AU2015201474B2

AU2015201474B2 - System and method of administering a pharmaceutical gas to a patient

Info

Publication number: AU2015201474B2
Application number: AU2015201474A
Authority: AU
Inventors: Duncan P. Bathe; Frederick J. Montgomery
Original assignee: Mallinckrodt Hospital Products IP Unlimited Co
Current assignee: Mallinckrodt Hospital Products IP Unlimited Co
Priority date: 2005-09-21
Filing date: 2015-03-20
Publication date: 2017-05-11
Anticipated expiration: 2026-09-13
Also published as: AU2015201474A1

Abstract

A method and system for delivering a pharmaceutical gas to a patient. The method and system provide a known desired quantity of the pharmaceutical gas to the patient independent of the respiratory pattern of the patient. The preferred pharmaceutical gases are CO and NO, both of 5 which are provided as a concentration in a carrier gas. The gas control system determines the delivery of the pharmaceutical gas to the patient to result in the known desired quantity (e.g. in molecules, milligrams or other quantified units) of the pharmaceutical gas being delivered. Upon completion of that known desired quantity of pharmaceutical gas over a plurality of breaths, the system can either terminate any further delivery of the pharmaceutical gas or can activate an 10 alarm to alert the user that the known quantity has been delivered. The system also has alarm functions to alert the user of possible malfunctions of the system.

Description

2015201474 18 Apr 2017

SYSTEM AND METHOD OF ADMINISTERING A PHARMACEUTICAL GAS TO A PATIENT

Background

The present disclosure relates to a method and system for administering a pharmaceutical gas to a patient and, more particularly, to a method and system for introducing carbon monoxide CO or nitric oxide NO to a patient in a predetermined quantity.

Background of the Invention

The normal or conventional way of giving a pharmaceutical drug to a patient is to prescribe the dose based on the quantity of drug (usually in weight) per unit weight of the patient (e.g. mg/Kg) with the dose being specified to be delivered over a period of time or being repeated at specified intervals of time. This allo ws the user to control fire quantity of drug and ensures the quantity of drug being delivered is in proportion to the patient's size. This is to reduce the patient to patient variability in response to the drug due to the size of the patient i.e. a 7Kg baby will not get the same quantity of drug as a 80 Kg adult.

In recent times there have been a number of gases which have been shown to have pharmaceutical action in humans and animals. Examples include Nitric Oxide (NO) Zapol et al US 5,485,827 and more recently Carbon Monoxide (CO) Otterbein et al (U.S. Published Patent Application No. 2003/0219496). In the Otterbein patent application, CO is described as having a pharmacological action in a number of medical conditions including ileus and vascular disease.

In these cases, the carbon monoxide gas needs to be delivered to the patients alveoli where it can move across the alveolar membrane and into the blood stream where its action can take effect. The current dosing used in these cases is for the patient to breath at a specified concentration of CO in ppm for a specified period of 1 2015201474 20 Mar 2015 time. Accurate dosing of CO for these treatments is important as CO reacts with the . hemoglobin in the blood to form carboxyhemoglobin which means the hemoglobin is no longer able to carry oxygen to the tissues of the body. If too much CO is given, the patient may exhibit the toxic effects of CO for which it is usually known. 5 There is a tight window for CO delivery between the therapeutic level and the level that causes carboxyhemaglobin above safe levels. Up until now CO has been delivered as a constant concentration in the gas breathed by the patient/animal for a specified period of time. For example in reference 3 of the Otterbein pnblication, (Example 2 pg 13) the therapeutic dose delivered to mice for the treatment of ileus 10 was 250 ppm of CO for 1 hour.

However, this method of dosing CO can be associated with large variability in the actual dose being delivered to the animal/humans alveoli. This variability is because the quantity of CO being delivered to the animal/patient is dependent on a number of variables including, but not limited to, the patients tidal volume, respiratory 15 rate, diffusion rate across the alveolar and ventilation/perfusion (V/Q) matching.

The amount of CO delivered into a patient’s alveoli can be determined by the ideal gas law as shown in the following equation: N = P. V / (Ru . T) (1)

Where: 20 N is the number of moles of the gas (mole) P is the absolute pressure of the gas (joule/m3) V is the volume of the particular gas (m3)

Ru is the universal gas constant, 8.315 (jouIe/(gmole. °K) T is the absolute temperature (°K) 25 If we assume atmospheric pressure (101,315 joule/m3) and 20 °C (293 °K) as tire temperature and we express the volume in mL ( xlO'6 m3 ) then equation (1) reduces to: 2 2015201474 20 Mar 2015 N = 4.16xl0's. V (moles) (2) 5

Equation (2) can be used to calculate the number of moles of gas delivered to a patient’s alveolar volume over a period of time when given a specified concentration by using the following equation: Nco = RR. t. Coo .10 ~6 · 4.16 x!0‘s. Va (3)

Where; Cco is the concentration of CO (ppm) Va is the alveolar volume (mL) RR is the respiratory rate in (BPM) t is the time in minutes (mins)

For example if the CO dose for ileus in humans was 250 ppm of CO for one hour (60 minutes), the alveolar volume is 300 mL and the patients respiratory rate is 12 breaths per minute (bpm) then the amount of CO gas in moles delivered to the patients alveoli over that period would be: 15 Nco= 12.60.250.10 ‘6 4.16 xiO 5 . 300 = 2.25 x 10'3 (moles)

This can be converted into the mass of drag delivered (Mco) using the gram molecular weight of CO which is 28 as shown in the following equation:

Mco = Nco · 28 = 63 x W3 (g) = 63 (mg) (4)

However, although this works for a given set of assumptions, a spontaneous 20 patient’s respiratory rate can vary widely from perhaps 8 to 20 breaths per minute depending on circumstances and the patient’s alveolar volume per breath can also vary significantly from say 200 to 400 mL depending on the metabolic need. These variables can have a dramatic effect on the amount of gaseous drug being delivered to the patient over the same period of time. For instance if the patients respiratory rate 25 was 8 bpm and the alveolar volume was 200 mL, the CO dose delivered to the patients alveoli would have been 27.8 (mg). Likewise if the patients respiratory rate was 20 bpm and die alveolar volume was 400 mL, then the dose delivered to the 3 2015201474 20 Mar 2015 patients alveoli would have been 139.2 (mg) thus representing a five fold difference in the amount of drug being delivered.

This means, in the example of CO, the quantity of gaseous drug a patient gets as measured in grams could vary substantially depending on the patient’s ventilation 5 pattern. For a dose based on constant concentration and time, the effect of these variables could mean that an individual patient could get significantly higher or lower doses of CO in grams and this could result in either high unsafe levels of catboxyhemaglobin or doses too low to be effective. Although not all die gaseous drug delivered to the alveoli will be taken up by the bodies bloodstream (due to 10 variables such as cardiac output and the diffusion coefficient of the gas) controlling the amount delivered to the alveoli takes away a major source of variability.

In addition, there is a need to administer NO to a patient in a predetermined quantity as described in “Cell-free hemoglobin limits nitric oxide bioavailabllity in sickle-cell disease”, Nature Medicine, Volume 8, Number 12, December 2002, pages 15 1383 et seq. This paper describes the use of inhaled NO to react with cell free hemoglobin to form plasma methemaglobin and so reduce the ability of the celt free hemoglobin in the plasma to consume endogenously produced NO (fig. 5, page 1386). The quantity of NO delivered to the patient blood needs to be equivalent to the amount of cell free hemoglobin that is in the patients plasma. The amount of NO 20 delivered to a sample of sickle cell patients was 80ppm of NO for 1.5 hours. However, there was variability in the amount of methemoglobin produced in individual patients as shown by die error bars on Fig. 4b. So, in a similar way to tire CO example, a known quantity of NO needs to be delivered to a patient to provide the desired therapeutic effect and again it is important to remove any variability of 25 delivery because of differences in the individual patient’s respiratory pattern.

Accordingly, it would be advantageous to have a system and method of introducing pharmaceutical gases (such as carbon monoxide and nitric oxide) that allows for the precise control of a known quantity of the pharmaceutical gas to be 4 delivered to the patients alveoli and which is not subject to change based on the patients 2015201474 19 Apr 2017 respiratory patterns.

Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment, or any form of suggestion, that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.

Summary of the Invention

Accordingly, the present disclosure provides a system and method for administering a pharmaceutical gas, such as carbon monoxide and nitric oxide, that allows a clinician to determine and control the desired quantity of the gas to be delivered to the patient. The method determines the desired quantity of the pharmaceutical gas to be administered to the patient and then administers the desired quantity of the pharmaceutical gas irrespective of the patients respiratory patterns. If the prescription is specified as a total quantity of drug, then the method terminates the administration of the pharmaceutical gas when the desired total quantity has been administered to the patient.

Thus, by the method presently disclosed, the amount of the pharmaceutical gas is delivered to the patient as a known desired quantity and that known desired quantity can be expressed in various units of measurement, such as, but not limited to, the weight of drug in micrograms (pg), milligrams (mg), grams (g) etc., the moles of drug in nanomoles (nM), micromoles (μΜ), millimoles (mM) moles (M) etc, or the volume of drug, at a known concentration or partial pressure, in microliters (pL), milliliters (mL), liters (L) etc. The desired quantity of the pharmaceutical gas can also be expressed as an amount per unit of time for a period of time such as mg/hour for 2 hours.

In an aspect, the present invention provides a system for administering to a patient a desired total quantity of a pharmaceutical gas, including at least one gas selected from carbon monoxide and nitric oxide. The system includes an inlet means that can be connected to the source of the pharmaceutical gas and an outlet that can be connected to a device that introduces the pharmaceutical gas to the patient. The system further includes a setting control to Set a desired quantity of pharmaceutical gas to be delivered to the patient over a plurality of breaths, and a gas control system to deliver said desired quantity of the pharmaceutical gas 5 to the patient during inspiration by the patient over the plurality of breaths independent of a patient's respiratory pattern, wherein an amount of pharmaceutical gas delivered in at least one breath varies from an amount of pharmaceutical gas delivered in at least one other breath in the plurality of breaths. That patient device can be any device that actually introduces the pharmaceutical gas into the patient such as a nasal cannula, endotracheal tube, face mask or the like. There is also a gas control system that controls the introduction of the quantity of a pharmaceutical gas from the gas source through the patient device. Again, therefore, the system provides a known quantity of gas to the patient, 2015201474 19 Apr 2017

As such, the present invention allows a user to set a desired quantity of gaseous drug to be delivered to a patient's alveoli and for the system to then deliver that gaseous drug over multiple breaths until the prescribed amount has been delivered.

As a further embodiment, the system may simply provide an alarm, visual and/or audible, to alert the user when the predetermined total quantity of the pharmaceutical gas has been administered to the patient and not actually terminate that administration. As such, the user is warned that the total predetermined desired quantity administered over the plurality of breaths has now been delivered to the patient so that the user can take the appropriate action, including a closer monitoring of the patient.

Also disclosed herein is a system for administering to a patient a desired total quantity of pharmaceutical gas including at least one gas selected from carbon monoxide and nitric oxide. The system includes an inlet to connect to a source of pharmaceutical gas and an outlet to connect to a device that introduces the pharmaceutical gas to the patient. The system further includes a setting control to determine a required quantity of pharmaceutical gas per unit of time to be delivered to the patient over a plurality of breaths and a gas control system to select one of a high amount and a low amount of pharmaceutical gas, the selection of the high amount or low amount being determined by comparing the amount of pharmaceutical gas per unit of time delivered to the patient over the past number of breaths to the required quantity of pharmaceutical gas per unit of time, the system configured to deliver the selected high amount or low amount of pharmaceutical gas to the patient. 6

Also disclosed herein is a nitric oxide delivery system. The system includes an inlet to connect to a source of pharmaceutical gas comprising nitric oxide and an outlet to connect to a device that introduces the pharmaceutical gas to a patient. The system further includes a breath trigger sensor to measure a patient's respiratory rate and a gas control system in communication with the breath trigger sensor that delivers a varying quantity of pharmaceutical gas to the patient based on changes in the patient's respiratory rate in breaths per unit of time, wherein one or more of the quantity delivered in a subsequent breath is greater than the quantity delivered in a previous breath in response to a decrease in the patient's respiratory rate, or the quantity delivered in a subsequent breath is less than the quantity delivered in a previous breath in response to an increase in the patient's respiratory rate. 2015201474 19 Apr 2017

These and other features and advantages of the present invention will become more readily apparent during the following detailed description taken in conjunction with the drawings herein.

As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude other additives, components, integers or steps.

Brief Description of the Drawings FIGS. 1 and 2 are views of a front panel of an apparatus for carrying out the present invention showing different user options; FIG 3 is a schematic view of the present invention used with a spontaneously breathing patient; and FIG. 4 is a schematic view of the present invention used with a patient being breathed by means of a ventilator.

Detailed Description of the Invention

In the following detailed description, CO is used as the pharmaceutical gas but the description can also be valid for NO. Referring now to Fig. 1, there is shown a front view of an apparatus that can be used in carrying out the present invention. As can be

6A 2015201474 20 Mar 2015 seen, tee is a front panel 10 that can be a part of the apparatus and on that panel there are input setting knobs and displays which allow the user to set and monitor the amount of CO that is to be delivered to the patient.

The means for deteamining the desired quantity of CO to be delivered is by 5 means of an input setting knob 12 with the set amount being shown on the setting display 8. The units shown in Fig. 1 are in milligrams per kilogram that is, the units am measured in a dosage per kilogram of the patient’s ideal body weight. Along with that input, there is a further input 14 whereby the user can enter the patient’s ideal body weight in kilograms with the amount also displayed on the setting display 8. With those 10 inputs, the user can set the quantity of the pharmaceutical gas to be administered to the patient in proportion to the size of the patient and which reduces the patient to patient variability in response to the pharmaceutical gas due to the size of the patient, i.e. a 7 kilogram baby will not be administered the same quantity of the pharmaceutical gas as a 80 kilogram adult. 15 The front panel 10 also has a monitor display 6 which can display total dose of CO (mg) to be delivered (shown at 16) as calculated for multiplying the dosage/kg by the patients ideal body weight in kg.

Once the desired quantity of gaseous drug has been set on the device the system then determines the amount of pharmaceutical gas that is to be delivered in 20 each breath and the amount of time and/or the number of breaths that it will take to deliver the total desired quantity of dreg. The monitor display 6 can also display a running total of the delivered dose of CO (mg) (shown at 17) as it is delivered to the patient so the user can monitor the progress of the treatment. This can be updated each breath as more pharmaceutical gas is delivered. 25 As stated, the units illustrated in Fig. 1 are in metric units, however, it can be seen that other units of mass and volume could be used in carrying out the present invention i.e. ounces and cubic inches and other designs of a front panel can be used as will later be understood. 7 2015201474 20 Mar 2015

Referring to Fig, 2, there is shown a similar front panel 10 for tire apparatus as shown in Fig. 1 but illustrating a different user setting option. The desired quantity of CO to be delivered to the patient is prescribed as a rate of delivery by means of input setting knob 13 and is in unite of mg/hr of CO to be delivered. In Ms option, the device 5 also allows the time duration (in hours) of treatment to be set by a means of an input setting knob 15. If required, the input setting by input setting knob 15 could be set to continuous where the dose per hour would run continuously until the user changed the setting. With these input settings, the apparatus can calculate and display the desired quantity of the pharmaceutical gas to be administered to the patient. 10 Also, as in Fig. 1, the front panel 10 also has a monitor display 6 which can display total dose of CO (mg) to be delivered (shown at 16) as calculated by multiplying the dosage/hr by the total time duration (hr.). Once the desired quantity of pharmaceutical gas has been set on the device, the system then determines the amount of pharmaceutical gas to be delivered in each breath and the amount of time and/or the 15 number of breaths that it will take to deliver the total desired quantity of drug. As before, the monitor display 6 can display a running total of the delivered dose of CO (mg) (shown at 17) as it is delivered to the patient so the user can monitor the progress of the treatment. This can be updated each breath as more pharmaceutical gas is delivered. 20 As can be appreciated, Figs. 1 and 2 illustrate two of the many options for setting the desired quantity and duration of pharmaceutical gas therapy. These options are not meant to be exhaustive and there are other setting options described or that can be understood from die detailed descriptions that follow.

Once the desired quantity of gaseous drug has been set on the device, the gas 25 control system can then determine the amount of pharmaceutical gas to be delivered in each breath and the amount of time and/or the number of breaths that it will take to deliver the desired quantity of pharmaceutical gas. 8 2015201474 20 Mar 2015

There are a number of different approaches that the gas control system can use to determine die amount per breath and how long to deliver that dose so the desired quantity of pharmaceutical gas is delivered independent of the respiratory pattern of the patient: 5 a) The user can set die quantity of pharmaceutical gas to be delivered during each breath (Mco tea») and the gas control system calculates the number of breaths (iw^s ) which will be required to deliver the total quantity of pharmaceutical gas (Mco) i-e-

ObreaiJis = Mco l Mco breath (5) 10 Once the total number of breaths (^.) required has been determined the value can be displayed on the front panel 12 by means of display 16 to inform the user of the number of breaths . b) The user can set the number of breaths (iibreaths) that will administer the total quantity of die pharmaceutical gas and die system calculates the amount per 15 breath (Mco braath) to be delivered.

Mco breath = Mco ! nbrcaths (mg) (6)

Once die amount per breath (Mco w-nQ to be delivered has been determined, the value can be displayed on die front panel 10 to inform the user of the amount. (c) The user could set die time duration for which die treatment is to be 20 delivered over. The amount per bread! would then be determined by calculating the quantity per minute and then, by monitoring the patients respiration rate in breaths per minute, the amount of breath can be calculated. This calculation can be repeated after every breath so any changes in the patients respiratory rate does not effect the overall quantity of gaseous drug being delivered. 25 d) If the desired quantity of pharmaceutical gas was entered as a dose per

Kg of die patient’s ideal body weight (pg/kg) along with the patient’s ideal body 9 2015201474 20 Mar 2015 weight (Kg) then the amount per breath (Mod breath) can be determined as a function of the patient’s ideal body weight (IBW), the set dose per kilogram (M^g) and the patient’s monitored respiratory rate (RR) or combinations thereof;

Mco breath = f (IBW, Mkg, RR) and the number of breaths can then be 5 calculated as;

Π)*»** = Mco / Mco breath CO

Once the amount per breath (Mco breath) and the number of breaths (nbreaths) required.to be delivered has been determined, the values can be displayed on the front panel 10 to inform the user of the amounts the device has selected. 10 e) Instead of the ideal body weight (IBW) of the patient, the height and sex of the patient could be entered (which is how EBW is determined), f) If the desired quantity of pharmaceutical gas per unit of time is entered into the device, then the device can calculate the quantity per breath to be delivered to the patient based on the current monitored respiratory breath rate (as determined by 15 the breath trigger sensor). This quantity per breath can be recalculated after every breath when new information on the respiratory rate is available to ensure the quantity per unit of time is maintained even if the patient respiratory breath pattern changes over time. g) There are also other ways of varying the quantity of pharmaceutical gas 20 delivered per breath to ensure the quantity per unit of time is maintained even if the patients respiratory rate changes. Another example is where the device has two different amounts of delivery per breath, a high amount and a low amount. The device chooses which one to use based on the calculated quantity per unit of time being delivered over tire past number of breaths. If the amount per unit of time is 25 greater than required, it uses the low amount per breath until die situation corrects itself; likewise, if the quantity per unit of time is running low, then the unit switches to the high amount per breath. 10 2015201474 20 Mar 2015

The device can also have programmed limits which restrict the maximum and minimum values that can be selected for Mco breath so that the system doesn’t select inappropriately too high or too low values. These limits can be set to vary based on tire patient’s ideal body weight, or other indicator of the patient size such as the 5 patient’s height, or the respiratory rate of the patient.

The aforesaid information is sufficient for the system of the present invention to deliver the dose to the patient and to determine the amount per breath, time of administration or other parameter in order to commence tire administration of CO and to terminate that administration when the user set quantity of the pharmaceutical gas 10 has been delivered to the patient.

Turning now to Fig. 3, there is shown a schematic of a system that can be used to carry out the present invention when the patient is breathing spontaneously. As can be seen, there is a patient device 18 that delivers the dosage of the pharmaceutical gas from the gas delivery system 22 to the patient 41 via a gas conducting conduit 19. As 15 indicated, the patient device 18 can be any one of a variety of devices that actually directs the pharmaceutical gas into the patient and may be a nasal cannula, a mask, an endotracheal tube and the like.

With the Fig. 3 embodiment, there is a source of the pharmaceutical gas by means of a gas supply tank 20 containing the pharmaceutical gas generally in a carrier 20 gas. When the pharmaceutical gas is carbon monoxide, for example, the conventional, commercially available carrier gas is air. The supply of carbon monoxide and air is provided in concentrations of 3000 ppm however, concentrations within the range of 1000 to 5000 ppm of CO in air are also possible alternatives. In the case of NO as the pharmaceutical gas, the carrier gas is conventionally nitrogen 25 and the typical available concentrations range from 100 ppm to 1600 ppm.

Accordingly, from the supply tank 20, there is a tank pressure gauge 21 and a regulator 23 to bring the tank pressure down to the working pressure of the gas delivery system 22. The pharmaceutical gas enters the gas delivery system 22 through 11 2015201474 20 Mar 2015 an inlet 24 that can provide a ready connection between that delivery system 22 and the supply tank 20 via a conduit. The gas delivery system 22 has a filter 25 to ensure no contaminants can interfere with the safe operation of the system and a pressure sensor 27 to detect if the supply pressure is adequate and thereafter includes a gas shut 5 off valve 26 as a control of the pharmaceutical gas entering the deliver system 22 and to provide safety control in the event the delivery system 22 is over delivering the pharmaceutical gas to the patient. In the event of such over delivery, the shut off valve 26 can be immediately closed and an alarm 42 sounded to alert the user that the gas delivery system lias been disabled. As such, die shut off valve 26 can be a 10 solenoid operated valve that is operated from signals directed from a central processing unit including a microprocessor.

Downstream from the shut off valve 26 is a flow control system that controls the flow of the pharmaceutical gas to the patient through the patient device 18. In the embodiment shown, the flow control system comprises a high flow control valve 28 15 and a low control valve 30 and just downstream from the high and low flow control valves 28, 30, respectively, are a high flow orifice 32 and a low flow orifice 34 and the purpose and use of the high and low flow valves 28, 30 and the high and low flow orifices 32, 34 will be later explained. A gas flow sensor 36 is also located in the flow of pharmaceutical gas to the patient device 18 and, as shown, is downstream from the 20 flow control system, however, the gas flow sensor 36 may alternatively be located upstream of the flow control system.

Next, there is a patient trigger sensor 38. When the patient breathes in during inspiration it creates a small sub atmospheric pressure in the nose or other area where the patient device 18 is located, and hence in the patient device 18 itself. The patient 25 trigger sensor 38 detects this pressure drop and provides a signal indicative of the start of inspiration of the patient Similarly, when the patient breathes out there is a positive pressure in the patient device 18 and the patient trigger sensor 38 detects that positive pressure and provides a signal indicative of the beginning of expiration. This 12 2015201474 20 Mar 2015 allows the patient trigger sensor 38 to determine not only the respiratory rate of the patient but also the inspiratory and expiratory times.

Finally there is a CPU 40 that communicates with the patient trigger sensor 38, the high and low flow valves 28, 30, die gas shut off valve 26 and other components 5 in order to carry out the purpose and intent of the present invention. The CPU 40 may include a processing component such as a microprocessor to carry out all of die solutions to the equations that are used by the gas delivery system 22 to deliver the predetermined quantity of the pharmaceutical gas to a patient. The CPU 40 is connected to the front panel 10 where the user can enter settings and monitor therapy. 10 Hie use of the delivery system 22 of the present invention for spontaneous breathing can now be explained. When the delivery system 22 detects by means of the patient trigger sensor 38 that inspiration has started, there is a signal that is provided to the CPU 40 to deliver a dose of a pharmaceutical gas (Mco breath) into the patient’s inspiratory gas flow, preferably during the first Vi of the inspiratory cycle. 15 This amount per breath has been determined based on the desired quantity of pharmaceutical gas that has been set on the system and the calculations made in a) to g) described earlier.

The actual volume of gas delivered during the breath depends on the concentration of the pharmaceutical gas in the carrier gas that is supplied by the 20 supply tank 20. A typical source concentration (Ceo ) for CO would be 3000 ppm (range 500 to 5000). The volume of source gas (Yd) per breath to provide a dose per breath (Mco breath ) when the source of CO is 3000 ppm is given by the following equation, combining equations 2,3,4 and 6;

Vd = Mco breath. / (28 . Cc0 4.16 xlO'1 *) (8) 25 Given that

Mco = 60 x 10'3 (g)

Cco = 3000 (ppm)

Ubreaths — 600

Then Va = 28.6 (mL) 13 2015201474 20 Mar 2015

To deliver the volume of source gas per breath (Va), that is, the pharmaceutical gas and the carrier gas, the delivery system 22 opens a flow control valve, such as high flow valve 28 or low flow valve 30 to allow the gas to flow to the patient until the volume per breath (V({) has been delivered. The presence of the high flow orifice 5 32 and the low flow orifice 36 limits the flow of gas to a fixed set level during the period that the high or low flow valves 28, 30 are open so the delivery system 22 can determine the period of time the high or low flow valves 28, 30 should be open to deliver the volume per breath (V<0 required. Also, as another option, the flow can be determined by the gas flow sensor 36 to monitor the gas flow to the patient device 18 10 and thus to the patient and can shut off the appropriate high or low flow control valve 28, 30 when the desired predetermined quantity of pharmaceutical gas dose has been delivered to the patient.

As can be seen, to provide enough range to cover all the possible doses, the use of multiple flow valves, that is, the high flow valve 28 and the low flow valve 30 15 along with corresponding multiple orifices, high flow orifice 32 and low flow orifice 34, can be used in parallel so as to provide high and low ranges of gas flow. For instance, the low flow gas flow through the low flow valve 30 could be set to 1 L/min and the high flow gas flow through the high flow control valve 28 could be set to 6 L/min. The flow range of the particular gas flow valve is selected to ensure that the 20 volume of gas per breath (V<j) can be delivered to the patient in at least iA the inspiratory time,

As an example, if the patient was breathing at 12 breaths per minute and had an I:E ratio of 1:2 then the inspiratory time would be 1.66 seconds and half that would be 0.83 seconds. 25 The time (t) taken to deliver a Vd of 28 mL can be calculated as follows. t = Vd .60 /(Q. 1000) (secs) (9)

When Q (the flow of gas when the high flow valve 28 is open) = 61/tnins t = 0.28 (secs) 14 2015201474 20 Mar 2015

That time is therefore well within ιΛ the inspiratory time allowed of 0.83 seconds.

Tie delivery system 22 can also include monitoring and alarm features to alert the user if die delivery system 22 is not working correctly. Those alarm conditions 5 can be determined by the CPU 40 and the alarm 42 activated to alert the user to the particular fault condition. The alarm 42 can be audible, visual or both and the alarm conditions can be any one or all of the following:

No breath detected

Low source gas pressure 10 Inaccurate delivery of the volume per breath (Va)

Over delivery of the volume per breath (Vd)

Under delivery of the volume per breath (Va)

Under certain conditions, such as when the delivery system 22 is over delivering the pharmaceutical gas, the CPU 40 may signal the gas shut off valve 26 15 and immediately cease any further delivery of the pharmaceutical gas and the alarm 42 also activated.

The use of the alarm 42 can also be an alternative to actually shutting off the supply of the pharmaceutical gas to a patient when the predetermined desired quantity of pharmaceutical gas has been fully delivered to the patient. In such case, as an 20 alternative to ceasing the further supply of (he pharmaceutical gas to the patient, the delivery system 22 may, by means of the CPU 40, activate the alarm 42 to alert the user that the total predetermined desired quantity of the pharmaceutical gas has been delivered. The user can then determine whether to manually deactivate the delivery system 22 or continue the delivery of the pharmaceutical gas under more watchful 25 control of the patient’s status.

Turning now to Fig. 4, there is shown a schematic view of a gas delivery system 44 used in conjunction with a patient being breathed by a ventilator 46. hr the Fig. 4 15 2015201474 20 Mar 2015 embodiment, again there is a supply tank 20 that includes a conventional gas regulator 23 and pressure gauge 21 to supply the pharmaceutical gas along with the carrier gas to an inlet 24 in the gas delivery system 44. Briefly summarizing the components of the Fig. 4 embodiment, since they are basically the same components as described with 5 respect to the Fig. 3 embodiment, there can be a filter 25 and a pressure sensor 27 in the gas delivery system 44. Again there is a shut off valve 26 to control the overall flow of the pharmaceutical gas through the gas delivery system 44.

The high and low flow control valves 28 and 30 control the flow of the pharmaceutical gas through the gas delivery system 44 and, the high and low flow 10 valves 28, 30 operate as described with respect to the Fig. 3 embodiment with high and low flow orifices 32, 34 located downstream of the flow control valves.

Again there is a gas flow sensor 36 and a patient trigger sensor 66, both of which communicate with the CPU 40. With this embodiment, however, the pharmaceutical gas is carried through an outlet conduit 70 to a patient device 72 that also receives the 15 breathing gas from the ventilator 46. As such, the ventilator 46 delivers a flow of gas through the inspiratory limb 74 and gas is returned to the ventilator 46 through the expiratory limb 76.

The flow of gas from the ventilator 46 is thus supplemented by the flow of pharmaceutical gas from the gas delivery system 44 where that gas is mixed at or 20 proximate to the patient device 72 for introduction into the patient 78. Since all of the pharmaceutical gas is still delivered to the patient over the plurality of breaths, basically the CPU 40 can carry out the same determination of flows and the like as explained with respect to the Fig. 3 embodiment. The main difference between this Fig. 4 embodiment, and that shown in Fig. 3 is that the patient trigger sensor 66 is designed to operate in a 25 way that works with a ventilator 46.

For instance, when the ventilator 46 provides gas flow to a patient during inspiration, it causes a positive pressure in the breathing circuit. The positive pressure is conducted through the outlet conduit 70 and is detected by the patient trigger sensor 66 16 2015201474 20 Mar 2015 and is recognized as the start of inspiration. This is the opposite to the embodiment of Fig. 3 where the patient breathes spontaneously and a negative pressure is generated during inspiration in the patient device 18; this negative pressure is conducted to the patient trigger sensor 38 of Fig. 3 and is recognized as the start of inspiration. As can be 5 appreciated, the patient trigger sensor 38 of Fig. 3 and the patient trigger sensor of Fig. 4 could be the same pressure sensor and the gas delivery system 44 can be set for work with a ventilator or a spontaneously breathing patient.

Those skilled in the art will readily recognize numerous adaptations and modifications which can be made to the pharmaceutical gas delivery system and method 10 of delivering a pharmaceutical gas of the present invention which will result in an improved method and system for introducing a known desired quantity of a pharmaceutical gas into a patient, yet all of which will fall within the scope and spirit of the present invention as defined in the following claims. Accordingly, the invention is to be limited only by the following claims and their equivalents. 17

Claims

CLAIMS The claims defining the invention are as follows:

1. A system for administering to a patient a desired total quantity of a pharmaceutical gas including at least one gas selected from CO and NO, the system comprising: an inlet to connect to a source of pharmaceutical gas; an outlet to connect to a device that introduces the pharmaceutical gas to the patient; a setting control to set a desired quantity of pharmaceutical gas to be delivered to the patient over a plurality of breaths; and a gas control system to deliver said desired quantity of the pharmaceutical gas to the patient during inspiration by the patient over the plurality of breaths independent of a patient's respiratory pattern wherein an amount of pharmaceutical gas delivered in at least one breath varies from an amount of pharmaceutical gas delivered in at least one other breath in the plurality of breaths.
2. The system of claim 1, wherein the system determines one or more of (1) the desired total quantity of pharmaceutical gas to be delivered; (2) the amount of time to deliver the total desired quantity of pharmaceutical gas; and (3) the number of breaths that it will take to deliver the total desired quantity of pharmaceutical gas.
3. The system of claim 1, wherein the system calculates a quantity of pharmaceutical gas to be delivered per breath to the patient.
4. The system of claim 3, wherein the system delivers pharmaceutical gas to the patient every breath.
5. The system of claim 1, wherein the device calculates the quantity per breath to be delivered to the patient based on a monitored respiratory breath rate.
6. The system of claim 5, wherein the system includes a breath trigger sensor to measure the monitored respiratory breath rate.
7. The system of claim 1, wherein the pharmaceutical gas is delivered to the patient with a carrier gas.
8. The system of claim 1, wherein the pharmaceutical gas is NO.
9. The system of claim 1, wherein the gas control system includes a central processing unit (CPU) and the CPU calculates the quantity of pharmaceutical gas to be delivered per breath based on one or more of the desired quantity of gas, the concentration of the pharmaceutical gas in the carrier gas and the respiratory rate of the patient.
10. The system of claim 1, wherein the setting control is in units of mass per unit of time.
11. The system of claim 1, wherein the setting control is in units of mass per unit of patient's ideal body weight per unit of time.
12. The system of claim 1, wherein the system includes a central processing unit (CPU) and wherein the CPU controls the amount of pharmaceutical gas delivered during the patient's breath based upon the concentration of the pharmaceutical gas in the carrier gas.
13. The system of claim 12, wherein the CPU delivers the pharmaceutical gas and carrier gas over a plurality of breaths until the desired quantity of pharmaceutical gas has been delivered based upon the concentration of pharmaceutical gas in the carrier gas.
14. The system of claim 1, further comprising an alarm.
15. The system of claim 14, wherein the system activates the alarm when the desired quantity of pharmaceutical gas has been delivered to the patient.
16. The system of claim 1, wherein determining the desired quantity of pharmaceutical gas to be administered to the patient comprises determining the desired quantity in units of mass per ideal body weight and the patient's ideal body weight or in units of mass per unit of time per ideal body weight and the patient's ideal body weight.
17. The system of claim 1, wherein the pharmaceutical gas is delivered during the first half of inspiration.