U.S. patent application number 15/887246 was filed with the patent office on 2018-06-07 for apparatus and method for generating nitric oxide in controlled and accurate amounts.
The applicant listed for this patent is NitricGen, Inc.. Invention is credited to Duncan P.L. Bathe, Cory Casper, Tye Gribb, Frederick John Montgomery.
Application Number | 20180155197 15/887246 |
Document ID | / |
Family ID | 48044382 |
Filed Date | 2018-06-07 |
United States Patent
Application |
20180155197 |
Kind Code |
A1 |
Montgomery; Frederick John ;
et al. |
June 7, 2018 |
Apparatus and Method for Generating Nitric Oxide in Controlled and
Accurate Amounts
Abstract
A nitric oxide generator generates nitric oxide from a mixture
of nitrogen and oxygen such as air treated by a pulsating
electrical discharge. The desired concentration of nitric oxide is
obtained by controlling at least one of a frequency of the
pulsating electrical discharge and duration of each electrical
discharge pulse.
Inventors: |
Montgomery; Frederick John;
(Sun Prairie, WI) ; Casper; Cory; (Monona, WI)
; Bathe; Duncan P.L.; (Fitchburg, WI) ; Gribb;
Tye; (Fitchburg, WI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NitricGen, Inc. |
Fitchburg |
WI |
US |
|
|
Family ID: |
48044382 |
Appl. No.: |
15/887246 |
Filed: |
February 2, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15372552 |
Dec 8, 2016 |
9896337 |
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15887246 |
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14347479 |
Mar 26, 2014 |
9573110 |
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PCT/US2012/058564 |
Oct 3, 2012 |
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15372552 |
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61542400 |
Oct 3, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J 2219/0801 20130101;
H05H 1/50 20130101; B01J 2219/0852 20130101; B01J 20/28047
20130101; B01J 2219/0883 20130101; C01B 21/203 20130101; B01D 53/02
20130101; H04L 9/30 20130101; B01J 19/088 20130101; B01J 20/20
20130101; B01J 20/22 20130101; H05H 1/46 20130101; A61K 33/00
20130101; B01J 2219/0809 20130101; B01J 2219/0869 20130101; B01D
46/00 20130101; B01J 20/103 20130101; B01J 2219/0875 20130101; B01J
2219/0894 20130101; B01J 2219/0815 20130101; C01B 21/32 20130101;
B01D 46/0084 20130101; B01J 2219/0826 20130101; B01J 20/08
20130101; B01J 20/041 20130101 |
International
Class: |
C01B 21/20 20060101
C01B021/20; B01J 20/20 20060101 B01J020/20; B01D 46/00 20060101
B01D046/00; B01D 53/02 20060101 B01D053/02; H04L 9/30 20060101
H04L009/30; B01J 20/28 20060101 B01J020/28; B01J 20/22 20060101
B01J020/22; A61K 33/00 20060101 A61K033/00; B01J 20/10 20060101
B01J020/10; B01J 20/08 20060101 B01J020/08; B01J 20/04 20060101
B01J020/04; B01J 19/08 20060101 B01J019/08 |
Claims
1. An apparatus for generating nitric oxide comprising: a reaction
chamber enclosing two electrodes separated by a gap, a gas inlet
port for introducing a gas mixture containing oxygen and nitrogen
into said reaction chamber, an electronic control circuit for
delivering a pulsed DC electric discharge between the two said
electrodes to generate nitric oxide; a magnetic field generator
proximate to said gap between the electrodes; and a gas outlet port
for delivering the gas mixture from said reaction chamber.
2. The apparatus of claim 1 wherein the magnetic field generator is
a permanent magnet.
3. The apparatus of claim 1 wherein the magnetic field generator is
two permanent magnets, one on each side of the gap.
4. The apparatus of claim 1 wherein the magnetic field generator is
an electric coil, which is energized by an electric current to
provide the magnetic field.
5. The apparatus of claim 1 wherein the magnetic field generator is
four permanent magnets, two on each side of the gap.
6. The apparatus of claim 1 wherein the electronic control circuit
is configured to control a pulse frequency of the pulsed DC
electric discharge and to control a pulse duration of the pulsed DC
electric discharge independent of the pulse frequency to produce a
desired concentration of nitric oxide.
7. The apparatus of claim 6 wherein the electronic control circuit
is configured to provide a substantially constant current during
the electrical discharge.
8. The apparatus of claim 1 further including a user input control
communicating with the electronic control circuit configured to set
a desired concentration of nitric oxide by a user.
9. The apparatus of claim 1 further including a flow device
communicating with the electronic control circuit to provide a
known gas flow through the reaction chamber.
10. The apparatus of claim 9 wherein the flow device is selected
from the group consisting of: a flow sensor measuring gas flow from
an external regulated source to produce the known gas flow, a pump
system operating to produce the known gas flow without flow
sensing, and a pump system with a flow sensor system providing
feedback control of the pump system to produce the known gas
flow.
11. The apparatus of claim 9 wherein the electronic control circuit
is configured to determine and control the pulse frequency and
pulse duration of the pulsed DC electric discharge according to a
nitric oxide concentration setting and a known gas flow provided by
the flow device to produce a desired nitric oxide
concentration.
12. The apparatus of claim 1 further including a nitrogen dioxide
filter attached to the gas outlet port for receiving the gas flow
therefrom and removing nitrogen dioxide.
13. The apparatus of claim 1 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
pulsed DC electric discharge to within a range of 0.1 and 100 Hz,
the pulse duration of the pulsed DC electric discharge within a
range of 20 microseconds and 500 milliseconds and an average
current during the electrical discharge within a range of 20 to
3000 milliamps.
14. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 0 and 45 Hz, and the pulse
duration of the electric discharge within a range of 0 milliseconds
and 5 milliseconds.
15. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0 milliseconds
and 4 milliseconds.
16. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0 milliseconds
and 2 milliseconds.
17. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0 milliseconds
and 1 millisecond.
18. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0 milliseconds
and 0.5 milliseconds.
19. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0 milliseconds
and 0.2 milliseconds.
20. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0.2
milliseconds and 4 milliseconds.
21. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0.2
milliseconds and 2 milliseconds.
22. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0.2
milliseconds and 1 millisecond.
23. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0.2
milliseconds and 0.5 milliseconds.
24. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0.5
milliseconds and 4 milliseconds.
25. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0.5
milliseconds and 2 milliseconds.
26. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0.5
milliseconds and 1 millisecond.
27. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 1 millisecond
and 4 milliseconds.
28. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 1 millisecond
and 2 milliseconds.
29. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 40 Hz, and the pulse
duration of the electric discharge within a range of 2 milliseconds
and 4 milliseconds.
30. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 1 and 5 Hz, and the pulse
duration of the electric discharge within a range of 0.5
milliseconds and 4 milliseconds.
31. The apparatus of claim 13 where the electronic control circuit
is configured to control at least one of the pulse frequency of the
electric discharge to within a range of 5 and 40 Hz, and the pulse
duration of the electric discharge within a range of 0.2
milliseconds and 4 milliseconds.
32. The apparatus of claim 1 where the electronic control circuit
includes a capacitor discharge circuit supplying a transient
current to a transformer to supply an initial voltage across the
electrodes sufficient to cause an electrical breakdown across said
electrode gap and a pulse duration control circuit with a
transistor to control the pulse duration of the electric discharge
and wherein the electronic control circuit includes an interface
circuit between said transformer and said transistor which includes
a high voltage diode to protect the transistor from high voltage
from said transformer and wherein said pulse duration control
circuit controls the transistor in a pulse width modulation mode to
control an average current during pulse duration phase of the
electric discharge and wherein the electronic control circuit
includes an inductor to smooth a pulse width modulated current from
said transistor prior to the electrode.
33. The apparatus of claim 1 further including a discharge sensor
for sensing the pulse duration.
34. The apparatus of claim 1 further including a lookup table
providing a desired concentration of nitric oxide as a function of
both pulse frequency and pulse duration.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional application of U.S. patent
application Ser. No. 15/372,552 filed Dec. 8, 2016 (U.S. Pat. No.
9,896,337, issued Feb. 20, 2018), which is a divisional application
of U.S. patent application Ser. No. 14/347,479 filed Mar. 26, 2014
(U.S. Pat. No. 9,573,110, issued Feb. 21, 2017), which is the
National Stage of International Application No. PCT/US2012/058564
filed Oct. 3, 2012, which claims the benefit of U.S. provisional
application 61/542,400 filed Oct. 3, 2011, each of which is hereby
incorporated by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
BACKGROUND OF THE INVENTION
[0002] This invention discloses a method and apparatus for the
production of nitric oxide (NO) in controlled and accurate amounts,
with low levels of impurities by controlling electric discharges
between two electrodes in an oxygen nitrogen gas mixture.
[0003] Nitric oxide is known to have many applications in
biological systems of both plants and animals.
[0004] In plants it is known that modifying the local atmospheric
concentration of nitric oxide can stimulate a number of beneficial
effects including, improved growth (U.S. Pat. No. 6,242,384),
reduction in seed dormancy (Bethke, 2006 and Sarath, 2006),
protection from fungal infections and disease (Lazar, 2008 and
Hong, 2007) and preservation of cut flowers and fruit (U.S. Pat.
Nos. 6,451,363 and 6,720,017).
[0005] In medical applications, gaseous nitric oxide administered
to the patient is known to have multiple applications as disclosed
in the following examples.
[0006] Anti-microbial: Nitric oxide has been demonstrated to reduce
bacterial infections as shown during in-vitro testing (Ghaffari,
2006) and in clinical applications such as skin tissue infections
(Ghaffari, 2007) and cystic fibrosis lung infections (Sagel,
2009).
[0007] Wound Healing: Nitric oxide has been demonstrated to improve
healing times in both sterile and infected wounds (Shekhter,
2005).
[0008] Hemoglobinopathy: (U.S. Pat. No. 5,885,621) with application
in sickle cell disease, where nitric oxide significantly reduced
pain associated with vaso-occlusive crisis in sickle cell patients
as compared to placebo (Head, 2010).
[0009] Selective pulmonary vasodilatation: (U.S. Pat. No.
5,485,827) with application in hypoxic respiratory failure of the
newborn, where nitric oxide therapy selectively dilates the
pulmonary vasculature and improves oxygenation, with no negative
impact on systemic blood pressure (Clark, 2000).
[0010] Anti-inflammatory: (U.S. Pat. No. 6,656,452) with
application in reducing ischemia reperfusion injury and the infarct
size after myocardial infarction (Liu, 2007).
[0011] It is clear that with all these potential commercial
applications that make use of the biological effects of nitric
oxide, there needs to be an apparatus to deliver nitric oxide in an
accurate and controlled amount that is reliable and efficient. One
issue that has to be taken into account when considering a method
of nitric oxide delivery is that of nitrogen dioxide (NO.sub.2)
generation. Nitric oxide, when in the presence of oxygen, reacts to
form nitrogen dioxide, which is am irritant to biological systems.
To resolve this issue, there are two main approaches for generating
and then controlling the delivery of nitric oxide to biological
systems. A first approach is to produce nitric oxide from chemical
precursors, for example, through the oxidation of ammonia and to
store the nitric oxide with a diluent gas that does not contain
oxygen (the gas used is normally nitrogen) in a high pressure
cylinder. As the nitric oxide is needed, a delivery system (for
example, a metering valve) controls the flow of nitric oxide gas
from the cylinder to provide the amount of nitric oxide needed for
any given application. The benefit of this approach is that it is
relatively easy to control the amount of nitric oxide gas needed
for a specific application and the purity of the nitric oxide can
be ensured by a well controlled production process in a centralized
production manufacturing location. The main problem with this
approach is that the cylinders of compressed nitric oxide gas are
large and heavy and are logistically difficult and expensive to
ship from the centralized location to the site of application.
[0012] A second approach is to generate the nitric oxide gas
in-situ from room air, using a controlled electric discharge to
ionize the gas at a locally higher temperature to form a plasma,
where oxygen and nitrogen in the air break down and reform to
produce nitric oxide. This nitric oxide generating approach has the
advantage that it does not have the logistical problems of the gas
cylinder storage method. It is however, more difficult to
accurately and controllably produce the required amounts of nitric
oxide with the required purity.
[0013] Before providing a description of the invention an overview
of background art will be described.
[0014] The use of electric discharges to produce nitric oxide in a
plasma reaction has a long history, a good summary of which is
included in U.S. Pat. No. 4,287,040 by Alamaro. This early prior
art was focused on the bulk production of nitric oxide as an
intermediary to the production of nitrogen based fertilizers and
describes a process that is not concerned with the accuracy, purity
and safety of the nitric oxide generated.
[0015] U.S. Pat. No. 5,396,882 (Zapol) was the first to disclose a
system for producing nitric oxide by electric discharge for use in
medicine. In this method, there is an electrically insulated
reaction chamber where a high voltage circuit is used to induce an
electric arc discharge between two electrodes that are separated by
an air gap to produce nitric oxide. The patent discloses gas
filters in the inlet conduit to the reaction chamber to remove
liquid droplets or solid particles from entering the reaction
chamber, and a soda lime filter in the outlet conduit of the
reactor chamber for removing impurities such as nitrogen dioxide
that may be formed in the plasma along with the nitric oxide. Also
described is a gas analyzer such as a chemiluminescence analyzer
for measuring the amount of nitric oxide produced. The high voltage
circuit includes a step up transformer, which takes standard AC
power of 110V and 60 Hz (230V and 50 Hz in Europe) in the primary
coil, and steps up the voltage so that the peak voltage is
sufficient to induce an electric arc across the electrode air gap.
There is a capacitor on the secondary side of the transformer,
which is charged up to the breakdown voltage, and subsequently
discharged across the gap when the breakdown voltage is reached.
The current to the primary side of the transformer is regulated by
an autotransformer (Variac), which controls the power to the
capacitor and hence on to the electric arc discharge. The current
from the capacitor is not controlled once break down voltage has
occurred, and this results in an arc discharge which is quick and
intense with a high current and high gas temperatures. The system
describes producing nitric oxide continuously and controls the
amount generated by controlling the current to the transformer, it
also describes controlling the amount of diluting gas flow to
provide the desired concentration.
[0016] There are a number of problems with this type of system
which include: electric arc discharges cause high current at high
temperatures which cause vaporization of the electrode material
which leads to excessive wear of the electrodes. Electrode wear is
a function of the intensity of the discharge across the electrodes,
which translates into the higher the current the higher the
electrode wear. The high temperature can also result in higher
levels of nitrogen dioxide being formed, which is not desired in a
number of biological applications. In addition, due to the
electrode wear, the amount of nitric oxide generated in this system
is not accurately predictable over periods of time and it requires
a nitric oxide gas analyzer to ensure the expected amount of nitric
oxide is being generated accurately. A gas analyzer adds expense,
bulk and requires the user to calibrate it prior to use, which
makes it undesirable for an optimum nitric oxide generation system.
The patent discloses a filter for removing nitrogen dioxide from
the nitric oxide gas mixture. However the soda lime filter material
disclosed has a finite life, and if it is not changed when the life
of the filter material is exhausted, the system would allow the
nitrogen dioxide to be delivered to the biological system, and this
could result in harm to the biological system.
[0017] In EP 0719159 (Jacobson), the problem of high energy arc
discharges eroding the electrodes was addressed by disclosing a
method of controlling the current across the air gap to a low level
to produce a "glow discharge" to produce nitric oxide. The
invention described multiple ways of initiating the glow discharge
such as; using a separate high voltage spark circuit, reducing the
pressure in the chamber or initially bringing the two electrodes
closer together to initiate the spark. Once the glow discharge was
established it was continuously maintained. To control the nitric
oxide concentration to be delivered to the biological system the
nitric oxide output was diluted with additional gas flow. The
disadvantages of this approach are that there is a limited range of
current that allows a glow discharge to be formed, and once formed
the glow discharge needs to be continuously maintained. This limits
the controllable range of the nitric oxide that can be produced.
The required nitric oxide concentration to the biological system is
achieved through diluting the nitric oxide flow from the reactor
chamber with an additional diluting gas flow. However, this means
both the gas flow rate and nitric oxide concentration cannot be
controlled independently. If lower concentrations of nitric oxide
at low gas flow rates are required, then a large portion of the
nitric oxide generated is discarded resulting in low efficiency of
operation and an additional apparatus associated with safely
disposing of the unused nitric oxide gas flow.
[0018] U.S. Pat. Nos. 6,296,827 & 6,955,790 (Castor, et al.)
disclose an alternative approach to avoiding electrode wear due to
high energy arc discharges. These patents disclose an apparatus
where a dielectric barrier material covers one of the electrodes
and a corona discharge is produced in high frequency discharge
pulses to avoid electrode wear. The reactor chamber has to be
operated between 400.degree. C. and 800.degree. C. so the
non-thermal plasma generates nitric oxide instead of nitrogen
dioxide (NO.sub.2). The device also discloses the use of a catalyst
operated at an elevated temperature to convert any NO.sub.2 formed
to nitric oxide. The temperature in the reactor is kept below
800.degree. C. to avoid electrode erosion caused by oxygen radicals
and above 400.degree. C. to avoid NO.sub.2 being formed instead of
nitric oxide. The apparatus disclosed that the nitric oxide gas
flow is diluted by additional gas to produce the desired
concentration of nitric oxide that is needed clinically. The
disadvantage of this apparatus is that it requires extra electrical
power to heat the gas to 400.degree. C. to 800.degree. C. and then
requires the gas to be actively cooled after the reactor chamber
before it can be used clinically. This significantly increases the
power and complexity of the apparatus. It also has the same problem
as EP 0719159, in that it provides a limited controllable range of
nitric oxide being produced, and also relies on gas dilution to
produce the desired nitric oxide concentration. Therefore it has
the same limitation as described in EP 0719159 in that in some
applications, it will result in unwanted nitric oxide gas flow that
will need to be discarded resulting in inefficient operation and
the need for additional apparatus for the safe disposal of the
unused nitric oxide.
[0019] U.S. Pat. No. 7,498,000 (Pekshev, et al.) discloses a device
for forming a nitric oxide containing gas flow using a continuous
stationary DC arc discharge. The arc discharge is maintained at a
constant voltage level of approximately 120V at 2.3 A, which
maintains an arc temperature of 3500.degree. K to 4000.degree. K.
The gas flow is then quenched in a water ethanol cooled chamber
where it is rapidly cooled to approximately 1000.degree. K to fix
the nitric oxide that was generated in the arc discharge, it then
goes on to a further cooling area where it is cooled to a
temperature of 150.degree. C. before it exits the outlet. The arc
discharge is initiated with a high voltage spark discharge from a 5
kV circuit, and uses a stabilization electrode to maintain the arc
discharge. The nitric oxide gas concentration at the apparatus
outlet is shown in FIG. 14 as 4,000 ppm nitric oxide, and the
concentration is shown to decrease as a function of the distance
from the outlet, dropping to about 500 ppm nitric oxide at a
distance of 200 mm. This drop in nitric oxide concentration is due
to the gas mixing with ambient air, and means a large part of the
nitric oxide generated never gets to the intended biological
target. It also means the user has to be very careful about the
distance of the apparatus outlet to the biological target so the
intended nitric oxide concentration is delivered correctly. The
apparatus disclosed has the same problems as previous art in that
the amount of nitric oxide generated is not well controlled and
relies on wasteful dilution of the nitric oxide prior to delivery
to the biological target. In addition there is no effort made to
remove harmful NO.sub.2 that will also be formed in the arc
discharge.
[0020] The prior art have the following disadvantages:
[0021] 1) The prior art does not disclose apparatus that can
control the amount of nitric oxide over a wide range of gas flows
and nitric oxide concentrations so that the device can be used for
multiple distinct dosing regimens depending on the target
application.
[0022] 2) The prior art does not disclose apparatus that allows for
a wide range of nitric oxide outputs without requiring additional
gas flow dilution. This results in excess nitric oxide generation
that has to be safely disposed of, causing extra cost and
complexity.
[0023] 3) The prior art that uses high voltage electric arc
discharges to generate nitric oxide has high electrode wear due to
electrode vaporization caused by the intense electric arc
discharges.
[0024] 4) The prior art that uses corona discharges require high
reaction chamber temperatures to be maintained that needs
additional power, and then require gas cooling systems to bring the
gas flow back down to acceptable temperature levels prior to
administration, thus adding to the cost, complexity and poor
efficiency of the system.
[0025] 5) None of the prior art provides a simple way of monitoring
the correct functioning of the arc discharge so the amount of
nitric oxide generated can be accurately predicted.
[0026] 6) None of the prior art discloses a consumable filter for
removing NO.sub.2 and other adulterants from the nitric oxide gas
flow that when consumed, can provide the nitric oxide apparatus
with a means of alerting the user that it needs to be replaced.
SUMMARY OF THE INVENTION
[0027] The present inventors have identified the above
disadvantages and the invention described in this specification
provides solutions to the above disadvantages and discloses methods
and apparatus for the accurate production of nitric oxide over a
wide range of output in a reliable and efficient way.
[0028] A feature of at least one embodiment of the invention is to
provide an improved apparatus and method for the generation of
nitric oxide using a gas plasma produced by electric discharges
across two electrodes, which overcome the disadvantages previously
described in the prior art. In solving the disadvantages of the
previously described prior art, the invention makes it particularly
appropriate for treating biological systems with nitric oxide that
is both accurately controlled and that ensures low levels of
impurities.
[0029] At least one embodiment of the invention includes a reactor
chamber with a gas inlet for a gas flow of air, or other oxygen and
nitrogen containing gases, to enter the reactor chamber, two
electrodes separated by a gap, an electronic control circuit
connected to the electrodes to generate an electric discharge
across the gap to produce nitric oxide, and an outlet for the
nitric oxide containing gas mixture to exit the chamber.
[0030] One embodiment of the invention produces nitric oxide in
accurately controlled amounts over a wide range of gas flow rates
and nitric oxide concentrations by controlling one or both of the
pulse frequency (number of complete electric discharges per second)
and/or the pulse duration (length of each complete electric
discharge) of electric pulse discharges across the electrode gap.
The amount of nitric oxide generated is proportional to both the
frequency and the duration of the electric pulse discharges and so
either one by itself of in combination with the two can provide a
wide control range of nitric oxide generation.
[0031] In one embodiment of the invention, the electronic control
circuit starts each electric discharge pulse with a short phase of
high voltage to initially ionize the gases and to allow electric
current to start flowing across the electrode gap, this is then
followed by a second phase of the pulse, which is of a lower
voltage and current. In one embodiment of the invention, the first
high voltage phase of the pulse is kept to a small period of time
that is just long enough to initially ionize the gases between the
electrodes and to allow electric current to flow in the electrode
gap. In the second phase of the pulse the voltage and the current
is reduced to lower values and this phase corresponds to the
adjustable duration phase of the electric pulse discharge. In one
embodiment of the invention the apparatus is designed so that the
majority of the nitric oxide is generated during the more efficient
second phase. There are a number of stable voltage and current
combinations that can be used in this second phase of discharge and
they have different advantages and disadvantages. This type of
electric discharge with intermittent pulse operation with
controlled frequency and/or duration at a controlled, predominantly
low current provides benefits including:
[0032] It produces nitric oxide efficiently by only producing the
amount of nitric oxide needed for the application without the need
for additional diluent gases.
[0033] It produces nitric oxide without significant increase in the
temperature of the gases going to the biological system and
therefore does not need cooling apparatus.
[0034] It significantly reduces electrode wear due to vaporization
of the electrode because the average electric current is low.
[0035] The low current and intermittent pulse electric discharge
generates nitric oxide efficiently without generating high levels
of NO.sub.2.
[0036] Another desired feature of at least one embodiment of the
invention is to generate nitric oxide more efficiently with lower
power consumption. One novel approach used in one embodiment of the
invention to improve the nitric oxide generating efficiency is to
provide a magnetic field across the electrode gap. This can be
achieved by using either electric coils or permanent magnets to
provide the magnetic field across the electrode gap. With a
magnetic field crossing perpendicular to the gap, an increase in
the quantity of nitric oxide generated of up to 45% for the same
electric discharge pulse settings was shown. Specific examples of
improved efficiency will be given in the detailed description
section of the invention.
[0037] Another feature of a nitric oxide generation apparatus
useful with biological systems is that undesirable changes in the
amount of nitric oxide generated may be anticipated to alert the
user to the alarm condition. The alarm can be an audio or visual
indicator or an external signal so that corrective action can be
taken such as getting a replacement nitric oxide generation system.
Examples of the typical kind of failures that can cause the nitric
oxide generation apparatus to stop functioning or to only produce
partial nitric oxide output are as follows:
[0038] The electrode gap becomes larger due to wear over time.
[0039] The electrical insulation in the high voltage circuit breaks
down and causes the electric charge to leak to ground without
passing through the electrodes.
[0040] A component failure in electronic control circuit due to
electromagnetic pulses from the electric discharges.
[0041] A power supply failure to the electronic control
circuit.
[0042] The gas flow through the reaction chamber is higher or lower
than desired.
[0043] In the prior art this was achieved with a nitric oxide gas
monitor, however the problem with this approach is that gas
monitors are complex, bulky and require periodic calibration by the
user adding to the overall complexity of use. In one embodiment of
the invention the need for gas monitoring is alleviated by
independently monitoring the pulse frequency and pulse duration of
the electric discharge in the reaction chamber and having a flow
sensor to redundantly monitor the gas flow through the reaction
chamber. The basic physics of gas plasma reactions is well
understood and if there is an independent sensor that monitors the
frequency and the duration of the electric discharge pulse then the
correct amount of nitric oxide being generated can be accurately
predicted. A number of different sensing technologies can be used
to independently monitor the electric discharge.
[0044] The discharge monitor sensor can be a photodiode in optical
connection to the reaction chamber, which monitors the light
generated by the electric discharge. The frequency and duration of
the light emitted by the electric discharge pulse and detected by
the photodiode will be in proportion to the electric discharge
pulse. If there is not a discharge pulse, or if it is intermittent,
or a different duration, then the photodiode will detect the
malfunction and cause an alarm. In one embodiment, the photodiode
may be used to provide feedback correction of the electric
discharge pulse to ensure consistent arc length and duration.
[0045] The discharge monitor sensor can also be an electric current
or voltage sensor that monitors the electric current or voltage
across the electrode gap when the pulse occurs to determine the
frequency and duration.
[0046] The discharge monitor sensor could also be a field effect
(Hall Effect) transducer that monitors the magnetic field or flux
across the electrode gap when the discharge pulse occurs. The
transducer can monitor magnetic field/flux that occurs when an
electrical discharge pulse is taking place, and its frequency and
duration can be monitored and an alarm generated if a malfunction
has occurred.
[0047] As well as monitoring the electric discharge is producing
the correct amount of nitric oxide, the apparatus may also monitors
the air flow rate through the reaction chamber with a gas flow
sensor. This ensures that the nitric oxide generated by the
apparatus is being delivered from the reaction chamber to the
biological system at the require flow rate. If the apparatus is set
to deliver a specific gas flow rate at a specific nitric oxide
concentration, then the combination of the discharge monitor sensor
(to determine the amount of nitric oxide being produced) and the
gas flow sensor can be used to ensure the nitric oxide
concentration is correct to the set level and provide an alarm if
incorrect.
[0048] Another requirement is that adulterants such as NO.sub.2 are
kept at acceptable levels when nitric oxide is being delivered to a
biological system. Previous prior art have described filters that
can be attached to the outlet of the device that can either convert
NO.sub.2 to nitric oxide or to remove NO.sub.2 from the gas stream.
The problem with these filters is they have a finite life that is
dependent on how much NO.sub.2 they are exposed to. If the user
does not replace them when they are consumed, then the biological
system may be unintentionally exposed to levels of adulterants that
can cause harm to the biological system. One embodiment of the
invention provides a novel way to ensure that the user is informed
when the filter is approaching its expiry limit and when it is
fully expired. It may also stop delivering nitric oxide when the
filter is expired if the biological system is especially sensitive
to the levels of NO.sub.2 that may be present without the
filter.
[0049] One embodiment of the nitric oxide generation apparatus has
a machine readable and programmable interface between the apparatus
and the filter and this interface communicates with a non-volatile
programmable and readable memory device located in the filter
assembly. The filter memory device can be programmed during
manufacturing with a number of parameters that can be read by the
nitric oxide generation apparatus when it is attached to the
device. These parameters can include the capacity of the filter in
hours, or in hours per quantity of nitric oxide (NO.sub.2 is
produced in amounts proportional to the amount of nitric oxide
generated) that is being delivered, and that the filter has been
shown to remove adulterants effectively. As the filter is consumed,
the filter programmable memory is updated with data that allows the
remaining capacity of the filter to be determined by the nitric
oxide generation apparatus. For instance, the filter memory can be
updated periodically with the new current filter capacity based on
the original filter capacity and the amount of time the nitric
oxide generation apparatus has been in use at a particular nitric
oxide setting. This means the filter always has an accurate
representation of the remaining capacity programmed into the filter
memory. This has the advantage that a completely used up filter can
not be accidentally put on the same or even a different device at
some point in the future resulting in the biological system getting
exposed to high levels of adulterants. There are a number of
programmable memory technologies that could be used for this
function. Two examples include EEPROM (electrically erasable
programmable read only memory) and FLASH, which was developed from
EEPROM and must be erased in fairly large blocks before these can
be rewritten with new data. One embodiment of this invention uses
an EEPROM with a serial interface for reading and reprogramming the
memory. Another embodiment uses a micro-controller which includes
EEPROM and FLASH memory and communicates to the nitric oxide
generator device by a serial interface. However, the invention is
not meant to be limited to these specific types of memory
technology and could equally apply to other types of programmable
memory.
[0050] As well as the filter life/capacity parameter there can also
be other useful parameters programmed into the filter that can
greatly simplify the setup and use of the apparatus. One set of
parameters that could also be programmed into the filter memory can
be related to the dosing information for the particular biological
system treatment regime. This could include the dose setting in
nmoles/sec, ppm at the desired flow rate through the reaction
chamber to the nitric oxide applicator, and the treatment time for
which the dose should be applied. The filter (with memory) can be
packaged and attached to the nitric oxide applicator for a
particular application so a user can simply open the applicator
package and connect it to the nitric oxide generation apparatus.
All the dose settings would be read automatically from the filter
memory when it is attached to update the apparatus settings prior
to use. Each application could have a custom applicator that is
optimized for that biological system with the correct sized filter
for the required dose and duration. The dose parameters can in some
cases be set to zero if the biological application is to be used in
a blinded placebo controlled study where some subjects would get
nitric oxide and some would only get a flow of gas. In these cases
the apparatus display would not display the actual dose setting but
would be blank or loaded with a dummy setting so the user would not
know which dosing regimen they were on. For added protection
against un-blinding a study, these dose parameters could be
encrypted at the factory and then de-encrypted by the device when
the filter was connected. The encryption would prevent users from
effectively reading the filter dose parameters with a memory
programming tool prior to use. This means a single nitric oxide
generating apparatus can have wide spread application with no
changes to the device itself, with only the nitric oxide
applicators being customized for the specific biological
system.
[0051] Another set of parameters that can be programmed into the
filter memory that are specific to individual biological systems
can revolve around the proper functions of the apparatus. These
parameters can set what alarms will be present for different
detected conditions, and whether they will involve audible and/or
visual alarms and/or if the device should stop generating nitric
oxide and stop gas flow through the reaction chamber when these
conditions occur. The conditions that can be detected by the
apparatus can include the following possible fault conditions:
[0052] 1) The flow through the reaction chamber is lower or higher
than the set value.
[0053] 2) The NO.sub.2 filter has no hours/capacity left or is
approaching that condition.
[0054] 3) The electric discharge pulses are not at the desired
frequency or duration for the dose setting resulting in either too
high or too low doses to the biological system.
[0055] The filter memory can be programmed with not only what type
of alarm should be activated when these conditions occur but also
the alarm limits that will cause the alarms to be initiated. This
can allow very sensitive biological systems that need very tight
dosing specifications to have tight alarm initiating limits and
those that only require loose limits can have them set
accordingly.
[0056] Yet another set of parameters that can be programmed into
the filter memory are what user adjustable settings may be active
on the nitric oxide generating apparatus user interface. For
instance some biological systems may require the dose to be slowly
reduced over time as the biological system responds to treatment,
or depending on the size of the biological system, the gas flow
rate through the chamber may need to be adjusted for the different
system size. In another option, it may be advantageous to allow the
user to set the alarm limits for the gas flow or the nitric oxide
concentration. The description in this specification of the
possible parameters that can be stored in the filter memory for a
given custom biological system application is not meant to be
exhaustive but allows the concept of custom parameters to be
described.
BRIEF DESCRIPTION OF THE FIGURES
[0057] FIG. 1 is a cross-sectional view of the reactor chamber
showing the main components of the reactor chamber design.
[0058] FIG. 2 is a schematic diagram of the nitric oxide generator
showing the components of the system and their electrical and
pneumatic connections.
[0059] FIG. 3 is an electronic schematic of the pulsed electric
discharge drive circuit.
[0060] FIGS. 4 is a graph that illustrates the wide performance
range of the system with the amount of nitric oxide being generated
varying from 0.27 to 711 nanamoles/second nM/s.
[0061] FIG. 5 is a graph that illustrates the improved generation
of nitric oxide when a magnetic field is used in the design.
[0062] FIG. 6 is a graph that illustrates the removal of NO.sub.2
by a filter.
[0063] These figures will now be described in more detail.
DETAILED DESCRIPTION OF THE INVENTION
[0064] In the following detailed description the term "air" will be
used to generally describe the oxygen and nitrogen gas mixture used
in reactor chamber to generate nitric oxide, but also other gas
mixtures containing oxygen and nitrogen that may have been produced
from alternative gas sources such gas cylinders that are commonly
used in anesthesia machines and may include alternate
concentrations.
[0065] FIG. 1 shows the nitric oxide reactor chamber 1 with a
reactor housing 2 which has a reactor gas inlet port 8 and a first
electrode 12 on one side and a reactor gas outlet port 10 and a
second electrode 20 on the other side. The electrodes can be
insulated with non-electrically conducting material 14 and 22 if
the chamber housing is made of a material that is electrically
conducting. The electrodes can have an electrode tip 16 and 24 made
of a material that is resistant to high temperatures and is less
susceptible to vaporization, oxidization and wear. Materials for
the electrode tips can be selected from the Nobel metal group of
the periodic table that includes tungsten and platinum. The
electrodes are connected to the electronic control circuit with the
insulated electrical cables 18 and 26.
[0066] In one embodiment of the invention the reactor chamber can
have magnets 30 and 32 located on the reactor housing 2 so they are
adjacent to the air gap between the electrodes 12 and 20, each
magnet with the opposite pole facing the chamber so they reinforce
the magnetic field across the air gap. One embodiment of the
invention has a magnet on each side of the air gap although a
single stronger magnet that exerts the same magnetic field strength
across the air gap is equally applicable. The magnetic field across
the air gap is believed to cause dispersal of the electrical
discharges across the air gap, which results in a larger plasma
cross-sectional area and more efficient generation of nitric oxide.
In one embodiment the magnets are rare earth magnets made from
neodymium iron and boron. In testing, the addition of magnets
resulted in approximately 45% more nitric oxide being generated for
exactly the same pulse discharge settings as without magnets (FIG.
5).
[0067] The reactor housing 2 can have a port 34 that allows a
photodiode 38 to be in optical communication with the inside of the
reactor chamber 1. The optical communication can be provided so the
photodiode is mounted directly to the port 34 in the reactor
housing or more preferably a fiber optic cable 36 is mounted to the
reactor chamber port and then to the photodiode so said photodiode
can be located away from the reactor chamber and the electrical
disturbances cause by the pulse electric discharges. The photodiode
38 provides a signal that is proportional to the light energy
falling on its active surface. When the pulsed electric discharges
occur, light is generated in the ionized plasma and the photodiode
detects this light. The light signal from the photodiode occurs at
the same frequency and pulse duration as the electric discharge as
long as the discharge takes place.
[0068] FIG. 2 is a schematic diagram of the nitric oxide generator.
There are three main subsystems that make up the nitric oxide
generator, the nitric oxide generator unit 50, the outlet filter
assembly 78 and the nitric oxide applicator 84. The nitric oxide
generator unit is where the nitric oxide is generated in controlled
amounts and where it is delivered to the generator gas outlet port
76. The generator unit 50 has a main electronic control circuit 60
that interfaces to the main electrical components of the system and
provides the main system control features. In one embodiment of the
invention this is a microprocessor based control circuit executing
a stored program held in a non transitory medium, but it is not
intended to limit the invention only to microprocessor based
control circuits, analog circuits could also be used. Attached to
the electronic control circuit are the main user controls
comprising of an input setting unit 52 a visual display unit 54, a
visual alarm indicator 56 and an audible alarm sounder 58, these
components are used to provide the desired settings to the main
control, display any preprogrammed settings that may have been
automatically set from the preprogrammed filter memory and provide
audible and visual alarms when there are fault conditions. The main
components in contact with the air flow though the device are, the
generator gas inlet 62 where the air is drawn into the unit, the
inlet filter 64 which is used to filter the air and remove any
unwanted contaminants, the air pump 66 is used to draw the air in
from the gas inlet port 62 and to adjust the amount of air flow
that is passed through the reactor chamber 1 under the control of
the electronic control circuit 60. If the air pump 66 provides
un-calibrated control of the gas flow, a gas flow meter 70 can be
used to provide the electronic control circuit an accurate
indication of the gas flow so the pump can be finely adjusted by
the electronic control circuit 60 until the gas flow is at the
desired set value. If the gas pump 66 provides oscillatory gas flow
output as in the case of a piston pump then a damping chamber 68
can be provided to smooth out the oscillations. The gas flow then
passes through the reaction chamber 1 where the electric control
circuit 60 controls the frequency and duration of the electric
discharges across the electrodes 12 and 20 such that nitric oxide
is generated in the air passing through the chamber. The gas
leaving the reaction chamber 1 passes through a second flow meter
72, which is used by the electronic control circuit to provide an
independent check that the flow through the reaction chamber is
correct. If there has been a failure in the gas pump 66 (indicated
by a zero flow rate) or the first flow meter 70 or 72 (indicated by
different readings between flow meter 70 and flow meter 72) such
that the gas flow through the reaction chamber is not correct, then
the electronic control circuit can initiate a visual and/or audible
alarm to alert the user to the failure. To detect if there has been
a failure in the electric discharge circuits there is the
photodiode 38 and/or the electrode current and/or voltage sensing
circuit 61 that are connected to the electronic control circuit 60,
which can determine if the right frequency and pulse duration has
been achieved. After the outlet gas flow meter 72 there is an
optional pressure trigger sensor 74 connected to the gas flow
conduit 73. This pressure trigger sensor 74 can be used by the
electronic control circuit 60 to control the nitric oxide delivery
as a bolus (when the pressure trigger sensor is activated) rather
than as a known concentration in a continuous gas flow rate of air.
The different modes of delivery will be described in more detail
later in the specification. The gas flow continues past the
pressure trigger sensor 74 to the gas outlet port 76, where it
connects to the outlet filter assembly 78 and out through the
nitric oxide applicator 84, where it is applied to the biological
system 92.
[0069] The outlet filter assembly 78 has an inlet filter port 80,
which connects to the gas outlet port of the nitric oxide generator
unit 50, a chamber containing adulterant filter material 82, and an
outlet port 86, which connects to the nitric oxide applicator 84.
Adulterant filter materials include materials such as soda lime,
activated charcoal, activated alumina and silica gel soaked in
ascorbic acid. These materials and others known in the art to
remove NO.sub.2 from gases containing nitric oxide while leaving
the nitric oxide levels substantially unchanged may be used.
[0070] Such materials may have a fixed capacity for removing or
converting NO.sub.2 before there effectiveness is consumed and they
therefore require replacing after a period of use. The size of the
filter and the amount of NO.sub.2 they are exposed to will impact
the usage time before they need replacing. The filter assembly 78
in addition includes a readable programmable memory 90, which
connects to the nitric oxide generator unit through a filter
electrical connection 88. The other side of connector 88 connects
to the electrical control circuit 60 where the readable
programmable memory 90 can be read and reprogrammed by the
electrical control circuit 60 as the filter is consumed. One
embodiment of the readable programmable memory is an EEPROM, which
has a serial interface for reading and programming the memory. An
alternative embodiment is where each individual EEPROM (and hence
filter assembly) has its own unique identifier included in a small
amount of read only memory (ROM). An example of this type of memory
is part number 24AA02E48T from Microchip Technology, this is a 2
KBIT EEPROM with each memory chip having its own MAC address
permanently programmed into a small section of read only memory.
This type of EEPROM with its unique identifier programmed into ROM
means that no two filter assemblies will have the same identifier
and the identifier will not be able to be updated during use as can
occur with the data in the EEPROM memory. This can provide
additional protection against reusing spent filters, as individual
filter identifiers can be stored in the nitric oxide generator when
they are used and then the generator will prevent filters with the
same identifiers being used in the future for example, as might
occur if the EEPROM usage data were improperly altered by a
corrupted system. An alternative embodiment is where a
micro-controller with embedded EEPROM and FLASH memory is used
instead of just a serial memory device. This embodiment has the
advantage that the reprogramming of the memory can be performed
locally by the micro-controller and reduce the processing overhead
of the electronic control circuit 60. An example of this type of
micro-controller is the ATtiny25/45/85 from Atmel.
[0071] Generally the EEPROM, may store usage information obtained
from the electronic control circuit 60 that reveals the historical
concentrations of NO being produced and thus the likely exhaustion
rate of the filter 82. Thus, when the filter 82 is used for high NO
concentrations and/or high flow rates this will be recorded and the
user instructed to replace the filter more frequently than if the
filter 82 is used for low NO concentration and/or low flow rate
applications. This exhaustion information may be derived both from
the concentration value determined by the electronic control 60 and
the flow rates determined from flow sensors 72 and 70. The EEPROM
may also include a proprietary code indicating that it is
authorized equipment preventing spoofing of the apparatus with
devices that may not provide the desired filtering. The proprietary
code may, for example, use any number of techniques including
public-key encryption techniques that prevent easy duplication of
spurious codes.
[0072] FIG. 3 shows a schematic of the electric discharge drive
circuit that is part of the electronic control circuit 60. This
represents one embodiment of the drive circuit and people of
ordinary skill in the art will appreciate there are other circuit
possibilities that can achieve the same function. To establish the
high voltage required to initially ionize the air between the
electrodes 12 and 20, a capacitor discharge circuit 116 discharges
current through a transformer 118 when triggered by a pulse trigger
controller 114. This results in a high voltage on the other side of
the transformer 118 which is sufficient to cause dielectric
breakdown and ionize the gas and initiate current across the
electrodes 12 and 20. The discharge pulse duration is maintained by
a second circuit, which is powered by a high voltage DC power
supply 100. In the case that the instantaneous current draw is
high, the DC power supply 100 is buffered by a capacitor 102 to
smooth out any high current fluctuations. The DC voltage and
current is controlled on or off by a transistor 104 that is
controlled by a pulse duration control circuit 112 which controls
the pulse duration by controlling the on time of the transistor.
The drive circuit functions as follows, the electronic control
circuit 60 calculates the desired electric discharge frequency and
pulse duration that will generate the desired quantity of nitric
oxide, it then triggers each discharge with the pulse trigger
controller 114 which causes a quick high voltage pulse from the
transformer 118, at the same time the electronic control circuit
turns on the transistor 104 for the desired pulse duration with the
pulse duration control circuit 112. The resulting pulse discharge
voltage across the electrodes is the desired initial high voltage
spike to ionize the gas between the electrodes followed by the
desired lower voltage and current for maintaining the desired pulse
duration. The actual voltage and current can be controlled by the
electronic control circuit 60 if the pulse duration control circuit
112 works in a pulse width modulation (PWM) mode during the on
phase of the pulse discharge. If this PWM mode is used it is
desirable to use an inductor 108 to smooth out the modulated
current during the electric discharge pulse. The interface circuit
110 joins the two control circuits prior to applying the discharge
voltage to the electrode. It is desirable that this interface
circuit 110 use high voltage diodes to prevent the high voltage
spikes from the pulse transformer damaging the transistor 104. The
diode 106 provides an additional mechanism that grounds any high
voltage spike greater than its breakdown voltage or negative
transients from getting to the pulse duration control circuit 112.
It can be appreciated that this circuit provides a great deal of
flexibility in controlling not only the pulse frequency and the
pulse duration but also the voltage and current levels during the
pulse duration phase of the electric discharge. This allows the
electronic control circuit to optimize the electric discharge
frequency and pulse duration settings to maximize the effectiveness
at generating the desired quantity of nitric oxide while at the
same time minimizing the electric discharge current and so reducing
the gas temperature and the electrode wear.
[0073] The pulses of electric discharge can be controlled over a
wide range depending on the nitric oxide requirements; a frequency
range of 0.1 to 100 Hz with the pulse duration range between 0.1 to
10 milliseconds (ms) has been demonstrated. FIG. 4 shows a graph of
nitric oxide output in nM/s against the discharge frequency (Hz)
for different pulse duration intervals from 0 up to 4 ms. It shows
nitric oxide being generated from 0.27 nM/s at 1 Hz and zero
injection up to 711 nM/s at 22 Hz and 4 ms of injection. This
example was where the high voltage DC power supply was at 1,000
volts and the pulse duration control circuit operated in PWM mode
so that the current across the electrodes was approximately 60 mA.
These parameters can be programmed into the electronic control
circuit, for example in a lookup table, so based on the required
rate of nitric oxide generation, the correct frequency, duration
and PWM control can be used. The values in the lookup table which
map desired concentration to the correct frequency and duration of
the arc may be determined empirically. In practice this means that
nitric oxide concentrations can be generated and controlled over
the wide range of concentrations of 1 to 1000 ppm in a flow rate in
the range of 0.5 to 2 L/min depending on the requirement of the
biological system being treated.
[0074] A further improvement of at least one embodiment of the
invention is the use of a magnetic field to increase the amount of
nitric oxide generated by the apparatus. FIG. 5 shows a graph of
the nitric oxide output from the apparatus in nM/s versus discharge
frequency (Hz) for different magnetic fields. The parameters used
for these tests were exactly the same (PWM was set for electrode
voltage 120V at a current 400 mA), with the only difference being
the number of magnets adjacent to the electrode gap. As can be seen
the nitric oxide output increases by approximately 45% when four
1/2'' diameter rare earth magnets, two on each side of the chamber
housing, are used in the design compared to no magnets. It is clear
from FIG. 5 that as the number of magnets (and hence the magnetic
field) increase, the amount of nitric oxide being generated also
increases.
[0075] The mode of operation will have some differences depending
on the type of biological system and what kind of dosing is
required. There may be some modes where the gas flow through the
system is at a constant flow rate and a constant concentration of
nitric oxide for the application is required. In others a bolus
mode of delivering the gas flow to the biological system may be
desired so an intermittent known quantity of nitric oxide is
required, for example nM/pulse. The intent is to be flexible so as
to cover all the main permutations of these delivery modes and how
this is achieved is covered in the following.
[0076] In general the electronic control circuit 60 gets the
desired setting for the nitric oxide dose from the user setting
unit 52, the readable programmable memory 90 on the filter assembly
78 or if it is a nitric oxide generator that is only configured for
one specific application with one dosing level then from the
electronic control circuit's 60 internal memory. The dose setting
selected can be displayed on the display unit 54 so the user knows
the dose level that is to be delivered.
[0077] The dose setting can be in different units depending on the
mode of delivery, it can be set as a concentration such as parts
per million (ppm) or micro liters per liter (uL/L), or it can be
set as a quantity per unit of time such as nanomoles per second
(nM/s) or nanomoles per minute (nM/min) or it can also be in terms
of a quantity of nitric oxide to be delivered per event which will
be described later in the specification. The dose setting entered
into the electronic control circuit 60 determines the required
pulse frequency and pulse duration of the electric discharge to
produce nitric oxide at the required rate.
[0078] If the dose setting was set as a concentration of nitric
oxide at a desired airflow rate Q then the amount of nitric oxide
in nM/s required to be generated in the gas flow can be calculated
by equation 1.
rNO=(Q/60)(C.sub.NO*1000)/Vm Equation 1
[0079] Where rNO is the rate of nitric oxide productionnM/s
[0080] Q is the gas flow rate (L/min)
[0081] C.sub.NO is the concentration of nitric oxide(ppm)
[0082] Vm is the mole volume (approx 24.8 L/M at 25.degree. C. 1
atm)
[0083] Once the rate of nitric oxide (rNO) has been calculated from
the input settings, the required electric discharge frequency and
pulse duration can be determined by the electronic control circuit
using the previously determined relationship between the parameters
(example FIG. 4) as enrolled in a lookup table in computer memory
or implemented algorithmically by an equation in computer memory.
The required gas flow rate (Q) through the chamber is delivered
from the gas pump 66 under the control of the electronic control
circuit 60. The flow meter 70 provides a signal proportional to the
gas flow to the electronic control circuit 60, which adjusts the
gas pump control until the desired gas flow is achieved. The use of
an air pump to provide the gas flow through the chamber is not the
only means to provide the gas flow and it is being used as an
example. For instance if the air supply was from a pressurize
pipeline or a gas cylinder then a control valve could be used to
control the flow of gas instead of the air pump. Also, if it was
required to add nitric oxide into an air flow stream that was being
controlled by another external device, then no control valve or air
pump would be required, in this case the gas flow meter 70 would be
used to provide the electronic control circuit with the measurement
of the air flow rate so the rate of nitric oxide generation can be
determined. If the external flow control device has means to
electronically communicate the gas flow measurement to the
electronic control circuit then even the gas flow meter 70 is not
needed for the correct functioning of the apparatus. With the
desired gas flow rate established and the required electric
discharge frequency and pulse duration determined the electronic
control circuit 60 can initiate electric discharges across the
electrodes 12 and 20 and the nitric oxide containing gas will flow
out through the gas outlet port 76.
[0084] When in the bolus mode of nitric oxide delivery, the input
setting unit 52 will be used to enter the nitric oxide as a known
quantity of nitric oxide in units such as nano-moles (nM) or
micrograms (.mu.g) and also the volume of the gas to deliver the
nitric oxide to the biological system. The electronic control
circuit will determine the number and the duration of electric
discharges required to produce that quantity of nitric oxide, and
the bolus of nitric oxide will be generated and delivered when the
pressure trigger sensor 74 is activated. One embodiment of the
pressure trigger sensor 74 is a pressure transducer with an
adjustable limit to set the level that the trigger is activated.
The pressure transducer can measure both positive and negative
pressure relative to ambient and the trigger to initiate the bolus
delivery can also be a positive or negative pressure.
[0085] For example, delivering nitric oxide to a cystic fibrosis
patient where the application is to combat their lung infection. If
the patient is breathing spontaneously and the nitric oxide
applicator is a nasal cannula connected to the patient's nose, then
as the patient breathes in, the pressure in the nitric oxide
applicator will go negative relative to ambient and the pressure
trigger sensor would need a negative pressure trigger setting to
trigger the bolus so it goes to the patients lung during
inspiration. However, if the patient is on a positive pressure
ventilator which has positive pressure in the breathing circuit
during inspiration, then the trigger setting limit would require a
positive pressure setting to trigger the bolus during inspiration.
When the pressure trigger sensor 74 is activated, the electronic
control circuit 60 initiates the electric discharge pulses required
to generate the nitric oxide set on the input setting unit 52 and
in addition the gas pump 66 is turned on to deliver the desired
volume of gas set by the input setting unit 52 or programmable
memory 90, once the volume of gas has been delivered the gas pump
is turned off again. In this way a bolus of gas is delivered to the
biological system each time the pressure trigger sensor 74 is
activated and the bolus of gas contains the desired set quantity of
nitric oxide. In the case of a patient breathing normally in and
out, the bolus of nitric oxide gas could be delivered to the
patient at each breath. The nitric oxide gas leaves the nitric
oxide generating unit at the gas outlet port 76 and goes through
the outlet filter assembly 78. The filter assembly 78 is attached
to the outlet port 76 and the gas will flow through the filter 82
where adulterants such as nitrogen dioxide (NO.sub.2) are removed.
As an example of the effective performance of a filter in removing
adulterant's an activated charcoal filter with 0.54 grams of
material was assembled into a filter housing, the gas concentration
of nitric oxide and nitrogen dioxide were analyzed over time before
and after the filter assembly. The conditions for the filter
performance testing were 225 ppm of nitric oxide at 2 L/min with 12
ppm of nitrogen dioxide in the gas mixture. FIG. 6 shows a graph of
the filter efficiency over time, efficiency being defined as the
percent of nitrogen dioxide in the gas being removed. The filter
efficiency remained over 80% after 300 minutes of continuous use
under these test conditions.
[0086] After the filter, the nitric oxide gas flow passes into the
nitric oxide applicator 84, which conducts and applies the nitric
oxide to the biological system 92. There is a wide range of designs
of nitric oxide applicators that can be tailored for the wide range
of potential applications in a wide range of biological systems. A
few of the different types of nitric oxide applicator will be
described to provide examples of the different types of
applications that can be supported by the nitric oxide generation
device:
[0087] A piece of tubing, with a diffuser on the distal end that
directs the nitric oxide gas flow directly to the surface of the
biological system. An example is a tube with a diffuser to apply
nitric oxide to a non-healing wound such as a diabetic ulcer.
[0088] A simple tube that connects to a chamber with the biological
system present. Examples include a chamber that holds dormant wheat
seeds that can be brought out of dormancy by exposure to nitric
oxide or the chamber may be a sterilizing chamber where articles
that are contaminated with bacterial or fungus can be sterilized by
exposure to nitric oxide.
[0089] A tube with a squeeze bulb in series that connects via a
probe into a chamber, which contains the biological system. The
probe is connected to the package and the bulb is squeezed which
triggers the pressure trigger sensor in the device to deliver a
bolus of nitric oxide gas in to the package. Example, the chamber
could be a gas tight plastic bag that holds a modified atmosphere
to ship cut flowers (e.g. tulips) and extend the life of the
product during shipping.
[0090] A tube connecting to a nasal cannula or a face mask that
attaches to a patients nose/mouth to treat a patient with a lung
infection such as occurs in cystic fibrosis. The gas flows from the
nitric oxide applicator could be continuous flow at a set
concentration or it could be pulsed as a bolus when the patient
breathes in or out and triggers the pressure trigger to deliver the
bolus.
[0091] A tube that connects to a ventilator breathing system
attached to a patient with a lung infection that triggers a bolus
of nitric oxide when the pressure in the circuit increases during
inspiration and triggers a bolus delivery of nitric oxide.
[0092] These examples are not meant to include a comprehensive list
of all possible nitric oxide applicators but to give a general view
of the wide potential of applications the nitric oxide generation
apparatus can be used for.
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