System and method of administering a pharmaceutical gas to a patient.

SYSTEM AND METHOD FOR ADMINISTERING A PHARMACEUTICAL GAS TO A PATIENT

Field of the Invention

The present invention 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 into a patient, in a predetermined amount.

Background of the Invention

The normal or conventional way to deliver a pharmaceutical drug to a patient is to prescribe the dose based on the amount of the drug (usually by weight) per unit weight of the patient (eg mg / Kg) with the dose that is specified to be delivered over a period of time or to be repeated at specified time intervals. This allows the user to control the amount of the drug and ensures that the amount of the drug to be delivered is in proportion to the size of the patient. This is to reduce patient-to-patient variability in response to the drug due to the size of the patient, that is, a 75g baby will not receive the same amount of the drug as an 80kg 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., (Published North American Patent Application No. 2003/0219496). In Otterbein's patent application, CO is described as possessing a pharmacological action in a number of medical conditions including ileus and vascular disease.

In these cases, carbon monoxide gas needs to be supplied to the alveoli of patients where it can move through the alveolar membrane and into the blood flow where its action can take effect. The dosage currently used in these cases causes the patient to breathe a specified concentration of CO in ppm, for a specified period of time. Exact dosing for these treatments is important since CO reacts with hemoglobin in the blood to form carboxyhemoglobin which means that hemoglobin can no longer transport oxygen to body tissues. If too much CO is supplied, the patient may exhibit the toxic effects of CO, which are usually known.

There is a narrow margin for CO administration between the therapeutic level and the level that causes carboxyhemoglobin levels above safe levels. Until now, CO has been supplied as a constant concentration in the gas breathed by the patient / animal for a specific period of time. For example, in reference 3 of Otterbein's publication (Example 2, p. 13) The therapeutic dose delivered to mice for the treatment of ileus was 250 ppm of CO for 1 hour.

However, this method of dosing CO can be associated with great variability in the actual dose that is being delivered to the animal / human alveoli. This variability is due to the amount of CO being supplied to animals / humans depending on a number of variables that includes, but is not limited to, the volume of lung respiration, the respiratory rate, the rate of diffusion through the alveoli and ventilation / perfusion agreement (V / Q).

The amount of CO delivered to a patient's alveoli can be determined using the ideal gas law in the following equation:

N = P. V / (Ru.T) (1)

Where:

N is the number of moles of the gas (mol)

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 (joule / (gmol. ° K)

T is the absolute temperature (° K)

If we assume the atmospheric pressure 101,315 joule / m³) and 20 ° C (293 ° K) as the temperature and we express the volume the mL (xl0 '⁶ m³) then equation (1) reduces to:

N = 4.16xl0 ~⁵ . V (moles) (2)

Equation (2) can be used to calculate the number of moles of gas delivered to an alveolar volume of the patient over a period of time, when a specified concentration is given using the following equation:

N_co= RR · t C_co· 10‘⁶ 4.16xl0 '⁵ · V_to (3)

Where:

C_co is the CO concentration (ppm)

V_to is the alveolar volume (mL)

RR is the respiratory rate in (BMP) t is the time in minutes (min)

For example, if the CO dose for human ileus was 250 ppm for one hour (60 minutes), the alveolar volume is 300 mL, and the patient's respiratory rate is 12 breaths per minute (bmp) then the amount of the molar CO gas supplied to the alveoli of the patients during that period would be:

N_co=12.6 0.2 5 0.10 ⁶ 4.16x10 '⁵.3 0 0 = 2.25 x 10 '³ (moles)

This can be converted to delivered drug mass (M_Co) using the molecular peroxide in grams of CO, which is 28, as shown in the following equation:

Meo = N_co.28 = 63X10 '³ (g) = 63 (mg) (4)

However, although this works for a set of given assumptions, the spontaneous respiratory rate of the patients can vary widely perhaps from 8 to 20 breaths per minute depending on the circumstances and the alveolar volume of the patients per breath, it can also vary significantly, let's say 200 to 400 mL, depending on metabolic needs. These variables can have a dramatic effect on the amount of the gaseous drug that is being delivered to the patient during the same period of time. For example, if the patient's respiratory rate was 8 bpm, and the alveolar volume was 200 mL, the CO dose delivered to the patient's alveoli would have been 27.8 (mg). Similarly, if the respiratory rate of the patients was 200 bmp and the alveolar volume was 400 mL, then the dose delivered to the alveoli of the patients would have been 139.2 (mg), which therefore represents a difference of five times the amount of drug being dispensed.

This means, in the CO example, that the amount of the gaseous drug that a patient receives, when measured in grams, could vary substantially depending on the patient's ventilation pattern. For a dose based on concentration and time, the effect of these variables could mean that an individual patient receives significantly higher or lower doses of CO, in grams, and this could result in unsafe high levels of carboxyhemoglobin or in too low doses. to be effective. Although not all of the gaseous drug delivered to the alveoli will be absorbed by the body's blood flow (due to variables such as cardiac output and gas diffusion coefficient) controlling the amount supplied to the alveoli eliminates a major source of variability.

Furthermore, there is a need to administer NO to a patient in a predetermined amount, as described in Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease, Nature Medicine, Volume 8, Number 12, December 2002, pages 1383 et I know that. This document describes the use of inhaled NO to react with the free hemoglobin of the cells to form plasma methemoglobin and thus reduce the ability of the free hemoglobin of the cells in the plasma to consume the endogenously produced NO (Fig. 5, page 1386). The amount of NO delivered to the patient's blood needs to be equivalent to the amount of the cell's free hemoglobin that is in the patient's plasma. The amount of NO supplied to a sample of sickle cell patients was 80 ppm NO for 1.5 hours. However, there was variability in the amount of hemoglobin produced in individual patients, as shown by the error bars in Fig. 4b. Thus, similar to the CO example, a known amount of NO needs to be supplied to a patient to provide the desired therapeutic effect and again, it is important to eliminate any variability in administration because of differences in the patient's respiratory pattern. individual.

Accordingly, it would be advantageous to have a system and method for introducing pharmaceutical gases (such as carbon monoxide and nitric oxide) that allows precise control of a known amount of the pharmaceutical gas to be delivered to the patients' alveoli, and which do not undergo changes based on patient breathing patterns.

Brief Description of the Invention

Accordingly, the present invention relates to a system and method for administering a pharmaceutical gas, such as carbon monoxide and nitric oxide, which enables a clinician to determine and control the desired amount of the gas to be administered to the patient . The method determines the desired amount of the pharmaceutical gas to be administered to the patient and when the desired amount of the pharmaceutical gas is administered regardless of the respiratory patterns of the patients. If the prescription is specified as a total amount of the drug, then the method ends the administration of the pharmaceutical gas when the desired total amount has been administered to the patient.

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

The invention also includes a system for administering a pharmaceutical gas, such as carbon monoxide or nitric oxide, and the system includes an intake means that can be connected to the source of the pharmaceutical gas and deliver the gas to a patient by means of a patient device. The patient's device can be any device that actually introduces the pharmaceutical gas into the patient, such as a nasal cannula, an endotracheal tube, a face mask, or the like. There is also a gas control system that controls the introduction of the amount of a pharmaceutical gas from the gas source through the patient's device. Again, therefore, the system provides

<td>an amount</td><td>gas known to the patient.</td><td></td><td></td>

<td>Per se</td><td>, the present invention allows</td><td>that a</td><td>user</td>

<td>receive a</td><td>desired amount of the drug</td><td>gaseous</td><td>To be</td>

<td>administered</td><td>to the alveoli of a patient</td><td>that he</td><td>system</td>

<td>supply</td><td>then that gaseous drug</td><td>during</td><td>several</td>

breaths until the prescribed amount has been delivered.

As a further embodiment, the system and method can simply provide an alarm, visual and / or audible, to indicate to the user when the predetermined total amount of the pharmaceutical gas has been administered to the patient, and does not in fact terminate that administration. As such, the user is instructed that the desired, predetermined amount administered over a plurality of breaths has been delivered to the patient at that time, such that the user can take appropriate action, including closer monitoring of the patient.

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.

Brief Description of Drawings

FIGS. 1 and 2 are views of the front panel of an apparatus for carrying out the present invention, showing the different options of the user;

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 who is breathing 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 may also be valid for NO. Referring now to Fig. 1, there is shown a front view of an apparatus that can be used to carry out the present invention. As can be seen, there is a front panel 10 that can be part of the apparatus. In this panel there are input adjustment knobs which allow the user to adjust and monitor the amount of CO that must be supplied to the patient.

The means of determining the desired amount of CO to be administered is by means of an input adjustment knob 12 with the amount of adjustment shown on the adjustment screen 8. The units shown in Fig. 1 are in milligrams per kilogram, that is, the units are measured at a dosage per kilogram of the patient's ideal body weight. Along with those inputs is an additional input 14 through which the user can enter the patient's ideal body weight in kilograms, with the amount also displayed on the adjustment screen 8. With these inputs, the user can set the amount of the pharmaceutical gas to be administered to the patient, in proportion to the size of the patient, and which reduces patient-to-patient variability in response to pharmaceutical gas, due to the size of the patient, is In other words, a 7-kilogram baby will not receive the same amount of pharmaceutical gas as an 80-kilogram adult.

The front panel 10 also has a monitoring screen 6 which can display the total dose of CO (mg) to be delivered (shown at 16) when calculated by multiplying the dose / kg by the patient's ideal body weight in kg.

Once the amount of the gaseous drug in the device has been established the system then determines the amount of the pharmaceutical gas that must be delivered in each breath, and the amount of time and / or the number of breaths it will take to deliver the total desired amount of the drug. The monitoring screen 6 can also display a total of administrations of the delivered dose of CO (mg) (shown in 17) when it is delivered to the patient, so that the user can monitor the progress of the treatment. This can be updated with each breath when more pharmaceutical gas is supplied.

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 to practice the present invention, i.e. ounces and cubic inches can be used and other designs as will be understood later.

Referring to Fig. 2 there is shown a similar front panel 10 for the apparatus shown in Fig. 1 but illustrating a different user setting option. The desired amount of CO to be delivered to the patient is prescribed as a rate of delivery via the input adjustment knob 13 and is in units of mg / hr of CO to be delivered. In this option, the device also allows the length to be adjusted. of time (in hours) of treatment, by means of an input adjustment knob 15. If required, the input setting via the input setting knob 15 could be set to continuous where the hourly dose runs continuously until the user changes the setting. With these input settings, the device can calculate and display the desired amount of the pharmaceutical gas to be supplied to the patient.

Also, as in Fig. 1, the front panel 10 also has a monitoring screen 6 which can display the total dose of CO (mg) to be administered (shown at 16) when calculated by multiplying the dose / hr by the total length of time (hr). Once the desired amount of pharmaceutical gas has been set in 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 number of breaths it will take to deliver the desired amount of the drug. As before, the monitoring screen 6 can display a total of administrations of the dose of CO delivered (mg) (shown in 17) when it is delivered to the patient, so that the user can monitor the progress of the treatment. This can be updated with each breath when more pharmaceutical gas is supplied.

As can be seen, Figs. 1 and 2 illustrate two of the many options for adjusting the desired amount and duration of pharmaceutical gas therapy. These options are not intended to be exhaustive and there are other adjustment options described or understandable from the detailed description that follows.

Once the desired amount of the gaseous drug has been adjusted in the device, the gas control system can then determine the amount of the pharmaceutical gas to be delivered in each breath and the amount of time and / or the number of breaths it will take to deliver the desired amount of the pharmaceutical gas.

There are several different techniques that the gas monitoring system can use to determine the amount per breath and how long to deliver that dose, such that the desired amount of pharmaceutical gas is delivered regardless of the patient's breathing pattern:

a) The user can set the amount of the pharmaceutical gas to be supplied during each breath (M_Cor breath) and the gas control system calculates the number of breaths (n_respi_raci_ORnions) which will be required to supply the total amount of pharmaceutical gas (M_Co) ie ^ breaths “Meo / Meo respiration (5)

Once the total number of required breaths (nbreaths) has been determined, the value can be displayed on the front panel 12 via display 16, to inform the user of the number of breaths.

b) The user can set the number of breaths

<td>(^ breaths)</td><td>than</td><td>will manage</td><td>the amount</td><td>total of</td><td>gas</td>

<td>pharmacist</td><td>and</td><td>the system</td><td>calculate the</td><td>quantity</td><td>by</td>

<td>breaths</td><td>(M_co</td><td>breathing) 3 · Being</td><td>supplied.</td><td></td><td></td>

<td colspan="2">I breathe</td><td>⁼ Meo / U-breaths</td><td>(mg)</td><td> (6)</td><td></td>

Once the amount per breath to be delivered has been determined (M_Cor breath)&gt; value can be displayed on the front panel 10 to inform the user of the amount.

c) The user could set the length of time for which the treatment must be provided. The amount per breath would then be determined by calculating the amount per minute and then, by monitoring the patient's respiratory rate in breaths per minute, the amount of respiration can be calculated. This calculation can be repeated until after each breath in such a way that any change in the respiratory rate of the patients does not affect the total amount of the gaseous drug that is being supplied.

d) If the desired amount of the pharmaceutical gas was entered as a dose per Kg of the patient's ideal body weight (pg / kg) along with the patient's ideal body weight (Kg) then the amount per breath (M_co respiration) can be determined as a function of the patient's ideal body weight (IBW), the fixed dose per kilogram (M_kg) and the patient's monitored respiratory rate (RR) or combinations thereof;

Meo respiration = f (IBW, M_kg, RR) and the number of breaths can then be calculated as;

^ breaths - Mqo / Mqo breath (7)

Once the amount per breath has been determined (M_Cor breath) and the number of breaths (n_beefpi_rations) required to be supplied, the values ​​can be displayed on the front panel 10 to inform the user of the quantities that the device has selected.

e) Instead of the patient's ideal body weight (IBW), the patient's height and sex could be entered (which is how the IBW is determined).

f) If the desired amount of pharmaceutical gas per unit of time is entered into the device, then the device can calculate the amount per breath to be delivered to the patient, based on the current monitored respiratory rate (as determined by the activated detector by breathing). This amount per breath can be recalculated after each breath when new information about the respiratory rate is available to ensure that the amount per unit of time is maintained even if the patient's breathing pattern changes over time.

g) There are also other ways to vary the amount of pharmaceutical gas delivered per breath, to ensure that the amount per unit time is maintained even if the patient's breathing rate changes. Another example is when the device has two different amounts of supply per breath, a high amount and a low amount. The device chooses which one to use based on the calculated amount per unit time, which is delivered in the last number of breaths. If the amount per unit of time is greater than required, he uses the low amount per breath until the situation corrects itself; likewise, if the amount per unit time is being administered in low doses, then the unit changes to the high amount per breath.

The device may also have program limits which restrict the maximum and minimum values ​​that can be selected for M_co so that the system does not inappropriately select too high or too low values. These limits can be adjusted to vary based on the patient's ideal body weight, or another indicator of the patient's height, such as the patient's height, or the patient's respiratory rate.

The aforementioned information is sufficient for the system of the present invention to deliver the dose to the patient and determine the amount per breath, the time of administration or other parameters, in order to start the administration of CO and to finish the administration when the User-set amount of pharmaceutical gas has been supplied to the patient.

Turning now to Fig. 3, there is shown a schematic of a system that can be used to practice the present invention when the patient is breathing spontaneously. As can be seen, there is a patient device 18 that supplies the patient with the dose of the pharmaceutical gas from the gas supply system 22 via a tube 19 that conducts the gas. As indicated, the patient's device 28 can be any of a variety of devices that actually direct the pharmaceutical gas into the patient and can be a nasal cannula, a mask, an endotracheal tube, and the like.

With the embodiment of Fig. 3, there is a source of the pharmaceutical gas by means of a gas supply tank 20 containing the pharmaceutical gas, usually in a carrier gas. When the pharmaceutical gas is carbon monoxide, for example, the conventional commercially available carrier gas is air. Supply of carbon monoxide and air is provided at concentrations of 3,000 ppm, however, possible concentrations within the range of 1,000 to 5,000 ppm in air are also alternatives. In the case of NO like pharmaceutical gas, the carrier gas is conventional nitrogen and the available concentrations vary from 100 ppm to 1600 ppm.

Accordingly, from the supply tank 20, there is a tank pressure gauge 21 and a regulator 23 to reduce the tank pressure to the working pressure of the gas supply system 22. The pharmaceutical gas enters the gas supply system 22 through an inlet 24 which can provide a ready connection between that supply system 22 and the supply tank 20 by means of a tube. The gas supply system 22 has a filter 25 to ensure that no contaminants can interfere with the safe operation of the system and a pressure detector 27 to detect if the supply pressure is adequate and then includes a gas shutoff valve 26 as a control of the pharmaceutical gas entering the supply system 22 and to provide security in the event that the supply system 22 is over supplying the pharmaceutical gas to the patient. In the event of over-supply, shutoff valve 26 can be closed immediately and an alarm 42 sounds to alert the user that the gas supply system has been disabled. In and of itself, shutoff valve 26 may be a solenoid operated valve that is operated by signals directed from a central processing unit that includes a microprocessor.

Downstream of shutoff valve 26 is a flow control system that controls the flow of pharmaceutical gas to the patient through patient device 18. In the embodiment shown, the flow control system comprises a high flow control valve 28 and a low flow control valve 30 and just downstream of the high and low flow control valves 28, 30, respectively, there is a high flow port and a low flow port 34 and the purpose and use of the high and low flow valves 28, 30 and high and low fluid ports 32, 34 will be explained later. A flow detector 36 is located in the flow of pharmaceutical gas to the patient device 18, as shown, is downstream of the flow control system, however, the gas flow detector 26 may alternatively be located upstream of the flow control system.

Next, there is a patient activation detector 28. When the patient inhales during inspiration it creates a small sub-atmospheric pressure in the nose and other areas where the device 18 of the patient is located, and therefore in the device 18 of the patient itself. The patient activation detector 38 detects this pressure drop and provides a signal indicative of initiation of patient inspiration. Similarly, when the patient exhales, there is a positive pressure in the patient device 18 and the patient activation detector 28 detects a positive pressure and provides a signal indicative of the onset of expiration. This allows the patient activation detector 38 to determine not only the patient's respiratory rate but also the inspiration and expiration times.

Finally, there is a CPU 40 that communicates with the patient activation detector 28, the high and low flow valves 28, 30, the gas shutoff valve 26 and other components, in order to carry out the purpose and intention of the present invention. The CPU 40 may include a processing component such as a microprocessor, to implement the solutions of the equations that are used by the gas supply system 22, to supply the predetermined amount of the pharmaceutical gas to the patient. The CPU 4 0 connects to the front panel 10 where the user can enter the settings and monitor the therapy.

The use of the delivery system 22 of the present invention for spontaneous respiration can now be explained. When the delivery system 22 detects that respiration has started, by means of the patient activation detector 28, there is a signal that is provided by the CPU 40 to deliver a dose of the pharmaceutical gas (M_Cor respiration) in the patient's inspiration gas flow, preferably during the first 1/2 of the inspiration cycle. This amount per breath has been determined based on the desired amount of the pharmaceutical gas that has been set in the system and the calculations made in a) to g) previously described.

The actual volume of gas supplied during respiration depends on the concentration of the pharmaceutical gas in the carrier gas supplied by the supply tank 2 0. A typical source concentration (C_c0) for CO would be 3 0 00 ppm (range from 500 to 5000). The volume of the source gas (V_d) per breath provides one dose per breath (M_co respiration) when the CO source is 3000 ppm, is given by the following equation, which combines equations 2, 3, 4, and 6.

V_d = Meo respiration- / (28. C_co· Four . lGxlO '¹¹) (8)

Given the

M_Co = 60xl0 '³ (g)

C_co= 3000 (ppm)

Breathing ⁼ 6 0 0

Then V_d= 28.6 (mL)

To supply the volume of the source gas per breath (Va) i.e. pharmaceutical gas and carrier gas, the supply system 22 opens a flow control valve, such as a high flow valve 28 or a flow valve 30 low, to allow gas to flow to the patient until the volume per breath has been delivered (V_d). The presence of high flow port 32 and low flow port 36 limits gas flow to a fixed level set during the period when high and low flow valves 28, 30 are open, such that the system Supply 22 can determine the length of time that high and low flow valves 28, 30 must be open to deliver the required volume per breath (V_d), Also, as another option, the flow can be determined by the gas flow detector 36 to monitor the flow of the gas to the patient device 18 and therefore to the patient and can close the valve 28, 30 of control of appropriate high or low flow, when the desired predetermined amount of the pharmaceutical gas dose has been delivered to the patient.

As can be seen, to provide a sufficient range to cover all possible doses, the use of various flow valves, i.e. the high flow valve 28 and the low flow valve 30, together with the various corresponding orifices, the high flow port 32 and low flow port 34 can be used in parallel to provide high and low range gas flow. For example, the flow of the low flow gas through the low flow valve 39 could be set to 1 L / min and the flow of the high flow gas 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 volume of gas per breath (V_d) can be delivered to the patient in at least 1/2 the inspiration time.

As in the example, if the patient was breathing at 12 breaths per minute and had an I: E ratio of 1: 2 then the inspiration time would be 1.66 seconds and half would be 0.83 seconds.

The time (t) it takes to supply a V_d 28 mL can be calculated as follows.

t = V_d.60 / (Q.1000) (sec) (9)

When Q (gas flow when high flow valve 28 is opened) = 6 L / min; t = 0.28 (sec)

That time will therefore be within 1/2 of the allowed inspiration time of 0.83 seconds.

The supply system 22 may also include alarm features to alert the user if the supply system 22 is not working properly. Those alarm conditions can be determined by CPU 40 and alarm 42 is triggered to alert the user to the particular fault condition. Alarm 42 can be audible, visual, or both, and alarm conditions can be any or all of the following:

Breath is not detected

Low source gas pressure

Inaccurate supply of volume per breath (V_d)

Over supply of volume per breath (V_d)

Volume supply per breath (V_d)

Under certain conditions, such as when the supply system 22 is over-supplying the pharmaceutical gas, the CPU 40 can send signals to the gas shut-off valve 26 and all further supply of the pharmaceutical gas is immediately stopped and alarm 42 also goes off. active.

The use of alarm 42 can also be an alternative to actually shutting off the delivery of the pharmaceutical gas to a patient when the predetermined desired amount of the pharmaceutical gas has been fully delivered to the patient.

In such a case, as an alternative to stopping the additional supply of the 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 predetermined, desired total amount of the pharmaceutical gas has been supplied. The user can then determine if the delivery system 22 is manually deactivated or the administration of the pharmaceutical gas is continued under closer monitoring of the patient's condition.

Turning now to Fig. 4, there is shown a schematic view of a gas supply system 44 used in conjunction with a patient being ventilated by a ventilator 46. In the embodiment of Fig. 4 there is again a tank Supply 2 0 including a conventional gas regulator 23 and a manometer 21 for supplying the pharmaceutical gas along with the carrier gas to an inlet 24 in the gas supply system 44. Briefly summarizing the components of the embodiment of Fig. 4, since these are basically the same components as described with respect to the embodiment of Fig. 3, there may be a filter and a pressure detector 27 in the system 44 gas supply. Again, there is a shutoff valve 2 6 to control the full flow of the pharmaceutical gas through the gas supply system 44.

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

Again, there is a gas flow detector 36 and a patient activation detector 66 which communicate with CPU 40. With this embodiment, however, the pharmaceutical gas is transported through a discharge tube 7 0 to a patient device 72 that also receives breathing gas from the ventilator 46. As such, the ventilator 46 supplies a gas flow through the limbus or aspiration member 74 and the gas returns to the ventilator 4 6 through the member 76 of expiration.

The gas flow from the ventilator 46 is therefore complemented by the pharmaceutical gas flow from the gas supply system 44 where the gas is mixed into or near the patient device 72 for introduction into the patient 78. Since all the pharmaceutical gas will be supplied even to the patient through the plurality of breaths, basically the CPU 40 can carry out some flow determinations and the like as explained with respect to the modality of Fig. 3. The The main difference between this embodiment of Fig. 4, and that shown in Fig. 3 is that the patient activation detector 66 is designed to operate in a manner that works with a ventilator 46.

For example, when ventilator 46 provides gas flow to a patient during inspiration, this causes positive pressure in the breathing circuit. Positive pressure is conducted through the discharge tube 7 0 and is detected by the patient activation detector 66 and is recognized as the start of inspiration. This is the opposite of the embodiment of Fig. 3 where the patient breathes spontaneously and a negative pressure is generated during inspiration in the patient's device 28; this negative pressure is led to the patient activation detector 38 of Fig. 3, and is recognized as the start of inspiration. As can be seen, the patient activation detector 38 of FIG. 2 and the patient activation detector of FIG. 4 they could be the same detector and the gas supply system 44 can be adjusted to operate with a ventilator or a spontaneously breathing patient.

Those of skill in the art will readily recognize the numerous adaptations and modifications which can be made to the pharmaceutical gas delivery system and to the method of supplying a pharmaceutical gas of the present invention, which will result in an improved method and system for introducing a known desired amount of a pharmaceutical gas in a patient, even all of which are within the scope and spirit of the present invention as defined in the following claims. Accordingly, the invention should be limited only by the following claims and their equivalents.