U.S. patent application number 13/751355 was filed with the patent office on 2013-10-17 for system and method for improving outcome of cerebral ischemia.
The applicant listed for this patent is ASTUCE, INC.. Invention is credited to Denise Barbut, Axel Heinemann, Allan Rozenberg.
Application Number | 20130273179 13/751355 |
Document ID | / |
Family ID | 49323954 |
Filed Date | 2013-10-17 |
United States Patent
Application |
20130273179 |
Kind Code |
A1 |
Barbut; Denise ; et
al. |
October 17, 2013 |
SYSTEM AND METHOD FOR IMPROVING OUTCOME OF CEREBRAL ISCHEMIA
Abstract
A method for improving outcome following cerebral ischemia is
provided. The method includes delivering nitric oxide into the
nasal cavity for absorption into the brain through the nasal
vasculature and preventing the inhalation of nitric oxide into the
lungs to prevent pulmonary vasodilatation.
Inventors: |
Barbut; Denise; (New York,
NY) ; Rozenberg; Allan; (San Diego, CA) ;
Heinemann; Axel; (New York, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ASTUCE, INC. |
San Diego |
CA |
US |
|
|
Family ID: |
49323954 |
Appl. No.: |
13/751355 |
Filed: |
January 28, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61624484 |
Apr 16, 2012 |
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61660793 |
Jun 17, 2012 |
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61661712 |
Jun 19, 2012 |
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61705910 |
Sep 26, 2012 |
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61712572 |
Oct 11, 2012 |
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61718396 |
Oct 25, 2012 |
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61751538 |
Jan 11, 2013 |
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Current U.S.
Class: |
424/718 ;
604/26 |
Current CPC
Class: |
A61M 2016/0039 20130101;
A61M 16/0479 20140204; A61K 33/00 20130101; A61M 13/003 20130101;
A61B 17/12136 20130101; A61B 17/24 20130101; A61M 16/12 20130101;
A61M 2202/0275 20130101; A61B 17/12181 20130101; A61M 16/0461
20130101; A61M 2016/1035 20130101; A61B 17/1204 20130101; A61M
16/0672 20140204; A61M 31/00 20130101; A61B 17/12104 20130101; A61B
17/12031 20130101; A61B 17/12099 20130101; A61B 17/12159 20130101;
A61K 9/0043 20130101; A61M 2210/0618 20130101; A61M 16/0459
20140204; A61M 16/0486 20140204 |
Class at
Publication: |
424/718 ;
604/26 |
International
Class: |
A61K 33/00 20060101
A61K033/00; A61B 17/12 20060101 A61B017/12 |
Claims
1. A method for improving outcome following cerebral ischemia
comprising: delivering NO into the nasal cavity for absorption into
the cerebral vasculature through the nasal vasculature, wherein
said outcome following cerebral ischemia is improved.
2. The method of claim 1 wherein delivering NO into the nasal
cavity is done solely into the nasal cavity.
3. The method of claim 1 further comprising preventing the
inhalation of NO into the lungs.
4. The method 3 wherein preventing the inhalation of NO into the
lungs prevents a reduction in pulmonary vasodilatation.
5. The method of claim 3 wherein preventing the inhalation of NO
into the lungs does not significantly altering the systemic
arterial levels of the NO or of its metabolites.
6. The method of claim 1 wherein delivering NO into the nasal
cavity is done in the absence of oxygen to prevent oxidation of
NO.
7. The method of claim 1 wherein said cerebral ischemia is caused
by stroke, TIA, traumatic brain injury, cardiac arrest, seizure,
complicated migraine, memory impairment, shock, vasospasm and
combinations of the foregoing.
8. The method of claim 1 wherein said outcome following cerebral
ischemia is improved by neuroprotection.
9. The method of claim 1 wherein said outcome following cerebral
ischemia is improved by increasing cerebral blood flow.
10. The method of claim 3 wherein preventing the inhalation of NO
into the lungs is accomplished while simultaneously allowing
inhalation of air into the lungs through the nose.
11. The method of claim 1 wherein delivering NO into the nasal
cavity is independent of the respiratory cycle.
12. The method of claim 1, wherein a flow rate of NO is between
1-10000 mL/min.
13. The method of claim 1, wherein said delivering of NO is between
1 second and 30 days.
14. The method of claim 1, further comprising occluding the nasal
cavity anterior to the choana and posterior to the site of
delivering said NO and allowing the concentration of NO to build up
in the nasal cavity.
15. The method of claim 1, further comprising providing an elongate
tubular member for delivering said NO.
16. The method of claim 14, wherein occluding the nasal cavity is
done by inflatable expandable member.
17. The method of claim 1 wherein said delivering NO into the nasal
cavity is done through one side of the nasal cavity or both sides
of the nasal cavity.
18. The method of claim 17 wherein said delivering NO into one side
of the nasal cavity comprises occluding a same side of the nasal
cavity.
19. The method of claim 1, wherein occluding the nasal cavity
includes occluding with a rigid member, an expandable member, a
compressible member, a sponge, a porous member, a plug, a balloon,
foam or combinations of the foregoing.
20. The method of claim 1, wherein a concentration of nitric oxide
is between 1 and 1000 ppm.
21. The method of claim 1, further comprising continuously or
intermittently delivering said NO.
22. The method of claim 1, further comprising diluting NO with one
or more gases prior to said delivering or simultaneously with said
delivering to form a mixture of gases.
23. The method of claim 22, further comprising providing an
elongate tubular member including one or more lumens for delivering
said one or more gases.
24. The method of claim 22, wherein the gases are selected from
air, nitrogen, oxygen, argon, helium, anesthetic gases, xenon,
nitrous oxide, other respiratory gases and combinations of the
foregoing.
25. The method of claim 22, wherein a concentration of each gas can
be individually controlled.
26. The method of claim 22, wherein delivering said NO is
controlled by feedback from monitoring a physiologic parameter.
27. The method of claim 26, wherein said physiologic parameter is
selected from cerebral blood flow, cerebral oxygen, cortical
electrical activity, cerebrospinal fluid marker and combinations of
the foregoing.
28. The method of claim 22, wherein the mixture of gases is at or
above room temperature during said delivering.
29. The method of claim 22, wherein the mixture of gases is
humidified prior to or during said delivering.
30. The method of claim 22, wherein delivering said NO is
controlled by feedback from monitoring of intranasal NO
concentration.
31. A method for improving outcome following cerebral ischemia
comprising: delivering NO into the nasal cavity for absorption into
the brain through the nasal vasculature; and preventing the
inhalation of NO into the lungs to prevent reduction in pulmonary
resistance or pulmonary vasodilatation.
32. A method for improving outcome following cerebral ischemia
comprising: delivering NO into the nasal cavity for absorption into
the brain through the nasal vasculature; and preventing the
inhalation of NO into the lungs without significantly altering the
systemic arterial levels of the NO or of its metabolites wherein
said outcome following cerebral ischemia is improved.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a system and method for
improving outcome following cerebral ischemia. In particular, the
invention involves intra-nasally delivered nitric oxide for direct
absorption into the cerebral circulation.
BACKGROUND OF THE INVENTION
[0002] Stroke occurs when focal cerebral ischemia is severe,
prolonged or both. Brain tissue where cerebral blood flow is under
17 mls/min/100 g dies within a minute or two (core), tissue with
blood flow 18-50 mls/min/100 g is viable for up to 30 minutes, and
tissue with higher blood flow is potentially viable indefinitely
(penumbra). Any procedure which increases perfusion to within the
penumbral range may salvage brain tissue indefinitely. Cerebral
perfusion augmentation early in the ischemic event has been shown
to reduce infarct size and improve outcome from stroke in animal
models. There are numerous methods for attempting to increase
cerebral perfusion but the hemodynamic effect on actual cerebral
perfusion has been inconsistent, and several of them have increased
the risk of cerebral hemorrhage.
[0003] None of the existing techniques has yet been shown to
improve outcome from stroke in human randomized trials. Moreover,
mechanical methods designed to augment perfusion are invasive
procedures requiring trained personnel, and they cannot be
administered early in the course of the ischemia. Improvements over
conventional therapies are thus desirable. In particular what is
needed is a therapy that is non-invasive and easily administrable
by first responders early in the course of ischemia.
BRIEF SUMMARY OF THE INVENTION
[0004] The shortcomings of conventional therapies are overcome by
the apparatus and method for improving outcome following cerebral
ischemia in a patient in accordance with the invention.
[0005] The novel invention includes the use of nitric oxide gas
delivered intranasally for direct absorption into the cerebral
circulation through the nasal vasculature in patients with cerebral
ischemia.
[0006] In one aspect of the invention a method for improving
outcome following cerebral ischemia includes delivering nitric
oxide into the nasal cavity for absorption into the cerebral
vasculature through the nasal vasculature, wherein said outcome
following cerebral ischemia is improved.
[0007] In another aspect of the invention a method for improving
outcome following cerebral ischemia includes delivering nitric
oxide into the nasal cavity for absorption into the brain through
the nasal vasculature; and preventing the inhalation of nitric
oxide into the lungs to prevent pulmonary vasodilatation.
[0008] In a further aspect of the invention a method for improving
outcome following cerebral ischemia includes delivering nitric
oxide into the nasal cavity for absorption into the brain through
the nasal vasculature; and preventing the inhalation of nitric
oxide into the lungs such that systemic arterial levels of nitric
oxide or of its metabolites are not significantly altered.
[0009] In another aspect of the invention a method for improving
outcome following cerebral ischemia includes delivering nitric
oxide into the nasal cavity for absorption into the cerebral
vasculature through the nasal vasculature; and maintaining nitric
oxide in the nasal cavity, to augment its effect on the cerebral
circulation.
[0010] In a further aspect of the invention a method of improving
outcome following cerebral ischemia includes delivering nitric
oxide into the nasal cavity for direct absorption into the brain
through the nasal vasculature; and maintaining nitric oxide in the
nasal cavity to prevent significantly increasing the systemic
arterial levels of the nitric oxide or of its metabolites.
[0011] In a further aspect of the invention a system for improving
outcome following cerebral ischemia is provided. The system
includes a source of a gas comprising nitric oxide; an elongate
tubular member for insertion into a nose including at least one
orifice thereon, the tubular member operably coupled to the source
of a gas, the elongate tubular member configured for delivering the
nitric oxide into a nasal cavity through the at least one orifice
for absorption into a cerebral vasculature through a nasal
vasculature; and a means for controlling flow of the gas, a
concentration of the nitric oxide in the gas, or both, wherein the
outcome following cerebral ischemia is improved.
[0012] In a further aspect of the invention a system for improving
outcome following cerebral ischemia includes a source of a gas
comprising nitric oxide; an elongate tubular member for insertion
into a nose including at least one orifice thereon the tubular
member operably coupled to the source of a gas, the elongate
tubular member configured for delivering the nitric oxide into a
nasal cavity through the at least one orifice for absorption into a
cerebral vasculature through a nasal vasculature; a first occlusive
member for occluding the nasal cavity anterior to the at least one
orifice; and a means for controlling flow of the gas, a
concentration of the nitric oxide in the gas, or both, wherein the
outcome following cerebral ischemia is improved.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] For a better understanding of the invention, and to show how
the same may be carried into effect, reference will now be made, by
way of example, to the accompanying drawings, in which:
[0014] FIG. 1 is an illustration depicting an intranasal delivery
catheter including a plurality of lumens in accordance with the
invention.
[0015] FIG. 2 is an illustration depicting an intranasal delivery
catheter including a plurality of lumens and further depicting
posterior nasal occlusion in accordance with the invention.
[0016] FIG. 3 is an illustration depicting an intranasal delivery
catheter including a plurality of lumens and further depicting
anterior nasal occlusion in accordance with the invention.
[0017] FIG. 4 is an illustration depicting an intranasal delivery
catheter including a plurality of lumens and further depicting a
posterior and anterior nasal occlusion in accordance with the
invention.
[0018] FIG. 5 is an illustration depicting an intranasal delivery
catheter showing a plurality of lumens and further depicting an
external anterior nasal occlusion in accordance with the
invention.
[0019] FIG. 6 is an anatomical side view of an intranasal delivery
catheter including posterior nasal occlusion in a nasal cavity in
accordance with the invention.
[0020] FIG. 7 is a schematic diagram of a means for controlling gas
flow and concentration in accordance with the invention.
[0021] FIG. 8 is a graph demonstrating doubling of cerebral blood
flow in intubated rodents using cortical laser Doppler during
intranasal administration of nitric oxide.
[0022] FIG. 9 is a Speckle laser Doppler tracing showing a
reduction of cerebral ischemia in intubated rodents given
intranasal nitric oxide.
[0023] FIG. 10 is a CT perfusion scan before and after treatment
with intranasal nitric oxide in a human with focal cerebral
ischemia showing improvement in cerebral perfusion following
treatment.
[0024] FIG. 11 is a CT perfusion scan before and after treatment
with intranasal nitric oxide in a human with focal cerebral
ischemia showing improvement in cerebral perfusion following
treatment.
DETAILED DESCRIPTION OF THE INVENTION
[0025] As used herein, cerebral ischemia should be understood in
its broadest sense and incorporate both focal and global cerebral
ischemia. Cerebral ischemia may be caused by stroke, transient
ischemia attack, traumatic brain injury, cardiac arrest, seizure,
complicated migraine, memory impairment, shock, vasospasm and
combinations of the foregoing.
[0026] Cerebral infarction occurs when cerebral ischemia is severe,
prolonged or both. The greater the ischemia, the faster infarction
occurs. Brain tissue with blood flow below a critical level (17-20
mls/mg/100 g) is referred to as the core and infarcts within
minutes. Tissue with blood flow between 18-50 mls/min/100 g is
viable for up to 30 minutes and tissue with a blood flow above 51
mls/min/100 g is potentially viable indefinitely. Brain tissue
which is salvageable surrounding the central core is referred to as
ischemic penumbra. Any procedure which increases perfusion from an
initial value of <20 mls/min/100 g to a value above 50
mls/min/100 g may salvage brain tissue. Cerebral perfusion
augmentation early in the ischemic event has been shown to reduce
infarct size and improve outcome from stroke in animal models.
Numerous methods have been described for augmenting cerebral
perfusion. Pharmacologic agents such as vasopressors elevate
systemic blood pressure but have inconsistent effects on cerebral
perfusion. Vasodilating agents such as nitroprusside and glyceryl
trinitrate can dilate cerebral vessels but do not improve cerebral
perfusion, because of the concomitant reduction in systemic blood
pressure. Intra-arterial nimodipine is used to treat vasospasm
following sub-arachnoid hemorrhage but requires the presence of an
interventional neuroradiologist and needs to be performed in a
catheterization lab setting. Thrombectomy is a mechanical method to
remove clot from an occluded vessel to improve flow in the ischemic
territory, but this technique is associated with high hemorrhage
rates into the core, especially in patients treated beyond the
first few hours of ischemia. Furthermore, vessel occlusion is not
visible angiographically in many patients. Partial aortic occlusion
at the level of the renal artery has also been shown to increase
cerebral perfusion during ischemia, and is not associated with
increased hemorrhage rates. Sphenopalatine ganglion stimulation may
also improve cerebral perfusion during ischemic events. None of the
techniques mentioned have yet been shown to improve outcome from
stroke in randomized trials. Furthermore, all the mechanical
methods mentioned are invasive procedures requiring trained
personnel. The benefit on stroke outcome from cerebral blood flow
augmentation is dependent on how early in the event treatment can
be initiated. Thus, novel treatments need to be non-invasive and
easily administrable by first responders to be beneficial for a
majority of stroke patients.
[0027] Stroke is a lay term to describe the consequence of focal
ischemia. Other examples of focal cerebral ischemia include
transient ischemic attacks, migraine and vasospasm following
aneurismal rupture. When ischemia affects the whole brain, it is
referred to as global cerebral ischemia and includes conditions
such as cardiac arrest, brain trauma, and seizures. Patchy,
regional cerebral blood flow reduction is also encountered in
patients with memory disorders. All of these conditions would
benefit from correction of the perfusion deficit in the ischemic
regions.
[0028] The inventors of the present application have discovered a
new non-invasive system and method for treating cerebral ischemia
and improving outcome from stroke. Nitric oxide gas is delivered
into the nasal cavity, for direct absorption through the nasal
vasculature into the adjacent cerebral circulation. The gas may be
prevented from being inhaled into the pulmonary circulation to
maximize the concentration in the nasal cavity and the brain, and
to prevent pulmonary vasodilation, systemic absorption, hypotension
or changes in coagulation.
[0029] The method of treating stroke in accordance with the
invention has not previously been described. The method in
accordance with the invention is non-invasive and avoids many of
the complications associated with nitric oxide inhalation while
enhancing its effect on the cerebral vasculature. In a first method
in accordance with the invention the vasodilator gas alone or in
combination with a second gas is delivered intra-nasally for
prolonged periods of time without reduction in pulmonary resistance
and without systemic absorption. The second gas may be selected
from the group consisting of hydrogen, xenon, oxygen, nitrogen,
nitrous oxide, other vasodilator gases, air and combinations of the
foregoing. The treatment selectively increases cerebral perfusion
and may also be neuroprotective in the treatment of cerebral
ischemia or cerebral trauma.
[0030] Nitric oxide is a neurotransmitter and a potent vasodilator
substance naturally made by vascular endothelium everywhere, and by
perivascular neurons in the brain. It plays a vital role in
maintaining and adjusting basal vascular tone systemically and in
the cerebral circulation. Changes in cerebral blood flow brought
about by CO2 or oxygen administration, and alternatively, by
somatosensory stimulation, are all mediated by intrinsic nitric
oxide. Conversely, intrinsic nitric oxide levels are diminished
during cerebral ischemia or trauma, because of endothelial
dysfunction. Replenishing nitric oxide to the cerebral vessels
during injury may improve the cerebral circulation and reduce the
damage caused by toxic metabolites. The foregoing may be achieved
by delivering extrinsic nitric oxide gas close to the cerebral
vessels.
[0031] Inhaled extrinsic nitric oxide is approved for use in
persistent pulmonary hypertension of the newborn, to dilate the
pulmonary vasculature. It is also widely used in adults in
respiratory failure from a variety of causes. Inhaled extrinsic
nitric oxide rapidly binds hemoglobin and is therefore effectively
neutralized as it enters the systemic circulation from the lungs.
This makes inhaled extrinsic nitric oxide a short-acting, selective
vasodilator in the pulmonary circulation. When sufficiently large
doses are inhaled, the small unbound fraction which becomes
dissolved in the blood can cause some degree of hypotension.
Furthermore, bleeding complications have been associated with
inhaled nitric oxide. In the context of cerebral ischemia, neither
of these is desirable. Hypotension may reduce cerebral perfusion
pressure rather than increasing cerebral blood flow, and an
increased bleeding tendency may cause hemorrhagic transformation of
an ischemic lesion.
[0032] The inventors have found that nitric oxide may be delivered
to the cerebral circulation directly to ensure sufficient amounts
reach these vessels during ischemia. Ideally, inhalation of
extrinsic nitric oxide into the pulmonary circulation is prevented,
because the majority of it would effectively "disappear" by binding
to hemoglobin, thus never reaching the vessels in the brain and
furthermore causing hypotension. Furthermore, the delivery method
should be non-invasive, such that it can be performed by first
responders in the setting of acute stroke. This will ensure that
all patients with stroke can receive treatment not only in the
emergency room but even in the ambulance. Most importantly, a
simple, non-invasive, safe method for increasing perfusion can be
administered very early during the course of the event, increasing
the likelihood of therapeutic success.
[0033] The nasal cavity is designed to filter out particulate
matter in inhaled air and to increase the temperature of inhaled
cold air, in addition to enabling smell. The convolutions in the
nasal conchae provide a large surface area over which this can
occur. Below the nasal mucosa, a rich plexus of arterio-venous
capillaries provide a means for temperature regulation as well as
gas exchange. This vascular plexus drains into the deep venous
plexus of the brain, and connects with the intracranial arterial
circulation. Gases entering the nasal circulation could thus enter
the cavernous sinus and the Circle of Willis directly, without
passing through the systemic circulation. nitric oxide is a soluble
gas, and when placed in the nasal cavity, may be absorbed directly
into the nasal plexus for delivery to the brain.
[0034] The inventors of the present invention have demonstrated
that intranasally delivered, non-inhaled nitric oxide augments
cerebral blood flow in rodents. Referring to FIG. 8, a graph
demonstrating the doubling of cerebral blood flow in intubated
rodents using cortical laser Doppler during intranasal
administration of nitric oxide is shown. In intubated rodents, the
inventors have shown that cerebral blood flow increases by 100%
within 60 minutes of intranasal nitric oxide delivery. The
inventors have also shown, in a carotid artery occlusion model,
that perfusion is improved in the ischemic hemisphere, both during
the carotid occlusion and following ligature release as best seen
in FIG. 9.
[0035] The inventors have also shown that gas treatment is
tolerated at high concentration in humans when delivered
intra-nasally and without inhalation. Furthermore, in intubated
patients with cerebral ischemia, the inventors have shown
augmentation of cerebral perfusion and normalization of regional
perfusion abnormalities during treatment with intranasal nitric
oxide using CT perfusion scanning. FIGS. 10 and 11 shown CT
perfusion scans before and after treatment with intranasal nitric
oxide in a human with focal cerebral ischemia showing improvement
in cerebral perfusion following treatment demonstrating the
foregoing.
TABLE-US-00001 TABLE 1 Improvement in perfusion with intranasal
nitric oxide Right Left Hemisphere Hemisphere Changes in ACA
(normal) (ischemic) Watershed Cerebral Pre Rx 49 31 37% lower on
Blood Flow ischemic side Post Rx 45 52 Normalization, 67% increase
in perfusion on L Mean Transit Pre Rx 6 10 4 sec delay Time (sec)
Post Rx 6.1 6.0 Normalization
[0036] Table I demonstrates an increase in cerebral blood flow in
the ischemic hemisphere following one hour of intranasal
non-inhaled nitric oxide, together with a reduction (normalization)
of mean transit time (MTT) of contrast material through the
ischemic hemisphere.
[0037] Given the magnitude of the cerebral blood flow response to
nasally delivered nitric oxide and the small volume of the nasal
cavity, the flow rates required to achieve moderate degrees of
cerebral blood flow increase are actually very low-much lower than
the concentration or volume required to achieve pulmonary
vasodilation. In respiratory disease, the concentration of approved
nitric oxide is up to 80 PPM at a minute volume of 6 L/minute. For
the purposes of cerebral ischemia, the concentrations might be as
low as 8 PPM or lower, more preferably 20 PPM or lower, more
preferably 40 PPM or lower, more preferably 60 PPM or lower, and
the volume of gas is of the order of milliliters rather than liters
per minute. Increasing cerebral blood flow too much or too fast
using nitric oxide might be deleterious in the treatment of stroke.
Therefore both of these variables need to be tightly monitored to
achieve the desired effect. Similarly, sudden discontinuation of
the gas (especially if given at low concentration or volume) might
decrease cerebral blood flow too fast and cause worsening of
symptoms. Lastly, the amount of inhaled nitric oxide needed to
increase cerebral blood flow is orders of magnitude higher than
intranasal nitric oxide because it binds hemoglobin in the lungs
and only tiny amounts ever reach the brain. Alternatively,
limitations to the amount of nitric oxide that can be given
systemically for fear of hypotension might well result in no or
very limited increases in cerebral blood flow.
[0038] Increase in cerebral blood flow is attributable to focal
intranasal or intra-oral effect of nitric oxide rather than to
systemic absorption of the gas. When air, rather than nitric oxide
is delivered intra-nasally and without inhalation, cerebral blood
flow does not increase as best seen in FIG. 9. The effect on
cerebral blood flow during intranasal delivery of nitric oxide with
concomitant air inhalation into the lungs is therefore a focal
effect on intranasal and intracranial vasculature attributable
specifically to nitric oxide. Nitric oxide delivered into the nasal
cavity did not enter the pulmonary circulation because both the
animals and human patients were intubated and access from the
nasopharynx or oropharynx to the trachea was mechanically blocked.
In a non-intubated patient, nitric oxide inhalation can be
prevented by occluding the nasal cavity anterior or posterior to
the site of gas delivery. This is achieved by means of an anterior
occlusion device such a rigid member, an expandable member, a
compressible member, a sponge, a porous member, a plug, a balloon,
foam and/or combinations of the foregoing, which prevent inhalation
through the nostrils while maintaining a high concentration of
nitric oxide in the nasal cavity. A non-intubated patient may be
allowed to inhale air into the lungs during nitric oxide delivery
into the nasal cavity by an optional central lumen with the distal
orifice beyond the sites of nasal gas delivery and occlusion
device. This focal trans-nasal penetration of nitric oxide to exert
cerebral vasodilation and cerebral blood flow increase has not been
previously demonstrated and is fundamental to the discovery set
forth in this patent.
[0039] While nitric oxide may be given intranasally and without
inhalation into the lungs to intubated, comatose individuals the
tolerability of intranasal nitric oxide in awake humans has not
previously been investigated. The inventors have tested the effect
of nitric oxide in humans (normal volunteers) during intranasal
delivery. Nitric oxide in concentrations up to 100 PPM does not
elicit any sensation during intranasal delivery. Therefore it can
easily be tolerated by awake, non-intubated patients.
[0040] The present invention delivers nitric oxide or a combination
of nitric oxide with other gases into the nasal cavity but prevents
its inhalation for the purposes of increasing cerebral blood flow
and improving outcome from cerebral ischemia. Those of skill in the
art will appreciate that other gases containing a combination of
nitrogen and oxygen may also be used. Inhalation can be prevented
by occluding the nostrils while delivering the nitric oxide to the
nasal cavity. Since the volume of the nasal cavity is only
approximately 150 mL, low flows are able to completely fill the
nasal cavity and still replenish any that may leak out via the
choana into the nasopharynx keeping the nitric oxide concentration
in the nasal cavity very near the concentration of the instilled
gas. For example, if 50 mL/min of 100 ppm nitric oxide is instilled
into the nasal cavity and the minute volume of the patient is 7.5
L/min, the effective concentration of nitric oxide getting to the
lungs assuming all occlusion mechanisms failed would still only be:
100.times.(50/7500)=0.67 ppm, which is <1% of that in the nasal
cavity.
[0041] The passage of the gases into the lungs may be prevented by
placing a nasal "clip" or otherwise occluding the entrance to the
nostrils, proximal to where the gas is delivered and delivering
small enough quantities which, even in the case of leakage, will be
so significantly diluted by respiratory gases to not have any
effect on the systemic circulation. In one aspect of the invention
using an anterior occlusion device, the gas may escape via a valve
or exit tube or be suctioned out into a vacuumed container.
[0042] In awake, non-intubated patients, the gas can be prevented
from entering the lungs by occluding the naris (or nares) posterior
to the gas delivery site. This can be achieved by means of
inflatable balloons or other similar occlusion devices as disclosed
herein. In an alternative embodiment, an intranasal delivery
catheter may consist of a wide-bore central lumen through which the
patient can inhale air into the lungs, while a smaller outer lumen
with pores/perforations proximal to the occluding balloon delivers
nitric oxide into the nasal cavity.
[0043] Referring now FIGS. 1 through 7, the system and method in
accordance with the invention will be described. FIG. 1 is an
illustration depicting first and second intranasal delivery
catheters 100 in accordance with the invention. First intranasal
delivery catheter 110 is used in one naris and second intranasal
delivery catheter 112 is used in the second naris. Each intranasal
delivery catheter 110, 112 includes a plurality of lumens
therewithin namely a lumen for the delivery of nitric oxide 114, an
optional lumen 116 for inflation of a posterior occlusion device
(not shown), a "breath through" or optional lumen for the delivery
of air to a patient's lungs 118 and optional suction lumen 120 for
removal of excess nitric oxide from the nasal cavity that has not
been absorbed directly into the cerebral vasculature. If suction
lumen 120 is included in the catheter delivery design then suction
orifices 122 are fluidly coupled to suction lumen 120 which in turn
may be coupled to a one-way valve. Nitric oxide orifices 124 (not
shown on intranasal delivery catheter 110) are fluidly coupled to
nitric oxide lumen 114 and a source of nitric oxide. As noted,
those of skill in the art will appreciate that the breath through
118 for delivery of air to a patient's lungs may be eliminated as
well as the suction lumen 120 depending on the particular delivery
catheter needed for any particular circumstance. Those of skill in
the art will appreciate that the number of nitric oxide and suction
orifices can be greater or fewer than as depicted in the FIGS. and
the size of the orifices may vary with the application. In
addition, suction orifices may be included on a first intranasal
delivery device while the nitric oxide orifices may be included on
the second delivery or they may be included on the same intranasal
delivery device. Many alternatives exist for the number and size of
the orifices and the present FIGS. are by way of illustration and
not of limitation.
[0044] Referring now to FIG. 2 an intranasal delivery catheter
depicting a posterior nasal occlusion in accordance with the
invention. Like features are numbered with like numerals. First
intranasal delivery catheter 210 is used in one naris and second
intranasal delivery catheter 212 is used in the second naris. Each
intranasal delivery catheter 210, 212 includes a plurality of
lumens therewithin namely a lumen for the delivery of nitric oxide
214, an optional lumen 216 for inflation of a posterior occlusion
device 226, a "breath through" or optional lumen for the delivery
of air to a patient's lungs 218 and optional suction lumen 220 for
removal of excess nitric oxide from the nasal cavity. If suction
lumen 220 is included in the catheter delivery design then suction
orifices 222 are fluidly coupled to suction lumen 220. Those of
skill in the art will appreciate that suction orifices 222 and
suction lumen 220 may be included on both delivery catheters 210,
212 or may be included on the first delivery catheter 210 while
being eliminated from the second delivery catheter 212 and vice
versa and still be within the scope of the invention. Similarly,
nitric oxide orifices 232 may be include on both delivery catheters
210, 212 or on one delivery catheter while being eliminated from
the other delivery catheter. The entire apparatus may also be
modified such that the gas is only delivered through one nostril
since such small volumes are required to increase cerebral blood
flow and cerebral vasodilation. In such a case, only one nostril
would need to be occluded to prevent inhalation, while the patient
would be free to breathe in the other nostril.
[0045] Nitric oxide orifices 224 (not shown on intranasal delivery
catheter 210) are fluidly coupled to nitric oxide lumen 214 and a
source of nitric oxide. As noted, those of skill in the art will
appreciate that one or both of the breath through 218 for delivery
of air to a patient's lungs and/or the suction lumen 220 may be
eliminated depending on the particular delivery catheter needed for
any particular circumstance. Posterior occlusion device 226 is
positioned at the distal end of the delivery catheters 210, 212
anterior to the choana and posterior to the nitric oxide orifices
224. When positioned in the nasal cavity of a patient, posterior
occlusion device 226 blocks any nitric oxide that may build up in
the nasal cavity from entering the nasopharynx and lungs as best
seen in FIG. 6. Posterior occlusion device 226 may comprise a rigid
member, an expandable member, a compressible member, a sponge, a
porous member, a plug, a balloon, foam and combinations of the
foregoing. Those of skill in the art will appreciate that if a
non-inflatable posterior occlusion device 226 is utilized, the
inflation lumen 216 in the catheter delivery device may be
eliminated.
[0046] Referring now to FIG. 3 an intranasal delivery catheter 300
depicting an anterior nasal occlusion in accordance with the
invention. Like features are numbered with like numerals. As noted
previously, first intranasal delivery catheter 310 is used in one
naris and second intranasal delivery catheter 312 is used in the
second naris. Each intranasal delivery catheter 310, 312 includes a
plurality of lumens therewithin namely a lumen for the delivery of
nitric oxide 314, an optional lumen 316 for inflation of an
anterior occlusion device 328 (in embodiments in which an
inflatable anterior occlusion device is utilized), a "breath
through" or optional lumen for the delivery of air to a patient's
lungs 218 and optional suction lumen 220 for removal of excess
nitric oxide from the nasal cavity. If suction lumen 220 is
included in the catheter delivery design then suction orifices 322
are fluidly coupled to suction lumen 220. Those of skill in the art
will appreciate that suction orifices 322 and suction lumen 320 may
be included on both delivery catheters 310, 312 or may be included
on the first delivery catheter 310 while being eliminated from the
second delivery catheter 312 and vice versa and still be within the
scope of the invention. Similarly, nitric oxide orifices 324 may be
include on both delivery catheters 310, 312 or on one delivery
catheter while being eliminated from the other delivery catheter
and one of the lumen for delivering the nitric oxide similarly
eliminated. Nitric oxide orifices 324 are fluidly coupled to nitric
oxide lumen 314 and a source of nitric oxide. As noted, those of
skill in the art will appreciate that one or both of the breath
through 318 for delivery of air to a patient's lungs and/or the
suction lumen 320 may be eliminated depending on the particular
delivery catheter needed for any particular circumstance. Anterior
occlusion device 326 is positioned at the proximal end of the
delivery catheters 310, 312 to occlude the nasal cavity anterior to
the nitric oxide orifices 324 and allows the nitric oxide to build
up in the nasal cavity but prevents it from exiting the nares.
Anterior occlusion device 328 may comprise a rigid member, an
expandable member, a compressible member, a sponge, a porous
member, a plug, a balloon, foam and combinations of the
foregoing.
[0047] Referring now to FIG. 4 another aspect of an intranasal
delivery catheter 400 depicting anterior and posterior nasal
occlusion devices 428, 426 in accordance with the invention is
shown. Like features are numbered with like numerals. Those of
skill in the art will appreciate that the intranasal delivery
catheter 400 depicted in FIG. 4 may be modified by the elimination
of certain elements and features as previously discussed and still
fall within the intended scope of the invention.
[0048] FIG. 5 depicts another aspect of an intranasal delivery
catheter 500 including an anterior occlusion device comprising a
mask 530. Like elements are numbered with like numerals. Those of
skill in the art will appreciate that the intranasal delivery
catheter 500 depicted in FIG. 5 may be modified by the elimination
of certain elements and features, such as the air breath through
lumen 518, suction orifices 522 and suction lumen 520 and/or the
first and/or second delivery catheters 510, 512 as previously
discussed and still fall within the intended scope of the
invention. Those of skill in the art will also appreciate that
anterior occlusion device 530 will allow minimal inhalation of
nitric oxide into the lungs. If it is desirable to prevent
inhalation of nitric oxide into the lungs a posterior occlusion
device (as best seen in FIGS. 2 and 4) may be added.
[0049] Turning now to FIG. 6 an anatomical side view including an
exemplary embodiment of an intranasal delivery catheter 610
including a posterior nasal occlusion device 632 positioned in a
nasal cavity 634 in accordance with the invention is depicted. As
can be seen intranasal delivery catheter 610 includes suction
orifices 636 and nitric oxide orifices 624. The buildup of nitric
oxide in the nasal cavity for absorption into the cerebral
vasculature through the nasal vasculature can be seen. Excess
nitric oxide is removed from the nasal cavity through suction
orifices 622 operably coupled to suction means on an external
control device (not shown). Posterior occlusion device 632 may
comprise a rigid member, an expandable member, a compressible
member, a sponge, a porous member, a plug, a balloon, foam or
combinations of the foregoing. Posterior occlusion device 632 is
positioned anterior to the choana and posterior to the nitric oxide
orifices 622 and the delivery of nitric oxide thus allowing the
concentration of nitric oxide to build up in the nasal cavity
without inhalation into the lungs.
[0050] Referring now to FIG. 7 a schematic diagram of a means for
controlling gas flow and concentration in accordance with the
invention is depicted. The means for controlling gas flow includes
a source of nitric oxide 740 fluidly coupled to the nitric oxide
lumen of the intranasal delivery catheter, an optional source of a
second gas 742, an optional vacuum means fluidly coupled to the
suction lumen in the intranasal delivery catheter in accordance
with the invention. Those of skill in the art will appreciate that
if a second gas is used then the source may be fluidly coupled to
the nitric oxide lumen of the intranasal delivery catheter for
delivery with the nitric oxide. Alternatively the source of second
gas 742 may be fluidly coupled to an additional "second gas" lumen
in the intranasal delivery catheter (not shown) where the mixing of
the two gases may occur inside the nasal to prevent oxidation of
nitric oxide during low flow delivery rather than in the intranasal
delivery catheter as above. The gases may be allowed to mix prior
to delivery or at the point of delivery. Volatile anesthetics,
arginine, an nitric oxide precursor, and other gases such as
hydrogen or nitrous oxide may also increase cerebral blood flow
when delivered into the nasal cavity.
[0051] A one way valve (not shown) may be included in the suction
line to prevent inhalation while allowing excess nitric oxide with
or without a second gas to be extracted from the nasal cavity with
optional suction means, as shown. The source of nitric oxide 740
and source of second gas 742 are each operably coupled to pressure
regulators 748, 750 and the vacuum means is coupled 744 is operably
coupled to vacuum regulator 752.
[0052] Mass flow controllers 754, 756, 758 are operably coupled to
the pressure regulators 748, 750 and vacuum regulator 752 and the
source of nitric oxide 740, source of second gas 742 and vacuum
means 744, respectively, to measure and control the flow of the
gases and vacuum. Electronic control means 746 is operably coupled
to mass flow controllers to monitor and control the flow of gas and
the concentration of gas being delivered to the intranasal delivery
catheter in accordance with the invention.
[0053] Those of skill in the art will appreciate that the system
and method in accordance with the invention may be modified to
incorporate a humidifier and warmer into the circuit to adjust the
humidity and temperature of the gas mixture.
[0054] Those of skill in the art will also appreciate that the
cerebral blood flow increase needs to be adjusted carefully.
Firstly, the degree of cerebral blood flow increase required will
vary from patient to patient, depending on the state and number of
existing patent collaterals, size of stroke, size of penumbral
tissue, degree of ischemia within the penumbra, time from symptom
onset and symptomatic relief. Should the presenting symptom be
hemiplegia, and should the hemiplegia recover with a 30% increase
in cerebral blood flow, then the flow rates and the gas
concentration required to get there needs to be maintained and not
increased. Similarly, should stable symptoms at a given gas dose
and cerebral blood flow increase suddenly start deteriorating; gas
dose (flow rate or concentration or both) should be increased. Or
if symptoms are stable for a while, gas dose should be reduced
until such level as symptoms recurred. This might mean switching
off the gas delivery altogether intermittently. The cerebral blood
flow may be measured using cerebral oximetry, other non-invasive
laser-Doppler techniques or transcranial Doppler, SPECT, CT or MR
perfusion or other imaging techniques. This information may be fed
back into the device and the dose adjusted accordingly. Cortical
activity may also be measured over the ischemic territory by MAG,
EEG, or other electrical measuring method and this information may
be fed back to adjust the dose of the gas. The discovery in this
instance is the coupling of cerebral blood flow increase and of
symptomatic relief to gas dosing regimen.
[0055] Furthermore, cerebral blood flow increase using intranasal
nitric oxide may be coupled with techniques which increase cortical
demand for blood, to further channel the increased delivery towards
the ischemic regions. Such techniques to increase cortical demand
may be peripheral stimulation in the affected domain, sensory,
motor, visual, auditory, and the like or it may be direct cortical
electrical or other stimulation over the affected cortex. In turn,
this may be achieved using transcortical magnetic stimulation or
ultrasound or epidural or subdural direct cortical stimulation. The
discovery in this instance is the coupling of nitric oxide delivery
to the cerebral blood flow or cortical electrical response
observed.
[0056] Cortical electrical activity is typically coupled to
regional blood flow. So cortical electrical activity may be
measured directly and fed back into the device to alter drug
delivery. Once cortical electrical activity normalized, the dose
maybe progressively reduced and even discontinued. Contrarily, if a
fairly normal cortical recording were to diminish or disappear or
become abnormal in some other way, the dose of drug delivery maybe
increased automatically.
[0057] Cerebral blood flow increase may be further modified by
modifying the temperature and humidity of the delivered gas. By way
of example, increasing the temperature in the nasal cavity may
cause vasodilation of the nasal vasculature and increase absorption
of drug focally. This may further increase cerebral blood flow or
serve to reduce the dose required to achieve any given cerebral
blood flow increase. Similarly, increasing the humidification in
the nasal cavity may serve to increase drug delivery and reduce the
dose required to attain any given cerebral blood flow increase.
Therefore, both of these parameters may be fed back to the device
to adjust gas delivery accordingly.
[0058] Cerebral oximetry, brain temperature, regional oxygen or
glucose consumption can also be used as alternate measures of
treatment efficacy and delivery parameters modified accordingly.
Regional metabolic consumption, such as oxygen or glucose
consumption and brain temperature typically increase as cortical
activity, cerebral blood flow or cortical stimulation increase. All
these factors can be fed back into the device and gas delivery
adjusted accordingly.
[0059] Various modifications and additions may be made to the
exemplary embodiments disclosed herein without departing from the
scope of the invention. For example, while the embodiments
disclosed herein refer to particular features, the scope of this
invention also includes embodiments having different combinations
of features and embodiments that do not include all of the
described features. Accordingly, the scope of the present invention
is intended to embrace all such alternative, modifications and
variations as fall within the scope of the claims and equivalents
thereof.
* * * * *