which are also illustrative of the best mode contemplated by the applicants, and in which like reference characters refer to like parts throughout, where:.

The present technology, generally speaking, is directed to systems and methods of injecting NO into fresh gas flow in the inspiratory limb of a ventilator breathing circuit such that NO<NUM> generation is minimized. The present technology takes advantage of previously unknown factors which applicant surprisingly found affect NO<NUM> generation. More specifically, systems and methods of the present technology can be used to deliver NO from a source of high concentration NO (e.g., <NUM> ppm NO source) into fresh gas flow in the inspiratory limb of a ventilator breathing circuit such that NO<NUM> generation is substantially minimized and/or the NO<NUM> generated is within a desired range (e.g., less than <NUM> ppm NO<NUM> delivered to the patient, the same or less NO<NUM> as generated by substantially lower concentration NO sources using conventional injector modules, etc.) by factoring in variables such as, but not limited to, location of injection of NO into fresh gas flow, fresh gas flow velocity, NO flow velocity, and/or ratio of impinging velocity of NO and fresh gas flow, to name a few.

Further, systems and methods of the present technology can be used with a ventilator breathing circuit by not substantially causing pressure drop, for example less than <NUM> H<NUM>O at <NUM> SLPM, minimizing flow profile changes, minimizing the increase in the compressible volume of fresh gas flow, and/or enabling for patient spontaneous breathing in the ventilator breathing circuit. Further still, systems and methods of the present technology can be used immediately downstream from flow sensors that require the fresh gas flow be laminar and/or can be used immediately upstream from at least one gas sampling line.

"Compressible volume" means the volume of a conduit and all components in fluid communication with and in line with the flow path of the conduit. For example, the compressible volume of breathing circuit is the volume of the breathing circuit and all of the components within it (e.g. humidifier, injector module, sample T's).

As used herein, "diffusion", "diffusing" and related terms refer to the overall transport of molecules of one gas (e.g. NO) into and throughout a stream of another gas (e.g. oxygen-enriched air). The use of the terms "diffusion", "diffusing" and related terms does not exclude the contribution of bulk fluid motion or other transport phenomena to the mixing and homogenization of two or more gas streams.

As noted above, prior to applicant's research, it was believed that NO<NUM> formation was predicated on the concentration of NO and O<NUM> (e.g., parts-per-million of NO, percent of O<NUM> (otherwise known as FiO<NUM>)), as well as the distance/dwell time between gas mixing and the patient. Following this belief, delivery of NO from a high concentration source (e.g., <NUM> ppm, <NUM>,<NUM> ppm NO cylinder) would result in substantially high levels of NO<NUM>. For example, a <NUM> ppm NO cylinder concentration reduced down to a set dose of <NUM> ppm is a turn down ratio of <NUM>:<NUM>, whereas a <NUM> ppm cylinder concentration reduced down to a <NUM> ppm set dose has a turn down ratio of <NUM>:<NUM>, theoretically NO<NUM> is generated at a rate approximately <NUM> times greater with a <NUM> ppm NO supply than with a <NUM> ppm NO supply cylinder for a dose of <NUM> ppm. Without a means of overcoming this problem, high concentrations sources of NO cannot be used for INO therapy as this would result in delivery of undesirably high levels of NO<NUM> to a patient, and many benefits associated with using high concentration sources of NO for INO therapy (e.g., smaller NO supply cylinders, increased portability of INO therapy devices, smaller volumes of NO-containing gas (e.g., nitrogen and NO gas blends) in the breathing circuit, reduced inspired oxygen dilution due to smaller injected NO-containing gas volumes, etc.) would be unrealized.

In exemplary embodiments, using a higher concentration source gas can reduce a portion of the NO<NUM> delivered to a patient. For example, the higher the NO concentration of the source gas, the smaller the volume of source gas required to be delivered to obtain the desired set NO dose. Even with the same NO<NUM> concentration in the source gas (e.g. the same NO<NUM> concentration in a gas cylinder), by using this lower volume of source gas, less volume of NO<NUM> from the source gas would be delivered and hence the patient receives less NO<NUM> from the NO source (e.g. cylinder).

In light of at least these unrealized benefits, applicant conducted extensive research and testing into NO<NUM> generation when injecting NO into the inspiratory limb of a ventilator breathing circuit.

From this research and testing, it was surprisingly found that NO<NUM> formation was greater during the expiratory phase of ventilation, in which fresh gas flow in the inspiratory limb of a ventilator is substantially slower, laminar (non-turbulent) than during the inspiratory non-laminar (turbulent) phase of ventilation. With this knowledge, further research and testing was conducted to determine the relationship between the NO<NUM> output and variables such as the impinging velocity of the NO-containing gas, the flow rate of the FGF, and the NO dose. In each of these experiments, the fresh gas was oxygen-enriched (e.g. <NUM>% O<NUM>/air), the NO<NUM> concentration was measured at a distance beyond the NO injection point (e.g. <NUM>,<NUM>), and the NO source concentration was either a low concentration (e.g. <NUM> ppm NO) or a high concentration (e.g. <NUM> ppm NO). The NO was injected and the gases were mixed using a conventional injector module. The results of this testing are shown in Tables <NUM>-<NUM> and <FIG>.

<FIG> and <FIG> show that the impinging velocity of NO with fresh gas flow in the breathing circuit can substantially impact the amount of NO<NUM> generated. Also, as can be seen by comparing <FIG> (low concentration) and <FIG> (high concentration), increasing the NO concentration generally increased the amount of NO<NUM> produced.

<FIG> show the respective amounts of NO<NUM> generated for different set NO dosages when the NO is injected into the FGF having different flow rates. As can be seen by comparing <FIG> (low concentration) and <FIG> (high concentration), increasing the NO concentration generally increased the amount of NO<NUM> produced, particularly at the lower flow rates of FGF. This is also shown by comparing <FIG> (low concentration) and <FIG> (high concentration), as the NO<NUM> output curve for <NUM> SLPM was drastically different between the low NO source concentration and the high NO source concentration.

Although the above is beneficial in understanding NO<NUM> generation, it substantially complicates minimizing NO<NUM> generation when NO (e.g., from a high concentration NO source) is being injected into the inspiratory limb of the ventilator breathing circuit. For example, the fresh gas flow velocity can vary (e.g., the fresh gas flow rate can vary over the course of the patient breathing cycle, etc.); the NO velocity injected into the fresh gas flow can vary (e.g., the NO flow rate can vary depending on the pressure in the NO delivery line, the dimensions of the NO injection port at the diffusing device, the dimensions of the NO delivery conduit in the NO delivery system, to name a few); and ratio-metric delivery, as may be required for INO therapy, for example, to achieve a constant inspired NO concentration, can require varying the NO delivered in proportion to the fresh gas flow. During the expiratory phase some ventilators use low bias flows (<NUM> SLPM) and have slower FGF in a ventilator breathing circuit, which may generate more NO<NUM> than during the inspiratory phase (faster FGF in the ventilator breathing circuit). For example, the data above shows that <NUM> to <NUM> times more NO<NUM> may be generated with <NUM> ppm NO than with <NUM> ppm NO at low FGF associated with ventilator exhalation bias flows over the same time period, where insufficient diffusing may occur with a conventional injector module.

Accordingly, in exemplary embodiments, a diffusing device can be designed to minimize NO<NUM> generation by controlling the impinging velocity of the NO and fresh gas flow and the location of injection of the NO into the FGF. In various embodiments, the velocity of the NO flow stream may be high enough relative to the FGF at the location the NO is injected to minimize the NO<NUM> generated. Without being bound by theory, it is thought the NO flow stream may penetrate the FGF stream perpendicularly and with proportional velocities. With very low NO velocity relative to FGF velocity, without being bound by theory, it is believed the NO stays at the outer wall of the FGF stream resulting in poor mixing. Conversely, if only the NO velocity is high and the FGF is not, the mixing time can also be extended resulting in high NO<NUM>.

While not wishing to be bound by any particular theory, it is believed that the initial contact diffusion rate of the two mixing gas streams may be primarily controlled by the molecular kinetic energy. In such a gas impingement mixing process, the dissipative exchange from gas momentum can provide direct acting mixing. This rapid diffusion can take place immediately in the vicinity of the nozzle outlet, or directly at the gas impingement point. The molecular kinetic energy is defined as ½ times the molar mass times the square of the velocity, and thus the velocity is inversely proportional to the square root of the molar mass. Equivalent volumes of different gases contain the same number of particles, and the number of moles per liter at a given temperature and pressure is constant. This indicates that the density of gas is directly proportional to its molar mass. Accordingly, this indicates the same mixing energy (i.e. same kinetic energy) would exist at approximately equal velocities or a ratio of <NUM>:<NUM>, due to the similar molecular weights of NO, N<NUM>, air and O<NUM>, which all range from <NUM> to <NUM> grams per mole. However, given the slight molecular weight imbalance between air/O<NUM> mixtures and NO/N<NUM> mixtures, the greatest diffusion from the dissipative energy exchange can be at velocity ratios less than <NUM>:<NUM> (FGF: NO), such as <NUM>:<NUM>, <NUM>:<NUM> or <NUM>:<NUM>, depending on the relative proportions of N<NUM>, NO, O<NUM> and air.

In various embodiments, the velocity of the two gas streams may be proportional to each other in order to minimize the NO<NUM> generated. The NO velocity can be controlled by changing the dimensions of the NO injection port, for example, as other factors (e.g., pressure in the NO delivery line, dimensions of the NO injection channel, etc.) may be fixed. It will be appreciated that any means for controlling the NO velocity can be used. However, controlling the fresh gas flow velocity can be substantially challenging as the velocity of the fresh gas flow is typically controlled by the ventilator. Further, as noted above, the velocity of the fresh gas flow during the expiratory phase can be substantially slow. In at least some instances, the impinging velocity of the fresh gas flow during at least the expiratory phase can be too slow to minimize NO<NUM> generation. Accordingly, in exemplary embodiments, the diffusing device can include at least one accelerator capable of accelerating the fresh gas flow to a desired impinging velocity, for example, that may be directed to a point of intersection with the NO-containing gas.

In one or more embodiments, the orifice diameter at the NO gas impingement point to the fresh gas flow tube can be sized appropriately to maintain a fixed aspect ratio outlet area between the diffusing module <NUM> tube diameter (i.e. the FGF tube diameter) to the NO nozzle outlet diameter area (i.e. the injection port orifice diameter). This ratio in tube outlet area can be proportional to the NO cylinder concentration over the NO set dose. For example, for an <NUM> ppm cylinder concentration at a set dose of <NUM> ppm, a <NUM> to <NUM> turn down ratio exists in NO flow rate. In order to maintain a <NUM>:<NUM> impinging gas velocity relationship, an injector module flow tube area to injection nozzle outlet area may be sized at <NUM>:<NUM> at the lowest expected fresh gas flow rate (e.g., <NUM> SLPM). As another example, for a <NUM> ppm cylinder concentration at a set dose of <NUM> ppm, a <NUM> to <NUM> turn down ratio exists in NO flow rate. In order to maintain a <NUM>:<NUM> impinging gas velocity relationship, an injector module tube area to injection nozzle outlet area may be sized at <NUM>:<NUM>.

In one or more embodiments, the dimensions of the injection channel and injection port may be adjusted so the ratio of NO velocity to FGF velocity is less than about <NUM>:<NUM>, such as about <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>: <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM> or <NUM>:<NUM>.

In exemplary embodiments, at least one accelerator can be any device or component capable of accelerating all or a portion of the fresh gas flow. For example, the accelerator can be a conical structure with a tapered surface, a tapered section, bi-directional conical structure, and/or any shapes or surfaces capable of accelerating fresh gas flow. Other examples include structures with surfaces similar to a wing, as gas flowing over the top of a wing (curved surface) has a faster velocity than the gas flowing underneath the bottom of the wing (relatively flat surface). These accelerator structures are only exemplary, and other structures capable of accelerating at least some portion of a gas flow are also within the scope of this technology.

Notably, when injecting NO into fresh gas flow, the device's configuration and dimensions may be adjusted to reduce the source NO concentration as quickly as possible. In various embodiments, mixing features may be added to the device downstream of the NO injection point. In various embodiments, mixing can be thought of in <NUM> phases. The first phase where the majority of NO<NUM> may be generated is the time from NO injection to when the NO concentration reaches the set dose (e.g., a homogeneous state equal to the set dose). The second phase of NO<NUM> generation is due to the residence time in the inspiratory limb at set dose. A majority of NO, may be generated at, or near, the first point of contact between the NO and fresh gas flow (e.g., O<NUM>). These two phases of NO generation can be seen in <FIG>, which shows the NO<NUM> concentration at various points downstream from the point of injection. As can be seen from <FIG>, the majority of the NO<NUM> is generated soon after the NO is injected (Phase <NUM>), with only a small portion of the NO<NUM> being generated after the initial injection and mixing of the NO (Phase <NUM>). This majority of the NO<NUM> being generated during the first phase follows the above NO<NUM> generation kinetics as the first phase of NO injection the local NO concentration is highest (e.g., as the NO has not yet diffused into the fresh gas flow to provide the homogenous set NO dose). By way of example, when injecting <NUM> ppm NO into the breathing circuit, at the point of injection the NO concentration is highest (e.g., approximately <NUM> ppm NO) as the NO has not yet diffused with the fresh gas flow. After this point of injection, the injected NO and the fresh gas flow diffuse together causing the NO concentration to decrease to a lower concentration (e.g., from <NUM> ppm NO to a desired dose of <NUM> ppm NO).

Accordingly, one approach for rapidly mixing the NO and FGF is the use of a mixing device placed immediately downstream or close to the point of NO injection to ensure that the combined gas stream has a homogenous NO concentration as soon as possible. For example, a plurality of blades, plates and/or fins can be placed downstream of the NO injection point to ensure prompt mixing of the two gas streams. <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or more blades, plates and/or fins can be used. <FIG> provide various views of an exemplary configuration of a mixing device having four blades. <FIG> provide various views of an exemplary configuration of a mixing device having three angled fins. <FIG> provide various views of an exemplary configuration of a mixing device having eight plates. <FIG> provide various views of an exemplary configuration of a mixing device having four curved blades. <FIG> provide various views of an exemplary configuration of a mixing device having four curved blades and an injection channel at a tapered section.

When a plurality of blades, plates and/or fins are used in a mixing device, the blades, plates and/or fins can be placed in parallel at the same distance downstream from the NO injection point and/or may be placed in series at various distances downstream from the NO injection point. For example, each blade, plate or fin may be placed <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> downstream from the NO injection point.

The presence of a mixing device can also be used to shorten the distance between the NO injection point and one or more sampling points for monitoring the composition of the combined gas, such as the O<NUM>, NO and NO<NUM> concentrations. For example, the first sampling point can be located <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> downstream from mixing device. Furthermore, a plurality of sampling points may be used, such as sampling points located at various distances from the NO injection point. <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or more sampling points may be used. The distance between sampling points can be <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. The plurality of sampling points can be used to separately analyze the combined gas stream as a function of length down the breathing circuit, or two or more sampling can be combined to provide an average for the composition of the gas.

Furthermore, the location of the point of injection of NO into the fresh gas flow can influence the reduction in NO<NUM> generation. In exemplary embodiments, the NO injection point can be located where the residence time of the initial high concentration is minimized and/or initial high concentration NO is rapidly dispersed. For example the point of injection of NO (e.g., high concentration NO, <NUM> ppm NO) may be located at the center of the annular body or as part of the tapered section, to reduce the amount of time that the NO remains at the initial high concentration. Accordingly, the point of NO injection can be located where the NO will be intermixed quickly with the fresh gas flow thereby minimizing the residence time of the high concentration NO and in turn reducing the NO<NUM> generated. While not wishing to be bound by any particular theory, it is believed that injecting the NO at a point in which the fresh gas flow has a high velocity will generate less NO<NUM> than other traditional techniques of injecting NO at the edge (i.e. wall) of the tube where fresh gas flow will have a low velocity.

<FIG> illustrates an exemplary velocity distribution of a gas flow through a tube. As can be seen from <FIG>, the gas flow has the lowest velocity closest to the edge boundary (e.g. wall of the tube) and has the highest velocity farthest from the edge boundary. Accordingly, in some embodiments the NO is injected at a distance from the edge boundary where the gas velocity is higher than the gas velocity at or close to the edge boundary.

In exemplary embodiments, to reduce NO<NUM> generation, the point of injection of NO into fresh gas flow can be located where the fresh gas flow is accelerated to the desired velocity. The accelerator may act to increase the fresh gas flow velocity from an inlet end to the outlet end, and the injection port located a distance from the inlet at which the fresh gas flow has increased to an intended velocity. The increase in velocity may be created by conversion of the gas's potential energy to kinetic energy. By way of example, the velocity may be increased by the reducing cross section of the tapered section, as the gas flows from a region of higher pressure to a region of lower pressure. The gas velocity being proportional to the change in cross-sectional area and change in gas density. Of course other techniques for increasing the velocity are envisioned.

Further complicating any potential solutions for minimizing NO<NUM> generation when injecting NO into the ventilator breathing circuit, ventilators require that any element (e.g., injector module, NO<NUM> minimization device, etc.) used with the ventilator breathing circuit not cause a substantial change to the ventilator inspiratory flow profile (by way of increased resistance to flow or increased compressible volume). Generally speaking, the allowable pressure drop across the entire breathing circuit can be <NUM> H<NUM>O at <NUM> SLPM for adults, <NUM> H<NUM>O at <NUM> SLPM for pediatrics and <NUM> H<NUM>O at <NUM> SLPM for neonates inclusive of ventilator outlet resistance. In light of this, the allowable pressure drop across the diffuser should be minimized. For example, current INOmax DS Injector Module is rated at <NUM> H<NUM>O at <NUM> SLPM. Accordingly, systems and methods of the present technology minimize NO<NUM> without affecting ventilator performance and/or causing substantial pressure drops, flow profile changes, and introducing substantial compressible volumes, for example, that may affect patient ventilation gas exchange.

Accordingly, in exemplary embodiments, the diffusing device can be configured and dimensioned so that at least the accelerator increase the fresh gas flow impinging velocity at the lowest expected fresh gas flow rate while not causing a substantial pressure drop in the highest peak fresh gas flow, not cause substantial changes to the inspiratory fresh gas flow's flow profile, and not create a substantial compressible volume in the breathing circuit. For example, the mouth and throat diameter may be selected to increase FGF velocity while minimizing delay in pressure changes and gas flow to a patient. To minimize changes to pressure, flow, and compressible volume the diffusing device can include a region for fresh gas flow to bypass the accelerator. For example, the diffuser can include a bypass gap which may be located about the periphery of the diffuser and/or accelerator.

After using the techniques disclosed herein to minimize NO<NUM> generation in the first phase (e.g., rapidly diffusing the NO and fresh gas flow at the point of injection, etc.), the NO may continue to traverse the remaining region of the breathing circuit at, or very close to, the desired set dose (e.g., <NUM> to <NUM> ppm NO). As this NO dose, or very close to the desired set dose, traverses the remaining region of the breathing circuit NO<NUM> may be generated (second phase); however, as described above, using the techniques disclosed herein, the majority of NO<NUM> that would have been produced will be substantially minimized thereby substantially reducing the total amount of NO<NUM> generated (e.g., immediate NO<NUM> generated and latent NO<NUM> generation).

To further mitigate NO<NUM> generation, NO may be introduced (e.g., in the ventilator breathing circuit) as close to the patient as technically feasible to reduce the contact time by reducing the time the NO and O<NUM> are in transit together, thus partly reducing NO<NUM> formation. NO<NUM> conversion time is the elapsed time NO and oxygen resides in combination prior to reaching the patient. NO<NUM> conversion time is therefore a function of ventilator flow rates (inspiratory and expiratory), ventilator I:E ratio, and breathing circuit volume from the point of NO injection to the patient airway end.

However, as explained above, in exemplary embodiments the downstream NO<NUM> generation (i.e. Phase <NUM>) is much less than the NO<NUM> generation upon injection (Phase <NUM>). Accordingly, in some embodiments the NO-containing gas is injected at a position that is significantly upstream from the patient, such as several feet from the patient, yet the NO<NUM> can be at an acceptable level (e.g. less than <NUM> ppm). Exemplary NO injection points include those at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> feet upstream from the patient. Such locations can be upstream of a patient "Y" piece, upstream of a humidifier, upstream of a nebulizer or other locations upstream from the patient in the ventilator breathing circuit.

In various embodiments, the second gas stream may be injected at an angle in the range of about <NUM>° to about <NUM>°, or at an angle in the range of about <NUM>° to about <NUM>°, or about <NUM>° to about <NUM>°, or about <NUM>° to about <NUM>°, or at about <NUM>° to the axis of the first gas stream.

An aspect of the present technology relates to an injection device for injecting a high concentration gas into a transverse gas stream.

In one or more embodiments, the device comprises an injection port that injects the second gas stream perpendicularly into the first gas stream.

In various embodiments, a high concentration NO-containing gas may be in the range of greater than <NUM> ppm NO to about <NUM> ppm NO, or about <NUM> ppm NO to about <NUM> ppm NO, or at about <NUM> ppm NO. Exemplary lower limits include about <NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, and about <NUM>,<NUM> ppm. Exemplary upper limits include about <NUM>,<NUM> pm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm, about <NUM>,<NUM> ppm and about <NUM>,<NUM> ppm. The high concentration NO-containing gas may be contained in a pressurized cylinder at a pressure in the range of about <NUM> psig and about <NUM> psig, or in the range of about <NUM> psig and about <NUM> psig, or about <NUM> psig and about <NUM> psig. Of course other sources of high concentration NO are envisioned.

<FIG> illustrate an exemplary device for diffusing a high concentration low volume gas flow and a high volume gas flow using the techniques disclosed above.

In one or more embodiments, the diffusing device <NUM> comprises a body <NUM> that may be an annular body formed by a cylinder having a wall <NUM> and a hollow (also referred to as open), internal region <NUM>. The body <NUM> may be configured and dimensioned to connect to tubing in a ventilator breathing circuit (e.g., <NUM>, <NUM> and <NUM>), fit into ventilator tubing, or have ventilator tubing fitted into the body. In various embodiments, the inlet end of the device comprises a male connection configured and dimensioned to join to a ventilator tube, and the outlet end comprises a female connection configured and dimensioned to join to a ventilator tube or humidifier chamber inlet. In a non-limiting example, the inlet end of the device comprises a <NUM> (O. ) male connection, and the outlet end comprises a <NUM> (I. ) female connection. In addition, in various embodiments the diffusing device <NUM> can be a component or part of an injector module which couples to a ventilator breathing circuit or component such as humidifier chamber, as is known in the art.

In one or more embodiments, the diffusing device <NUM> comprises a body <NUM> that may be rectangular, cubic or other geometric shapes that are configured and dimensioned to connect to tubing in a ventilator breathing circuit (e.g., <NUM>, <NUM> and <NUM>), and having a hollow internal region. For convenience, in embodiments where the body comprises a cylindrical wall, the body is referred to as an annular body in the specification.

In one or more embodiments, an annular body <NUM> may have an outside diameter 'A' at an inlet end and/or an outlet end. The outside diameter 'A' may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in. ), where the ventilator tubing may be fitted around the outside of the inlet end OD and inside the outlet end ID. In various embodiments, a ventilator tube may be connected to an inlet end and/or outlet end of a diffusing device utilizing a friction-fit connection, as would be known in the art. In various embodiments, the OD at the inlet end may be the same or different from the OD of the outlet end.

In one or more embodiments, the annular body may have an inside diameter 'B' at an outlet end and/or an inlet end. The inside diameter 'B' may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in. ), where the ventilator tubing may be fitted into the inside of the inlet end ID. In various embodiments, a ventilator tube may be connected to an inlet end and/or outlet end of a diffusing device utilizing a friction-fit connection, as would be known in the art. In various embodiments, the ID at the inlet end may be the same or different from the ID of the outlet end.

In one or more embodiments, gas(es) may enter the inlet end of the diffusing device <NUM> and exit the outlet end of the diffusing device, where the gas(es) may comprise a mixture of breathable gases. In various embodiments, the breathable gases may comprise air, or air and additional oxygen.

In various embodiments, the wall thickness 'C' of a cylindrical wall <NUM> may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in.

In one or more embodiments, the diffusing device may have a length 'D' in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in.

In one or more embodiments, a nipple <NUM> for attaching a delivery tube to the diffusing device may protrude from the outer surface of the cylindrical wall <NUM>. In various embodiments, the nipple may have a diameter 'M' <NUM> diameter (<NUM>") and protrude from the outer surface of the cylindrical wall <NUM> a height 'N' <NUM> (<NUM> in. In various embodiments, the nipple may comprise hose barbs for affixing a delivery tube.

In one or more embodiments, the device further comprises a projection <NUM> extending from the inner surface of the cylindrical wall <NUM>. In various embodiments, the projection <NUM> may extend a radial distance 'P' into the hollow internal region <NUM>. In various embodiments, the projection <NUM> may extend up to or close to the center of the hollow internal region <NUM>, which would be half of the ID of the wall <NUM>. In various embodiments, distance 'P' is slightly under half the ID so that the NO-containing gas will project out forward from the nozzle orifice to the middle, where the FGF gas velocity is higher than at the inner surface of the cylindrical wall. Accordingly, in various embodiments, the difference between 'P' and 'B'/<NUM> is in the range of from about <NUM> to about <NUM>, or about <NUM> to about <NUM>. In exemplary embodiments, the difference between 'P' and 'B'/<NUM> is about <NUM>, i.e. the projection <NUM> ends about <NUM> from the center of the hollow internal region <NUM>. Exemplary differences between 'P' and 'B'/<NUM> can have a lower limit of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> and about <NUM>, and exemplary upper limits can be about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> and about <NUM>.

In some embodiments, 'P' is provided as a certain percentage of 'B', such as about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>% or about <NUM>% of 'B'. In exemplary embodiments, 'P' is between about <NUM>% and about <NUM>% of 'B'.

In one or more embodiments, the dimensions 'B', 'P', 'L', etc. may be selected to achieve desired relationships between the dimensions and/or desired relationships between gas properties under certain conditions. For example, 'B' and 'L' may be selected such that for a given source gas concentration and a given desired NO dose (e.g. <NUM> ppm), the gas velocity at the lowest expected FGF will be approximately equal to the gas velocity of the NO-containing gas. As another example, 'B' and 'L' may be selected such that for a given source gas concentration, the gas velocity of the FGF will be similar to the gas velocity of the NO-containing gas over a range of desired NO doses (e.g. <NUM> ppm to <NUM> ppm). As another example, 'B' and 'P' may be selected such that the NO-containing gas projects out forward from the nozzle orifice to a distance from the inner surface of the cylindrical wall, such as at or near center of the hollow internal region <NUM>. As a further example, 'B' and 'P' may be selected such that the NO-containing gas projects out forward from the nozzle orifice to a portion of the FGF having a certain percentage of the peak velocity of the FGF, such as <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>% or <NUM>% of the peak velocity of the FGF.

In various embodiments, an injection channel <NUM> leading to an injection port <NUM> may be formed in the nipple, where the injection channel <NUM> has an inside diameter of 'L'. In various embodiments, the inside diameter 'L' may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in. Exemplary lower limits include about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> and about <NUM>. Exemplary upper limits include about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> and about <NUM>. The injection channel provides a flow path for delivery of a gas (e.g., NO) to the hollow internal region <NUM> of the diffusing device <NUM>.

In one or more embodiments, the diffusing device <NUM> does not comprise a nipple <NUM> projecting from the body <NUM>, but has a female connector into which a delivery tube may be plugged, where the female connector allows the delivery tube to be connected to and in fluid communication with the injection channel <NUM>. In various embodiments, the ID of the delivery tube and the ID of the injection channel are the same and/or have a uniform cross-sectional area.

In one or more embodiments, the injection port <NUM> may be an orifice allowing a gas flowing through the injection channel <NUM> to enter the hollow internal region <NUM> at an intended rate and/or velocity. In various embodiments, the injection port may be an opening of fixed dimension that may be the same or different from the diameter of the injection channel, which provides an intended flow velocity related to the flow rate. In various embodiments, more than one injection port <NUM> can be used, such as by having multiple injection ports <NUM> along the length of the projection <NUM> and/or by having multiple projections <NUM>, with each projection <NUM> having one or multiple injection ports <NUM>. As set forth above, the injection ports may inject the NO-containing gas into a portion of the FGF that is a distance from the edge boundary so that the NO-containing gas is injected into FGF having a high velocity, not a portion of the FGF having zero or low velocity. In some embodiments, when more than one injection ports <NUM> are used, the diameters of the injection ports <NUM> have smaller diameters than would be used for a single injection port <NUM> to ensure that the velocity of the NO-containing gas is not reduced and is maintained in proportion to FGF velocity.

In some embodiments utilizing multiple injection ports <NUM>, only one or some of the injection ports <NUM> may be used at a time, with selection dependent on the set dose of NO. For example, the multiple injection ports <NUM> can have varying orifice diameters, with a smaller orifice diameter being used for lower set doses of NO and a larger orifice diameter being used for higher set doses of NO. In this way, the ratio of the velocities of the NO-containing gas and the FGF can be maintained at a constant ratio, even with different set doses of NO. In some embodiments, more ports <NUM> are used at higher set doses of NO and less injection ports <NUM> are used at lowers set doses of NO, to tailor the velocities of the NO-containing gas and the FGF to the desired ratio. In other embodiments, all of the multiple injection ports <NUM> may be used concurrently. In various embodiments, multiple injection ports <NUM> may be multiple proportional control valves as part of the injector module.

In one or more embodiments, a valve (not shown) and/or variable orifice can be in fluid communication with the injection port <NUM> and/or can be located at the injection port <NUM>. The proportional valve and/or variable orifice can be adjusted to control the velocity of gas being injected from the injection channel <NUM> into the hollow internal region <NUM>. In various embodiments, the size of a valve orifice and/or variable orifice and velocity of gas being injected through the injection port <NUM> may be adjusted in relation to the FGF velocity, where the valve and gas velocity may be controlled through a feedback loop. In various embodiments, the feedback loop may comprise a flow sensor capable of measuring fresh gas flow in the breathing circuit, where the flow sensor may be in electrical communication with a control module that controls the dosage of NO fed into the diffusing module <NUM> through the injection channel <NUM> and the valve and/or variable orifice by adjusting the valve and/or variable orifice. In one or more embodiments, the diffuser and flow sensor capable of measuring fresh gas flow are incorporated into a single piece, such as being integral to an injector module.

In one or more embodiments, the diffusing module <NUM> comprises a proportional control valve, an NO flow sensor and a FGF flow sensor for measuring the fresh gas flow in the breathing circuit and delivering a flow of NO-containing gas that is proportional to the FGF to provide the desired set dose of NO. In such embodiments, the proportional control valve and/or flow sensor can be eliminated from the control module. Such a configuration can eliminate a compressed gas volume between the control module and the diffuser, as the proportional valve within the diffusing module <NUM> is used as the primary valve for regulating the flow of the NO-containing gas into the breathing circuit. While not wishing to be bound by any particular theory, it is believed that having both a proportional valve in the diffusing module <NUM> and a proportional valve in the control module can result in compressed gas being stored within the injection channel and NO delivery tube at the end of each inspiratory cycle, and that this compressed gas may then decompress, allowing a quantity of NO-containing gas to enter the breathing circuit and causing over delivery of NO. This potential problem can be magnified with high concentration NO, due to the decreased delivery volume. Accordingly, substituting a proportional control valve in the diffusing module <NUM> for the proportional control valve in the control module can reduce or eliminate the impact of this potential problem.

In one or more embodiments, the NO-containing gas is injected into the FGF as a plurality of pulses from one or more injection ports <NUM>. The plurality of pulses can be used to provide a higher velocity of the NO-containing gas than if the flow of the NO-containing gas was constant. By providing pulses (e.g. NO flow OFF-ON-OFF-ON), a higher instantaneous NO volumetric flow rate can be provided with a corresponding increase in instantaneous NO velocity, without providing a higher average volumetric flow rate than needed to provide the desired NO concentration in the combined gas stream. As an example, if the system was to detect low FGF bias flow (e.g. <NUM> SLPM), the NO can be delivered as a plurality of high-velocity pulses to maintain the correct quantity of NO-containing gas volume during this phase. In this way, the NO delivery system can utilize pulse width modulation of NO flow (e.g. during expiratory bias flow) to maintain a higher gas velocity of NO in proportion to FGF gas velocity, while maintaining the desired average NO flow rate or set dose concentration.

During expiratory phase only delivery of pulsatile high peak flow to increase the NO exit velocity. In order to maintain the correct quantity of gas volume during this phase. The pulsatile flow would be Off-ON-Off-On to meet the average flow rate required to meet set Dose. Pulse width modulation of NO flow.

Aspects of the technology also relate to method of diffusing a high concentration gas into a transverse gas stream comprising passing at least a portion of a first gas longitudinally through a hollow internal region of a body having an inner surface surrounding the hollow internal region, and passing a second gas stream through an injection channel to an injection port projecting into the hollow internal region of the body, wherein the second gas stream enters and at least partially diffuses with the first gas stream within the hollow internal region.

<FIG> illustrate another exemplary device for diffusing a high concentration low volume gas flow and a high volume gas flow using the techniques disclosed above. Of course, other configurations capable of diffusing a high concentration low volume gas flow and a high volume gas flow using the above techniques are envisioned. The dimensions are exemplary for a <NUM> nominal diffuser for use with adult breathing circuits/fittings. It should be noted that the non-limiting examples of dimensions and/or configurations are intended for standard adult breathing circuits, and the dimensions and proportions of the device may be adjusted for applications involving standard neonate breathing circuits, standard pediatric breathing circuits, or other non-standard-sized breathing circuits without undue experimentation.

In one or more embodiments, the diffusing device <NUM> comprises an annular body <NUM> that may be a cylinder having a wall and a hollow internal region. The body may be configured and dimensioned to connect to tubing in a ventilator breathing circuit (<NUM>, <NUM> and <NUM>), fit into ventilator tubing, or have ventilator tubing fitted into the body. In various embodiments, the inlet end of the device comprises a male connection configured and dimensioned to join to a ventilator tube, and the outlet end comprises a female connection configured and dimensioned to join to a ventilator tube or humidifier chamber inlet. In a non-limiting example, the inlet end of the device comprises a <NUM> (O. ) male connection, and the outlet end comprises a <NUM> (I. ) female connection. In addition, the diffusing device <NUM> can be a component or part of an injector module which couples to a ventilator breathing circuit, as is known in the art.

In one or more embodiments, the annular body <NUM> may have an outside diameter 'A' at an inlet end and/or an outlet end. The outside diameter 'A' may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in. ), where the ventilator tubing may be fitted around the outside of the inlet end OD and inside the outlet end ID. In various embodiments, a ventilator tube may be connected to an inlet end and/or outlet end of a diffusing device utilizing a friction-fit connection, as would be known in the art.

In one or more embodiments, the annular body may have an inside diameter 'B' at an outlet end and/or an inlet end. The inside diameter 'B' may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in. ), where the ventilator tubing may be fitted into the inside of the inlet end ID. In various embodiments, a ventilator tube may be connected to an inlet end and/or outlet end of a diffusing device utilizing a friction-fit connection, as would be known in the art.

In various embodiments, the wall thickness 'C' of the diffusing device <NUM> may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or in the range of about <NUM> to about <NUM>.

In one or more embodiments, the device further comprises a tapered section <NUM> comprising a wall, which may have a truncated cone, a funnel, or a bell shape, where the tapered section <NUM> narrows from an inside diameter 'E' at a first (inlet) end to an inside diameter 'F' at a second (outlet) end opposite the first end, wherein the opening at the first (inlet) end has a larger diameter than the opening at the second (outlet) end. In various embodiments, the first end having a larger diameter is a mouth <NUM>, and the second end having the smaller diameter is a throat <NUM>.

In one or more embodiments, an accelerator may comprise a tapered section or a bi-directional tapered section.

In various embodiments, the inside diameter 'E' at the mouth <NUM> may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in.

In various embodiments, the inside diameter 'F' at the throat <NUM> may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in.

In one or more embodiments, the tapered section <NUM> may have a length 'I' from the leading edge of the mouth <NUM> to the trailing edge of the throat <NUM>. In various embodiments, the length 'I' of the tapered section <NUM> may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in.

In one or more embodiments, the inside surface of the tapered section forms a sharp corner at the leading edge of the mouth <NUM>, so there are no flat surfaces perpendicular to the axis of the tapered section. In various embodiments, the wall of the tapered section may have a thickness in the range of about <NUM> to about <NUM> or about <NUM>.

In one or more embodiments, the tapered section <NUM> may be located inside the body <NUM> of the diffusing device <NUM>. In various embodiments, the tapered section may be suspended from a cylindrical wall <NUM> of the annular body <NUM> by a support <NUM>, wherein the support <NUM> may extend from an inner surface of the cylindrical wall <NUM> into the open internal region <NUM>. In various embodiments, the annular body <NUM>, tapered section <NUM>, and support joining the tapered section <NUM> to the annular body may be one integral piece, where the annular body <NUM>, tapered section <NUM>, and support <NUM> are molded as a single piece, so the components comprise a single unitary construction. In various embodiments, the tapered section <NUM> and the annular body <NUM> are coaxial. In one or more embodiments, the projection <NUM> may form the support <NUM> by interconnecting the body <NUM> and the tapered section <NUM>.

In one or more embodiments, there may be a gap <NUM> between the rim of the mouth <NUM> and the inside surface of the cylindrical wall <NUM>, where the gap <NUM> has a size 'G' in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), which provides an opening around the rim of the mouth <NUM>. In various embodiments, the opening allows at least a portion of the incoming gas(es) to by-pass the tapered section <NUM> by flowing along the periphery of the internal region and around the tapered section <NUM>.

In one or more embodiments, the opening has a cross-sectional area in the range of about <NUM>% to about <NUM>% of the cross-sectional area of the internal region.

In one or more embodiments, the gap <NUM> has a cross-sectional area in the range of about <NUM>% to about <NUM>% of the cross-sectional area of the internal region where the internal region defined as B diameter is <NUM>.

In one or more embodiments, the tapered section <NUM> may be a distance 'H' from the leading edge of the annular body <NUM>. In various embodiments, the distance 'H' from the leading edge of the annular body <NUM> may be in the range of <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. In various embodiments, dimension H may be reduced to thereby minimize the size and weight of the device.

In one or more embodiments, the tapered section <NUM> may be a distance 'J' from the trailing edge of the annular body <NUM>. In various embodiments, the distance 'J' from the trailing edge of the annular body <NUM> may be in the range of <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), In various embodiments, dimension J may be reduced to thereby minimize the size and weight of the device.

In one or more embodiments, a nipple <NUM> for attaching a delivery tube to the diffusing device may protrude from the outer surface of the cylindrical wall <NUM>. In various embodiments, the nipple may have a diameter 'M' of about <NUM> diameter (<NUM> in. ) and protrude from the outer surface of the cylindrical wall <NUM> a height 'N' of about <NUM> (<NUM> in.

In various embodiments, an injection channel <NUM> leading to an injection port may be formed in the nipple, where the injection channel <NUM> has an inside diameter of 'L'. In various embodiments, the inside diameter 'L' may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in.

In one or more embodiments, the opening forming the injection port <NUM> at the internal end of the injection channel <NUM> may be located proximal to region where fresh gas velocity is maximized in diffuser device (e.g. a distance 'K' from the outlet end of the tapered section <NUM>. In various embodiments, the distance 'K' may be in the range of about <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in. ) from the outlet end of the tapered section <NUM>).

In one or more embodiments, the NO injection port may terminate at the throat wall, or an extension tube may project further into the throat from the internal surface of the tapered section. In various embodiments, the extension tube may project into center of the throat.

In one or more embodiments, the injection port may be <NUM> from the leading edge of the tapered section.

In one or more embodiments, the tapered section may be suspended within a hollow cylindrical portion of a housing, wherein the housing is adapted to connect to ventilator tubing. In various embodiments, the housing may have a shape other than cylindrical or annular while having an inlet and outlet configured and dimension to connect to suitable ventilator tubing. For example a rectangular housing of a diffusing device may have cylindrical inlet and outlet openings with an I. to connect to tubing.

In one or more embodiments, a diffusing device may be utilized in a ventilator circuit, with a nasal cannula, or with a face mask.

<FIG> illustrates an exemplary embodiment of a tapered section <NUM> having a funnel shape.

In one or more embodiments, the funnel shaped tapered section <NUM> has an internal surface that is convex, and directs gas(es) entering the mouth <NUM> towards the throat <NUM>. In various embodiments, the convex contour of the internal surface may have a constant curvature or a changing curvature.

<FIG> illustrates an exemplary embodiment of a tapered section <NUM> having a cone shape.

In one or more embodiments, the cone shaped tapered section <NUM> has an internal surface that is straight from the mouth <NUM> of the tapered section <NUM> to the throat <NUM>, and directs gas(es) entering the mouth <NUM> towards the throat <NUM>.

<FIG> illustrates an exemplary embodiment of a tapered section <NUM> having a bell shape, where the bell shape may have constant curvature or a changing curvature.

In various embodiments, a tapered section, as depicted in <NUM>, <NUM>, and <NUM> may be adjoined throat-to-throat to provide a bi-directional tapered section to allow for insertion and use in a ventilation circuit in either orientation. <FIG> illustrates an exemplary embodiment of a bi-directional tapered section. A bi-directional tapered section <NUM> may comprise two tapered sections <NUM> coupled at their throats, where the injection valve provides for injection of a gas at the narrowest portion of the bidirectional tapered section <NUM>. In various embodiments, the two tapered sections may be coupled at a throat comprising a cylindrical section <NUM>. In various embodiments, the injection port would be located where the two tapered sections join, and the FGF velocity should be at a maximum at the lowest expected FGF rate. In some embodiments, a tapered section is utilized in environments in which the FGF rate is expected to be low, e.g. less than <NUM> SLPM.

In one or more embodiments, the bell shaped tapered section <NUM> has an internal surface that is concave, and directs gas(es) entering the mouth <NUM> towards the throat <NUM>.

<FIG> illustrates an exemplary tapered section <NUM> depicting a contour of an inside surface of a tapered section wall <NUM>.

Principles and embodiments of the present invention also relate to diffusing device comprising a tapered section <NUM> comprising a decreasing cross-sectional area that increases the velocity of the gas flow past the injection port and exiting the throat, so a high concentration gas is quickly dispersed and diffused with the ventilator gas.

In one or more embodiments, the tapered section <NUM> can be an axially-symmetrical tube with a variable cross-sectional area, where area is decreasing from the mouth area to the throat area. In various embodiments, the wall <NUM> may have a straight, parabolic, hyperbolic, catenoidal, or funnel contour.

In one or more embodiments, the tapered section <NUM> may comprise a cylindrical section <NUM> with a constant diameter and cross-sectional area that extends a length 'P' from the point that the cross-sectional area is at a minimum, and/or the slope of the tapered section becomes <NUM> (zero) (i.e., horizontal).

In various embodiments, the tapered section creates an increasing pressure gradient, so flow or boundary separation cannot occur because of the favorable pressure gradient. The avoidance of boundary separation also avoids reverse-flow regions and vortices that may deplete the energy of the gas flow and increase flow resistance. The pressure drop for a volumetric flow rate of <NUM> SLPM may be approximately <NUM> H<NUM>O, and at <NUM> SLPM may be approximately <NUM> H<NUM>O.

In one or more embodiments, the contour of the tapered section wall <NUM> has a constant curvature with a radius R<NUM>, where R<NUM> may be in the range of <NUM> (<NUM> in. ) to about <NUM> (<NUM> in. ), or about <NUM> (<NUM> in.

An aspect of the present technology relates to a method of diffusing a high concentration gas into a transverse gas stream.

<FIG> illustrates an exemplary embodiment of a second gas passing through an injection channel <NUM> into a first gas passing through a tapered section <NUM>. (Gas flows are indicated by straight and curved arrows.

In one or more embodiments, at least a portion of a first gas enters a diffusing device <NUM> and passes through a tapered section <NUM> comprising a wall <NUM> having a thickness, an outer surface and an inner surface, an inlet end having a first diameter, and an outlet end having a second diameter opposite the inlet end, wherein the second diameter is smaller than the first diameter; and passing a second gas stream through an injection channel <NUM> to an injection port <NUM> in the inner surface of the tapered section <NUM>. In various embodiments, the second gas stream enters and at least partially diffuses with the first gas stream within the tapered section <NUM>. In various embodiments, the injection of the second gas at an intended flow rate and velocity into the stream of the first gas creates sufficient diffusing at the point contact or confluence of the two gas streams. In various embodiments, the intended volumetric flow rate of the second gas (NO at <NUM>-<NUM> ppm dose) may be in the range of about <NUM> SMLPM to about <NUM> SMLPM for <NUM> ppm NO, where the volumetric flow rate of the second gas (NO) is proportional to the volumetric flow rate of the first gas (FGF) when the first gas flow rate is in the range of about <NUM> SLPM to about <NUM> SLPM.

In one or more embodiments, at least a portion of the first gas passes around at least a portion of the outer surface of the tapered section, wherein the tapered section <NUM> is within an annular body <NUM> having an outer surface and an inner surface, and an inside diameter that is larger than the first diameter of the tapered section. In various embodiments, at least a portion of the first gas passes through the gap <NUM> between the rim <NUM> of the mouth <NUM> and the inside surface of the cylindrical wall <NUM>.

In one or more embodiments, the first gas is a breathable gas comprising molecular N<NUM> and molecular O<NUM>, and the second gas comprises molecular NO and molecular N<NUM>.

In one or more embodiments, the first gas is provided by a ventilator at a flow rate in the range of about <NUM> liters per minute (SLPM) to about <NUM> liters per minute (SLPM). In some instances, as described herein, during expiratory flow there may be flows in the range <NUM> SLPM to <NUM> SLPM that may result in higher NO<NUM> being generated. Accordingly, in at least some instances, the disclosed techniques may be directed towards these lower flow rates.

In various embodiments, the concentration of NO in the second gas is in the range of greater than <NUM> ppm to about <NUM> ppm, or about <NUM> ppm to about <NUM> ppm, or about <NUM> ppm.

In one or more embodiments, the flow rate of the second gas is linearly proportional to the flow rate of the first gas.

In one or more embodiments, the second gas stream initially enters the first gas stream at an angle in the range of about <NUM>° to about <NUM>°, or at an angle in the range of about <NUM>° to about <NUM>°, or about <NUM>° to about <NUM>°, or about <NUM>° to about <NUM>°, or at about <NUM>° to the axis of the first gas stream. In various embodiments, the second gas may be injected perpendicularly to the first gas stream, where the two perpendicular gas streams act to impart turbulence at the point of contact, to reduce NO<NUM> levels to a value equal to or less than the amount generated by the current 800ppm therapy.

Without being limited by theory, it is believed that sufficient diffusion results when FGF is impinged by intersecting NO flow, where the NO and FGF have sufficient velocity at ventilator bias flows. In addition, a short annular outlet just after the point of NO injection may allow for a quick divergence of the once compressed FGF gas within the tapered section, now combined with NO, to exit abruptly and freely diffuse with bypass flow around the tapered section.

In one or more embodiments, the second gas exits the injection port <NUM> at a flow rate in the range of about <NUM> milliliters per minute (SMLPM) to about <NUM> SLPM, or about <NUM> milliliters per minute (SMLPM) to about <NUM> SLPM, or about <NUM> milliliters per minute (SMLPM) to about <NUM> SLPM. A gas flow rate of <NUM> SLPM has a velocity of approximately <NUM> meters/sec. through an injection channel and injection port with a <NUM> I. A gas with this velocity would not experience noticeable compression at this velocity when passing through the diffusing device, which is less than <NUM> x the speed of sound (i.e., Mach Number < <NUM>). A gas flow rate of <NUM> SLPM has a velocity of approximately <NUM> meters/sec. through an injection channel and injection port with a <NUM> I. It can be helpful to manage NO<NUM> conversion during periods of very low ventilator flow rates (e.g., bias flow during exhalation ≤<NUM> SLPM), increased oxygen concentrations (FiO<NUM> ≥ <NUM>%), and higher NO set dosage (≥<NUM> ppm).

In one or more embodiments, the velocity of the first gas is greater at the second diameter of the tapered section <NUM> than the velocity of the first gas at the first diameter of the tapered section <NUM>.

In one or more embodiments, the velocity of the first gas is greater at the second diameter of the tapered section than the velocity of the first gas at the first diameter of the tapered section, wherein the second gas enters the first gas at a point of greater velocity. In various embodiments, the tapered section generates an increase gas velocity and pressure gradient towards the middle of the annular body, such that the highest gas velocity is along the axis of the tapered section <NUM>. For example, a reduction of the tapered section <NUM> I. from <NUM> at the mouth to <NUM> at the throat would result in an increase in the first gas velocity. In some instances, the ratio of inlet to outlet gas velocities is proportional to the ratio of inlet to outlet areas.

As can be seen in <FIG>, the second gas enters the first gas at the injection port <NUM>, which is closer to the throat of the tapered section <NUM>, and where the velocity of the first gas flow has increased compared to the first gas velocity at the mouth of the tapered section.

<FIG> illustrates an exemplary embodiment of a diffusing device <NUM> inserted into a ventilator circuit <NUM>. In various embodiments, the ventilator system may provide elevated (><NUM>%) fractional inspired oxygen (FiO<NUM>) concentrations along with NO doses to mechanically ventilated patients. Oxygen concentration in patient ventilator circuits may range from medical air (<NUM>% O<NUM>) to medical oxygen (<NUM>% O<NUM>), but are generally elevated to <NUM>% for patients receiving INO therapy. The NO in a high concentration NO gas source <NUM> may be diluted with nitrogen N<NUM>.

In one or more embodiments, a diffusing device <NUM> (e.g., as a component in an injector module <NUM>, downstream of a flow sensor <NUM> capable of measuring fresh gas flow in the breathing circuit, etc.) may be connected to and in fluid communication with ventilator tubing coming from a ventilator <NUM>. The ventilator may be connected to and in fluid communication with a fresh gas source <NUM>. The diffusing module <NUM> may also be connected to and in fluid communication with a control module <NUM> that controls the dosage of NO fed into the diffusing module <NUM>. The control module <NUM> may be connected to and in fluid communication with a NO gas source <NUM>. In various embodiments, the fresh gas source <NUM> and NO gas source <NUM> may have regulators to control the pressure from the cylinders. In various embodiments, the diffusing device may be connected to and in fluid communication with a humidifier <NUM> that adds water vapor content to the inspiratory gas flow to the patient. In various embodiments, the distance from the diffusing device <NUM> to the patient may be approximately <NUM> meter. In various embodiments, the humidifier may have a compressible volume of about <NUM>. In various embodiments, the diffusing device <NUM> and the flow sensor <NUM> are integral to the injector module <NUM>.

In one or more embodiments, the diffusing device diffuses the incoming fresh gas flow from the ventilator <NUM> and fresh gas source <NUM> with the incoming NO-containing gas from the NO gas source <NUM> flowing through the control module <NUM>. The gas flow being delivered to the patient may be sampled at a sampling tee <NUM> inserted down stream from the humidifier <NUM> and/or diffusing device <NUM>. In various embodiments, NO, NO<NUM>, and/or O<NUM> concentrations may be monitored before reaching the patient. The sampling tee <NUM> can be placed at various positions in the breathing circuit, depending on how quickly the NO-containing gas and FGF combine to provide a homogenous gas stream at the set dose. Furthermore, a plurality of sampling points may be used, such as sampling points located at various distances from the NO injection point. <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or more sampling points may be used. The distance between sampling points can be <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. The plurality of sampling points can be used to separately analyze the combined gas stream as a function of length down the breathing circuit, or two or more sampling can be combined to provide an average for the composition of the gas.

As explained in the Examples below, an increase in temperature has surprisingly been found to decrease the amount of NO<NUM> that is generated under otherwise similar conditions. Accordingly, embodiments of the present technology also relate to minimizing NO<NUM> generation by heating one or more portions of the NO delivery system and/or ventilator circuit. While not wishing to be bound by any particular theory, it is believed that an increase in gas temperature can increase the available kinetic energy with the gas molecules, which can promote initial mixing resulting in further NO<NUM> reduction.

For example, a heating element may be added to the NO delivery system, the tubing from the NO delivery system to the injector module, the injector module and/or the tubing of the inspiratory limb of the ventilator circuit, and/or may be placed at any other location upstream, downstream or at the point of injection. The heating element may be a heated humidifier or may be a dedicated heating component. Exemplary heating elements include, but are not limited to, a thermoelectric cooling device or a resistive heating element. A heating element in the NO delivery system can help minimize NO<NUM> generated internally within the NO delivery system. Likewise, heating elements placed in, and/or in thermal communication with, the tubing that deliver the NO to the injector module and from the injector module to the patient can help minimize NO<NUM> generation at those points.

In various embodiments, the heating element can heat the NO source gas and/or the combined NO and FGF to a desired temperature. Exemplary temperatures include, but are not limited to, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or about <NUM>.

The present technology is further described by means of the examples, presented below. The use of such examples is illustrative only and in no way limits the scope and meaning of the technology or of any exemplified term.

A NO delivery system utilizing a high NO source concentration (e.g. <NUM> ppm) and an injector module with an exemplary diffuser as described herein (e.g. a diffuser as shown in <FIG>) was compared to a conventional NO delivery system utilizing a low NO source concentration (e.g. <NUM> ppm) and a conventional injector module. The FGF was provided by a neonatal ventilator with exemplary ventilation parameters (e.g. respiratory rate of <NUM>, tidal volume of <NUM>, FiO<NUM> of <NUM>%, <NUM> SLPM bias flow, etc.). As can be seen from <FIG>, the high NO source concentration system utilizing a diffuser (System <NUM>) produced a comparable amount of NO<NUM> as the conventional NO delivery system at a lower NO source concentration (System <NUM>), despite a significantly higher NO source concentration.

System <NUM> and System <NUM> were also compared to a NO delivery system utilizing a high NO source concentration (e.g. <NUM> ppm) and an injector module with an exemplary accelerator as described herein (e.g. an accelerator as shown in <FIG>), which is designated System <NUM>. <FIG> show the NO<NUM> produced for each system at various NO set doses and FGF flow rates. As can be seen from <FIG>, both Systems <NUM> and <NUM> at the high NO source concentration produced a comparable or lower amount of NO<NUM> at a set dose of <NUM> ppm as the conventional NO delivery system at a lower NO source concentration. While not wishing to be bound by any particular theory, it is believed that the relatively low NO<NUM> values for Systems <NUM> and <NUM> at <NUM> ppm is a result of the FGF and NO-containing gases having similar velocities. As can be seen from Table <NUM> below, the velocity of the NO-containing gas was most similar to the FGF velocity at <NUM> ppm for the particular configurations tested as Systems <NUM> and <NUM>.

The NO delivery system used in System <NUM> of Example <NUM> was then used with a heated ventilator breathing circuit (e.g. about <NUM>). As can be seen from <FIG>, heating the ventilator breathing circuit reduced the NO<NUM> levels under all conditions tested.

The NO delivery system used in System <NUM> of Example <NUM> was modified to have various NO source concentrations and to provide various ratios of the FGF velocity to the NO-containing gas velocity. A plurality of gas sampling points was used for NO and NO<NUM> concentration measurements, which was averaged to account for any inhomogeneous distribution of the gases within the cross-section of the tube. The NO<NUM> concentration was measured at three different points downstream from the NO injection point T0: T1 (<NUM> downstream from NO injection point), T2 (<NUM> downstream from NO injection point) and T3 (<NUM> downstream from NO injection point). For the experiments described below, the region from T0 to T1 was considered to have a non-homogenous gas distribution and the region from T2 to T3 was considered to have a homogenous gas distribution. The NO<NUM> conversion rate was determined by subtracting the NO<NUM> contribution from the NO source cylinder from the measured NO<NUM> concentration, and dividing the net gain in NO<NUM> concentration by the residence time between sample points (volumetric flow rate divided by the volume of the segment).

<FIG> shows the NO<NUM> generated in the initial T0-T1 region with various NO source cylinder concentrations ranging from <NUM> ppm to <NUM> ppm with a gas velocity ratio (FGF : NO) of approximately <NUM>:<NUM>. As can be seen from <FIG>, by having a gas velocity ratio of approximately <NUM>:<NUM>, the NO<NUM> generation rate is comparable between various cylinder concentrations at the same set dose (<NUM> ppm) and the same FGF flow rate (<NUM> or <NUM> SLPM).

<FIG> show the NO<NUM> generated in the initial T0-T1 region with various NO source cylinder concentrations ranging from <NUM> ppm to <NUM> ppm with a varying gas velocity ratio (FGF:NO) and a set dose of <NUM> ppm NO. As can be seen from each of <FIG>, gas velocity ratios below <NUM>:<NUM> provide a lower NO<NUM> generation rate than gas velocity ratios above <NUM>:<NUM>, even when the NO source concentration, FGF flow rate and the NO set dose are the same.

<FIG> shows the NO<NUM> generated in the initial T0-T1 region with a <NUM> ppm NO source cylinder concentration and a set dose of <NUM> ppm, with a varying gas velocity ratio (FGF:NO). As can be seen by comparing <FIG> and <FIG>, the relationship between NO<NUM> generation rate and gas velocity ratio is also seen at other set dose concentrations.

<FIG> show the NO<NUM> generated in the initial T0-T1 region with various NO source cylinder concentrations ranging from <NUM> ppm to <NUM> ppm with a varying gas velocity ratio (FGF:NO) and a set dose of <NUM> ppm NO. As can be seen from <FIG>, gas velocity ratios below <NUM>:<NUM> provide a lower NO<NUM> generation rate than gas velocity ratios above <NUM>:<NUM>, even when the NO source concentration, FGF flow rate and the NO set dose are the same. As <FIG> are plotted on a logarithmic base <NUM> scale for both the x and y axes, this demonstrates that the instantaneous NO<NUM> generation is non-linear.

<FIG> shows the NO<NUM> generated in the initial T0-T1 region with a <NUM> ppm NO source cylinder concentration and a set dose of <NUM> ppm, with a varying gas velocity ratio (FGF:NO). <FIG> also shows the average NO<NUM> generation rate from T2 to T3. As can be seen from <FIG>, the NO<NUM> generation rate from T0-T1 is significantly higher than the NO<NUM> generation rate from T2 to T3. Also, the NO<NUM> generation rate from T2 to T3 (shown in triangles) does not vary with the gas velocity ratio, showing that a constant rate of NO<NUM> generation rate is achieved after the combined gas stream reaches a homogenous phase at T2. <FIG> further provides the size of the inner diameter of the FGF pipe for each configuration: <NUM> in, <NUM> in or <NUM> in. As can be seen, decreasing the FGF pipe diameter did not reduce NO<NUM> generation, but instead resulted in higher NO<NUM> generation rates. This is consistent with the observed phenomenon of NO<NUM> generation being minimized with lower FGF:NO velocity ratios, particularly those below <NUM>:<NUM>.

The NO delivery system of Example <NUM> was modified to simulate a ventilator with varying flow rates. A square wave flow with a minimum flow of <NUM> SLPM and a maximum flow of <NUM> SLPM was used, with a varying inspiratory to expiratory ratio (high to low flow ratio) ranging from <NUM>:<NUM> to <NUM>:<NUM>. <FIG> show the NO<NUM> generated in ppm and as a percentage of the set dose of NO. As can be seen from <FIG>, the most NO<NUM> was generated with a higher expiratory (low flow) ratio. As can be seen from <FIG>, a high percentage of the NO was converted to NO<NUM> at the low set doses, with almost <NUM>% of the NO being converted to NO<NUM> when the inspiratory : expiratory ratio was <NUM>:<NUM> and the NO set dose was <NUM> ppm.

The NO<NUM> generation rate of a NO delivery system utilizing a suspended funnel (System <NUM> of Example <NUM>) and the NO delivery system of Example <NUM> was compared from T0 to T1 at a set dose of <NUM> ppm NO and a cylinder concentration of <NUM> ppm NO. The results of this comparison are shown in Table <NUM> below.

Claim 1:
A device (<NUM>) for use in combining a first gas stream comprising molecular oxygen (O2) and a second gas stream comprising nitric oxide (NO) for delivery of a combined gas stream to a patient, characterized in that the diffusing of NO and O<NUM> occurs sufficiently rapidly that less than <NUM> ppm of NO<NUM> is delivered to the patient, wherein the second gas stream is provided by an NO source having an NO concentration of greater than <NUM> ppm to about <NUM>,<NUM> ppm.