U.S. patent application number 12/408131 was filed with the patent office on 2009-07-23 for electrical treatment of bronchial constriction.
This patent application is currently assigned to ElectroCore, Inc.. Invention is credited to Joseph P. Errico, Hecheng Hu, Steven Mendez, James R. Pastena, Arthur Ross, Bruce Simon.
Application Number | 20090187231 12/408131 |
Document ID | / |
Family ID | 40877065 |
Filed Date | 2009-07-23 |
United States Patent
Application |
20090187231 |
Kind Code |
A1 |
Errico; Joseph P. ; et
al. |
July 23, 2009 |
Electrical Treatment Of Bronchial Constriction
Abstract
Devices, systems and methods for treating bronchial constriction
related to asthma, anaphylaxis or chronic obstructive pulmonary
disease wherein the treatment includes stimulating selected nerve
fibers responsible for smooth muscle dilation at a selected region
within a patient's neck, thereby reducing the magnitude of
constriction of bronchial smooth muscle.
Inventors: |
Errico; Joseph P.; (Green
Brook, NJ) ; Pastena; James R.; (Succasunna, NJ)
; Mendez; Steven; (Chester, NJ) ; Hu; Hecheng;
(Cedar Grove, NJ) ; Ross; Arthur; (Mendham,
NJ) ; Simon; Bruce; (Mountain Lakes, NJ) |
Correspondence
Address: |
GIBSON & DERNIER L.L.P.
900 ROUTE 9 NORTH, SUITE 504
WOODBRIDGE
NJ
07095
US
|
Assignee: |
ElectroCore, Inc.
Morris Plains
NJ
|
Family ID: |
40877065 |
Appl. No.: |
12/408131 |
Filed: |
March 20, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11591340 |
Nov 1, 2006 |
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12408131 |
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60736001 |
Nov 10, 2005 |
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60772361 |
Feb 10, 2006 |
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60814313 |
Jun 16, 2006 |
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60786564 |
Mar 28, 2006 |
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Current U.S.
Class: |
607/42 |
Current CPC
Class: |
A61N 1/36146 20130101;
A61N 1/0551 20130101; A61N 1/3601 20130101; A61N 1/3611 20130101;
A61N 1/0517 20130101; A61N 1/0519 20130101; A61N 1/36017 20130101;
A61N 1/36053 20130101; A61N 1/0526 20130101 |
Class at
Publication: |
607/42 |
International
Class: |
A61N 1/36 20060101
A61N001/36 |
Claims
1. A method of treating bronchial constriction in a patient
comprising stimulating selected nerve fibers responsible for smooth
muscle dilation to increase the activity of said nerve fibers.
2. The method of claim 1 wherein the selected nerve fibers are in a
neck of the patient.
3. The method of claim 1 wherein the selected nerve fibers are
within a carotid sheath of the patient.
4. The method of claim 1 wherein the selected nerve fibers are
associated with the vagus nerve.
5. The method of claim 1 wherein the selected nerve fibers are
efferent parasympathetic nerve fibers.
6. The method of claim 1 wherein the selected nerve fibers are
afferent parasympathetic nerve fibers.
7. The method of claim 1 wherein the selected nerve fibers are
nonadrenergic noncholinergic nerve fibers.
8. The method of claim 1 wherein the selected nerve fibers are
efferent sympathetic nerves that directly innervate the smooth
muscle.
9. The method of claim 1 wherein the selected nerve fibers are
efferent sympathetic nerves that directly modulate parasympathetic
ganglia transmission.
10. The method of claim 1 wherein the stimulating step is carried
out by applying at least one electrical impulse to a target
location adjacent to or in close proximity with a carotid sheath of
a patient.
11. The method of claim 10 further comprising introducing one or
more electrodes to the target location.
12. The method of claim 10 wherein the introducing step is carried
out by introducing the electrodes through a percutaneous
penetration in the patient's neck.
13. The method of claim 10 wherein the introducing step is carried
out by introducing the electrodes through the esophagus of the
patient.
14. The method of claim 10 wherein the introducing step is carried
out by introducing the electrodes through the trachea of a
patient.
15. The method of claim 10 wherein the introducing step is carried
out by implanting the electrodes in the target region.
16. The method of claim 1 wherein the stimulating step is carried
out without substantially stimulating a second set of nerve fibers
responsible for increasing the magnitude of constriction of smooth
muscle.
17. The method of claim 1 further comprising blocking or inhibiting
a second set of nerve fibers responsible for increasing the
magnitude of constriction of smooth muscle.
18. The method of claims 16 or 17 wherein the second set of nerve
fibers are associated with the vagus nerve.
19. The method of claims 16 or 17 wherein the second set of nerve
fibers are parasympathetic cholinergic nerve fibers.
20. The method of claim 10 wherein the electrical impulse is of a
frequency between about 15 Hz to 50 Hz.
21. The method of claim 10 wherein the electrical impulse is of a
frequency about 25 Hz.
22. The method of claim 10 wherein the electrical impulse is of an
amplitude of between about 1 to 12 volts.
23. The method of claim 10 wherein the electrical impulse has a
pulsed on-time of between about 50 to 500 microseconds.
24. The method of claim 10 wherein the electrical impulse has a
frequency of about 25 Hz, a pulsed on-time of about 200-400
microseconds, and an amplitude of about 6-12 volts.
25. The method of claim 1 wherein the bronchial constriction is
associated with an acute symptom of asthma.
26. The method of claim 1 wherein the bronchial condition is
associated with an acute symptom of anaphylaxis.
27. The method of claim 1 wherein the bronchial condition is
associated with an acute symptom of chronic obstructive pulmonary
disease.
28. A method of treating bronchial constriction in a patient
comprising applying an electrical impulse of a frequency of about
15 Hz to 50 Hz to a selected region of a neck of the patient to
reduce a magnitude of constriction of bronchial smooth muscle.
29. The method of claim 28 wherein the frequency is about 25
Hz.
30. The method of claim 28 wherein the electrical impulse is
sufficient to stimulate a first set of nerve fibers that are
responsible for bronchodilation to increase the activity of the
first set of nerve fibers.
31. The method of claim 28 wherein the electrical impulse is
insufficient to substantially stimulate a second set of nerve
fibers that are responsible for increasing the magnitude of
constriction of smooth muscle.
32. The method of claim 30 wherein the first set of nerve fibers
are nonadrenergic noncholinergic nerve fibers.
33. The method of claim 31 wherein the second set of nerve fibers
are parasympathetic cholinergic nerve fibers.
34. The method of claim 28 wherein the electrical impulse is of an
amplitude of at least 6 volts.
35. The method of claim 28 wherein the electrical impulse has a
pulsed on-time of between about 50 to 500 microseconds.
36. The method of claim 28 wherein the electrical impulse has a
pulsed on-time of about 200-400 microseconds.
37. A method for treating bronchial constriction in a patient
comprising applying an electrical impulse to a target region in the
patient and acutely reducing a magnitude of bronchial constriction
in the patient.
38. The method of claim 37 further comprising reducing a magnitude
of bronchial constriction in the patient in less than about 2
hours.
39. The method of claim 37 further comprising reducing a magnitude
of bronchial constriction in the patient in less than 1 hour.
40. The method of claim 37 further comprising reducing a magnitude
of bronchial constriction in the patient in less than 15
minutes.
41. The method of claim 37 wherein the electrical impulse is
sufficient to increase an FEV.sub.1 of the patient by a clinically
significant amount in a period of time less than about 6 hours.
42. The method of claim 37 wherein the electrical impulse is
sufficient to increase an FEV.sub.1 of the patient by at least 12%
in a period of time less than about 3 hours.
43. The method of claim 37 wherein the electrical impulse is
sufficient to increase an FEV.sub.1 of the patient by at least 12%
in a period of time less than about 90 minutes.
44. The method of claim 37 wherein the electrical impulse is
sufficient to increase an FEV.sub.1 of the patient by at least
19%.
45. A device for treating bronchial constriction in a patient
comprising: a source of electrical energy; and an introducer
configured for introduction to a target region of a patient's neck
and having one or more electrodes coupled to the source of
electrical energy, wherein the source of electrical energy is
configured to apply an electrical impulse to the electrodes to
reduce a magnitude of constriction of bronchial smooth muscle.
46. The device of claim 45 wherein the introducer further comprises
one or more electrical leads coupling the electrodes to the source
of electrical energy, the electrodes lead being configured for
insertion through a percutaneous penetration in the patient's
neck.
47. The device of claim 45 wherein the introducer comprises a
nasogastral tube configured for introduction into the patient's
esophagus.
48. The device of claim 45 wherein the introducer comprises an
endotracheal tube configured for introduction into the patient's
trachea.
49. The device of claim 45 wherein the electrical impulses has a
frequency of about 15 Hz to 50 Hz.
50. The device of claim 49 wherein the frequency is about 25
Hz.
51. The device of claim 45 wherein the electrical impulse is
sufficient to stimulate selected nerve fibers that are responsible
for bronchodilation to increase the activity of the first set of
nerve fibers.
52. The device of claim 51 wherein the selected nerve fibers are
nonadrenergic noncholinergic nerve fibers.
53. The method of claim 45 wherein the electrical impulse is of an
amplitude of at least 6 volts.
54. The method of claim 45 wherein the electrical impulse has a
pulsed on-time of between about 50 to 500 microseconds.
55. The method of claim 45 wherein the electrical impulse has a
pulsed on-time of about 200-400 microseconds.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 11/591,340, filed Nov. 1, 2006 which in turn
claims the benefit of Provisional Patent Application Nos.
60/736,001, filed Nov. 10, 2005; 60/772,361, filed Feb. 10, 2006;
60/814,313, filed Jun. 16, 2006; and 60/786,564, filed Mar. 28,
2006, the entire disclosures of which are hereby incorporated by
reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to the field of delivery of
electrical impulses (and/or fields) to bodily tissues for
therapeutic purposes, and more specifically to devices and methods
for treating conditions associated with bronchial constriction
[0003] There are a number of treatments for various infirmities
that require the destruction of otherwise healthy tissue in order
to affect a beneficial effect. Malfunctioning tissue is identified,
and then lesioned or otherwise compromised in order to affect a
beneficial outcome, rather than attempting to repair the tissue to
its normal functionality. While there are a variety of different
techniques and mechanisms that have been designed to focus
lesioning directly onto the target nerve tissue, collateral damage
is inevitable.
[0004] Still other treatments for malfunctioning tissue can be
medicinal in nature, in many cases leaving patients to become
dependent upon artificially synthesized chemicals. Examples of this
are anti-asthma drugs such as albuterol, proton pump inhibitors
such as omeprazole (Prilosec), spastic bladder relievers such as
Ditropan, and cholesterol reducing drugs like Lipitor and Zocor. In
many cases, these medicinal approaches have side effects that are
either unknown or quite significant, for example, at least one
popular diet pill of the late 1990's was subsequently found to
cause heart attacks and strokes.
[0005] Unfortunately, the beneficial outcomes of surgery and
medicines are, therefore, often realized at the cost of function of
other tissues, or risks of side effects.
[0006] The use of electrical stimulation for treatment of medical
conditions has been well known in the art for nearly two thousand
years. It has been recognized that electrical stimulation of the
brain and/or the peripheral nervous system and/or direct
stimulation of the malfunctioning tissue, which stimulation is
generally a wholly reversible and non-destructive treatment, holds
significant promise for the treatment of many ailments.
[0007] Electrical stimulation of the brain with implanted
electrodes has been approved for use in the treatment of various
conditions, including pain and movement disorders including
essential tremor and Parkinson's disease. The principle behind
these approaches involves disruption and modulation of hyperactive
neuronal circuit transmission at specific sites in the brain. As
compared with the very dangerous lesioning procedures in which the
portions of the brain that are behaving pathologically are
physically destroyed, electrical stimulation is achieved by
implanting electrodes at these sites to, first sense aberrant
electrical signals and then to send electrical pulses to locally
disrupt the pathological neuronal transmission, driving it back
into the normal range of activity. These electrical stimulation
procedures, while invasive, are generally conducted with the
patient conscious and a participant in the surgery.
[0008] Brain stimulation, and deep brain stimulation in particular,
is not without some drawbacks. The procedure requires penetrating
the skull, and inserting an electrode into the brain matter using a
catheter-shaped lead, or the like. While monitoring the patient's
condition (such as tremor activity, etc.), the position of the
electrode is adjusted to achieve significant therapeutic potential.
Next, adjustments are made to the electrical stimulus signals, such
as frequency, periodicity, voltage, current, etc., again to achieve
therapeutic results. The electrode is then permanently implanted
and wires are directed from the electrode to the site of a
surgically implanted pacemaker. The pacemaker provides the
electrical stimulus signals to the electrode to maintain the
therapeutic effect. While the therapeutic results of deep brain
stimulation are promising, there are significant complications that
arise from the implantation procedure, including stroke induced by
damage to surrounding tissues and the neurovasculature.
[0009] One of the most successful modern applications of this basic
understanding of the relationship between muscle and nerves is the
cardiac pacemaker. Although its roots extend back into the 1800's,
it was not until 1950 that the first practical, albeit external and
bulky pacemaker was developed. Dr. Rune Elqvist developed the first
truly functional, wearable pacemaker in 1957. Shortly thereafter,
in 1960, the first fully implanted pacemaker was developed.
[0010] Around this time, it was also found that the electrical
leads could be connected to the heart through veins, which
eliminated the need to open the chest cavity and attach the lead to
the heart wall. In 1975 the introduction of the lithium-iodide
battery prolonged the battery life of a pacemaker from a few months
to more than a decade. The modern pacemaker can treat a variety of
different signaling pathologies in the cardiac muscle, and can
serve as a defibrillator as well (see U.S. Pat. No. 6,738,667 to
Deno, et al., the disclosure of which is incorporated herein by
reference).
[0011] Another application of electrical stimulation of nerves has
been the treatment of radiating pain in the lower extremities by
means of stimulation of the sacral nerve roots at the bottom of the
spinal cord (see U.S. Pat. No. 6,871,099 to Whitehurst, et al., the
disclosure of which is incorporated herein by reference).
[0012] The smooth muscles that line the bronchial passages are
controlled by a confluence of vagus and sympathetic nerve fiber
plexuses. Spasms of the bronchi during asthma attacks and
anaphylactic shock can often be directly related to pathological
signaling within these plexuses. Anaphylactic shock and asthma are
major health concerns.
[0013] Asthma, and other airway occluding disorders resulting from
inflammatory responses and inflammation-mediated
bronchoconstriction, affects an estimated eight to thirteen million
adults and children in the United States. A significant subclass of
asthmatics suffers from severe asthma. An estimated 5,000 persons
die every year in the United States as a result of asthma attacks.
Up to twenty percent of the populations of some countries are
affected by asthma, estimated at more than a hundred million people
worldwide. Asthma's associated morbidity and mortality are rising
in most countries despite increasing use of anti-asthma drugs.
[0014] Asthma is characterized as a chronic inflammatory condition
of the airways. Typical symptoms are coughing, wheezing, tightness
of the chest and shortness of breath. Asthma is a result of
increased sensitivity to foreign bodies such as pollen, dust mites
and cigarette smoke. The body, in effect, overreacts to the
presence of these foreign bodies in the airways. As part of the
asthmatic reaction, an increase in mucous production is often
triggered, exacerbating airway restriction. Smooth muscle
surrounding the airways goes into spasm, resulting in constriction
of airways. The airways also become inflamed. Over time, this
inflammation can lead to scarring of the airways and a further
reduction in airflow. This inflammation leads to the airways
becoming more irritable, which may cause an increase in coughing
and increased susceptibility to asthma episodes.
[0015] Two medicinal strategies exist for treating this problem for
patients with asthma. The condition is typically managed by means
of inhaled medications that are taken after the onset of symptoms,
or by injected and/or oral medication that are taken chronically.
The medications typically fall into two categories; those that
treat the inflammation, and those that treat the smooth muscle
constriction. The first is to provide anti-inflammatory
medications, like steroids, to treat the airway tissue, reducing
its tendency to over-release of the molecules that mediate the
inflammatory process. The second strategy is to provide a smooth
muscle relaxant (e.g. an anti-cholinergic) to reduce the ability of
the muscles to constrict.
[0016] It has been highly preferred that patients rely on avoidance
of triggers and anti-inflammatory medications, rather than on the
bronchodilators as their first line of treatment. For some
patients, however, these medications, and even the bronchodilators
are insufficient to stop the constriction of their bronchial
passages, and more than five thousand people suffocate and die
every year as a result of asthma attacks.
[0017] Anaphylaxis likely ranks among the other airway occluding
disorders of this type as the most deadly, claiming many deaths in
the United States every year. Anaphylaxis (the most severe form of
which is anaphylactic shock) is a severe and rapid systemic
allergic reaction to an allergen. Minute amounts of allergens may
cause a life-threatening anaphylactic reaction. Anaphylaxis may
occur after ingestion, inhalation, skin contact or injection of an
allergen. Anaphylactic shock usually results in death in minutes if
untreated. Anaphylactic shock is a life-threatening medical
emergency because of rapid constriction of the airway. Brain damage
sets in quickly without oxygen.
[0018] The triggers for these fatal reactions range from foods
(nuts and shellfish), to insect stings (bees), to medication (radio
contrasts and antibiotics). It is estimated 1.3 to 13 million
people in the United States are allergic to venom associated with
insect bites; 27 million are allergic to antibiotics; and 5-8
million suffer food allergies. All of these individuals are at risk
of anaphylactic shock from exposure to any of the foregoing
allergens. In addition, anaphylactic shock can be brought on by
exercise. Yet all are mediated by a series of hypersensitivity
responses that result in uncontrollable airway occlusion driven by
smooth muscle constriction, and dramatic hypotension that leads to
shock. Cardiovascular failure, multiple organ ischemia, and
asphyxiation are the most dangerous consequences of
anaphylaxis.
[0019] Anaphylactic shock requires advanced medical care
immediately. Current emergency measures include rescue breathing;
administration of epinephrine; and/or intubation if possible.
Rescue breathing may be hindered by the closing airway but can help
if the victim stops breathing on his own. Clinical treatment
typically consists of antihistamines (which inhibit the effects of
histamine at histamine receptors) which are usually not sufficient
in anaphylaxis, and high doses of intravenous corticosteroids.
Hypotension is treated with intravenous fluids and sometimes
vasoconstrictor drugs. For bronchospasm, bronchodilator drugs such
as salbutamol are employed.
[0020] Given the common mediators of both asthmatic and
anaphylactic bronchoconstriction, it is not surprising that asthma
sufferers are at a particular risk for anaphylaxis. Still,
estimates place the numbers of people who are susceptible to such
responses at more than 40 million in the United States alone.
[0021] Tragically, many of these patients are fully aware of the
severity of their condition, and die while struggling in vain to
manage the attack medically. Many of these incidents occur in
hospitals or in ambulances, in the presence of highly trained
medical personnel who are powerless to break the cycle of
inflammation and bronchoconstriction (and life-threatening
hypotension in the case of anaphylaxis) affecting their
patient.
[0022] Unfortunately, prompt medical attention for anaphylactic
shock and asthma are not always available. For example, epinephrine
is not always available for immediate injection. Even in cases
where medication and attention is available, life saving measures
are often frustrated because of the nature of the symptoms.
Constriction of the airways frustrates resuscitation efforts, and
intubation may be impossible because of swelling of tissues.
[0023] Typically, the severity and rapid onset of anaphylactic
reactions does not render the pathology amenable to chronic
treatment, but requires more immediately acting medications. Among
the most popular medications for treating anaphylaxis is
epinephrine, commonly marketed in so-called "Epi-pen" formulations
and administering devices, which potential sufferers carry with
them at all times. In addition to serving as an extreme
bronchodilator, epinephrine raises the patient's heart rate
dramatically in order to offset the hypotension that accompanies
many reactions. This cardiovascular stress can result in
tachycardia, heart attacks and strokes.
[0024] Chronic obstructive pulmonary disease (COPD) is a major
cause of disability, and is the fourth leading cause of death in
the United States. More than 12 million people are currently
diagnosed with COPD. An additional 12 million likely have the
disease and don't even know it. COPD is a progressive disease that
makes it hard for the patient to breathe. COPD can cause coughing
that produces large amounts of mucus, wheezing, shortness of
breath, chest tightness and other symptoms. Cigarette smoking is
the leading cause of COPD, although long-term exposure to other
lung irritants, such as air pollution, chemical fumes or dust may
also contribute to COPD. In COPD, less air flows in and out of the
bronchial airways for a variety of reasons, including loss of
elasticity in the airways and/or air sacs, inflammation and/or
destruction of the walls between many of the air sacs and
overproduction of mucus within the airways.
[0025] The term COPD includes two primary conditions: emphysema and
chronic obstructive bronchitis. In emphysema, the walls between
many of the air sacs are damaged, causing them to lose their shape
and become floppy. This damage also can destroy the walls of the
air sacs, leading to fewer and larger air sacs instead of many tiny
ones. In chronic obstructive bronchitis, the patient suffers from
permanently irritated and inflamed bronchial tissue that is slowly
and progressively dying. This causes the lining to thicken and form
thick mucus, making it hard to breathe. Many of these patients also
experience periodic episodes of acute airway reactivity (i.e.,
acute exacerbations), wherein the smooth muscle surrounding the
airways goes into spasm, resulting in further constriction and
inflammation of the airways. Acute exacerbations occur, on average,
between two and three times a year in patients with moderate to
severe COPD and are the most common cause of hospitalization in
these patients (mortality rates are 11%). Frequent acute
exacerbations of COPD cause lung function to deteriorate quickly,
and patients never recover to the condition they were in before the
last exacerbation. Similar to asthma, current medical management of
these acute exacerbations is often insufficient.
[0026] Unlike cardiac arrhythmias, which can be treated chronically
with pacemaker technology, or in emergent situations with equipment
like defibrillators (implantable and external), there is virtually
no commercially available medical equipment that can chronically
reduce the baseline sensitivity of the muscle tissue in the airways
to reduce the predisposition to asthma attacks, reduce the symptoms
of COPD or to break the cycle of bronchial constriction associated
with an acute asthma attack or anaphylaxis.
[0027] Accordingly, there is a need in the art for new products and
methods for treating the immediate symptoms of bronchial
constriction resulting from pathologies such as anaphylactic shock,
asthma and COPD.
SUMMARY OF THE INVENTION
[0028] The present invention involves products and methods of
treatment of asthma, COPD, anaphylaxis, and other pathologies
involving the constriction of the primary airways, utilizing an
electrical signal that may be applied directly to, or in close
proximity to, a selected nerve to temporarily stimulate, block
and/or modulate the signals in the selected nerve. The present
invention is particularly useful for the acute relief of symptoms
associated with bronchial constriction, i.e., asthma attacks, COPD
exacerbations and/or anaphylactic reactions. The teachings of the
present invention provide an emergency response to such acute
symptoms, by producing immediate airway dilation and/or heart
function increase to enable subsequent adjunctive measures (such as
the administration of epinephrine) to be effectively employed.
[0029] In one aspect of the present invention, a method of treating
bronchial constriction comprises stimulating selected nerve fibers
responsible for reducing the magnitude of constriction of smooth
bronchial muscle to increase the activity of the selected nerve
fibers. In a preferred embodiment, the selected nerve fibers are
inhibitory nonadrenergic noncholinergic nerve fibers (iNANC) which
are generally responsible for bronchodilation. Stimulation of these
iNANC fibers increases their activity, thereby increasing
bronchodilation and facilitating opening of the airways of the
mammal. The stimulation may occur through direct stimulation of the
efferent iNANC fibers that produce bronchodilation or indirectly
through stimulation of the afferent sympathetic or parasympathetic
nerves which carry signals to the brain and then back down through
the iNANC nerve fibers to the bronchial passages.
[0030] In one embodiment, the iNANC nerve fibers are associated
with the vagus nerve and are thus directly responsible for
bronchodilation. In an alternative embodiment, the iNANC fibers are
interneurons that are completely contained within the walls of the
bronchial airways. These interneurons are responsible for
modulating the cholinergic nerves in the bronchial passages. In
this embodiment, the increased activity of the iNANC interneurons
will cause inhibition or blocking of the cholinergic nerves
responsible for bronchial constriction, thereby facilitating
opening of the airways.
[0031] The stimulating step is preferably carried out without
substantially stimulating excitatory nerve fibers, such as
parasympathetic cholinergic nerve fibers, that are responsible for
increasing the magnitude of constriction of smooth muscle. In this
manner, the activity of the iNANC nerve fibers are increased
without increasing the activity of the cholinergic fibers which
would otherwise induce further constriction of the smooth muscle.
Alternatively, the method may comprise the step of actually
inhibiting or blocking these cholinergic nerve fibers such that the
nerves responsible for bronchodilation are stimulated while the
nerves responsible for bronchial constriction are inhibited or
completely blocked. This blocking/inhibiting signal may be
separately applied to the inhibitory nerves; or it may be part of
the same signal that is applied to the iNANC nerve fibers.
[0032] In an alternative embodiment, a method of treating bronchial
constriction comprises stimulating, inhibiting, blocking or
otherwise modulating selected efferent sympathetic nerves
responsible for mediating bronchial passages either directly or
indirectly. The selected efferent sympathetic nerves may be nerves
that directly innervate the bronchial smooth muscles. It has been
postulated that asthma patients typically have more sympathetic
nerves that directly innervate the bronchial smooth muscle than
individuals that do not suffer from asthma. In yet other
embodiments, the method includes stimulating, inhibiting, blocking
or otherwise modulating nerves that release systemic
bronchodilators or nerves that directly modulate parasympathetic
ganglia transmission (by stimulation or inhibition of preganglionic
to postganglionic transmissions).
[0033] In another aspect of the invention, a method of treating
bronchial constriction includes applying an electrical impulse to a
target region in the patient and acutely reducing the magnitude of
bronchial constriction in the patient. As used herein, the term
acutely means that the electrical impulse immediately begins to
interact with one or more nerves to produce a response in the
patient. The electrical impulse is preferably sufficient to
increase the Forced Expiratory Volume in 1 second (FEV.sub.1) of
the patient by a clinically significant amount in a period of time
less than about 6 hours, preferably less than 3 hours and more
preferably less than 90 minutes. A clinically significant amount is
defined herein as at least a 12% increase in the patient's
FEV.sub.1 versus the FEV1 measured prior to application of the
electrical impulse. In an exemplary embodiment, the electrical
impulse is sufficient to increase the FEV1 by at least 19% over the
FEV.sub.1 as predicted.
[0034] In another aspect of the invention, a method for treating
bronchial constriction comprises applying one or more electrical
impulse(s) of a frequency of about 15 Hz to 50 Hz to a selected
region within a patient to reduce a magnitude of constriction of
bronchial smooth muscle. In a preferred embodiment, the method
includes introducing one or more electrodes to a target region in a
patient's neck and applying an electrical impulse to the target
region to stimulate, inhibit or otherwise modulate selected nerve
fibers that interact with bronchial smooth muscle. Preferably, the
target region is adjacent to, or in close proximity with, the
carotid sheath.
[0035] Applicant has made the unexpected discovered that applying
an electrical impulse to a selected region of a patient's neck
within this particular frequency range results in almost immediate
and significant improvement in bronchodilation, as discussed in
further detail below. Applicant has further discovered that
applying electrical impulses outside of the selected frequency
range (15 Hz to 50 Hz) does not result in significant improvement
and, in some cases, may worsen the patient's bronchoconstriction.
Preferably, the frequency is about 25 Hz. In this embodiment, the
electrical impulse(s) are of an amplitude between about 0.5 to 12
volts and have a pulsed on-time of between about 50 to 500
microseconds, preferably about 200-400 microseconds. The preferred
voltage will depend on the size and shape of the electrodes and the
distance between the electrode(s) and the target nerves. In certain
embodiments wherein the electrical impulse is applied through a
percutaneous lead, or from within the patient's esophagus or
trachea, the electrical impulse preferably has an amplitude of at
least 6 volts and more preferably between about 7-12 volts. In
other embodiments wherein the electrical impulse is applied
directly to a nerve (e.g., via a nerve cuff), the amplitude is
preferably lower, i.e., less than 6 volts and more preferably
between about 0.1 to 2 volts.
[0036] The electrical impulse(s) are applied in a manner that
reduces the constriction of the smooth muscle lining the bronchial
passages to relieve the spasms that occur during anaphylactic
shock, acute exacerbations of COPD or asthma attacks. In some
embodiments, the mechanisms by which the appropriate impulse is
applied to the selected region within the patient include
positioning the distal ends of an electrical lead or leads in the
vicinity of the nervous tissue controlling the pulmonary and/or
cardiac muscles, which leads are coupled to an implantable or
external electrical impulse generating device. The electric field
generated at the distal tip of the lead creates a field of effect
that permeates the target nerve fibers and causes the stimulating,
blocking and/or modulation of signals to the subject muscles,
and/or the blocking and/or affecting of histamine response. It
shall also be understood that leadless impulses as shown in the art
may also be utilized for applying impulses to the target
regions.
[0037] The electrical leads may be positioned at the target site
within the patient through a variety of different methods. In one
embodiment, an introducer comprising an electrode is passed
percutaneously through the patient's neck to a region adjacent to
or in close proximity to the carotid sheath. In an alternative
embodiment, the introducer is advanced through the patient's
esophagus to a position adjacent to or in close proximity to the
vagus nerve. In this embodiment, the introducer may be, for
example, a nasogastral (NG) tube having an internal passageway and
at least one electrode coupled to the external surface of the NG
tube. In yet another embodiment, the introducer is advanced through
the patient's tracheal, e.g. via an endotracheal tube. In yet
another embodiment, an electrode is implanted in the patient
adjacent to or around the vagus nerve and activated by a remote
control mechanism outside of the patient. In this embodiment,
activation of such impulses via the remote control may be directed
by a health care provider or manually by a patient suffering from
bronchospasm.
[0038] The novel systems, devices and methods for treating
bronchial constriction are more completely described in the
following detailed description of the invention, with reference to
the drawings provided herewith, and in claims appended hereto.
Other aspects, features, advantages, etc. will become apparent to
one skilled in the art when the description of the invention herein
is taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] For the purposes of illustrating the various aspects of the
invention, there are shown in the drawings forms that are presently
preferred, it being understood, however, that the invention is not
limited by or to the precise data, methodologies, arrangements and
instrumentalities shown, but rather only by the claims.
[0040] FIG. 1 is a schematic view of a nerve modulating device
according to the present invention;
[0041] FIG. 2 illustrates an exemplary electrical voltage/current
profile for a blocking and/or modulating impulse applied to a
portion or portions of a nerve in accordance with an embodiment of
the present invention;
[0042] FIG. 3 is a schematic view of a nerve modulating device for
introduction through a patient's esophagus according to one
embodiment of the prevent invention;
[0043] FIG. 4 illustrates an alternative embodiment of an exemplary
nerve modulating device for use in a patient's trachea;
[0044] FIGS. 5-14 graphically illustrate exemplary experimental
data obtained on guinea pigs in accordance with multiple
embodiments of the present invention;
[0045] FIGS. 15-18 graphically illustrate exemplary experimental
data obtained on human patients in accordance with multiple
embodiments of the present invention;
[0046] FIGS. 19-24 graphically illustrate the inability of signals
taught by U.S. patent application Ser. No. 10/990,938 to achieve
the results of the present invention; and
[0047] FIGS. 25 and 26 graphically illustrates the inability of
signals taught by International Patent Application Publication
Number WO 93/01862 to achieve the results of the prevent
invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0048] In the present invention, electrical energy is applied to
one or more electrodes to deliver an electromagnetic field to a
patient. The techniques of the present invention may be performed
in a conventional open surgery environment or in a minimally
invasive manner through a natural body orifice (e.g., esophagus or
trachea), percutaneously through the patient's skin or using
cannulas or port access devices. The invention is particularly
useful for applying electrical impulses that interact with the
signals of one or more nerves, or muscles, to achieve a therapeutic
result, such as relaxation of the smooth muscle of the bronchia. In
particular, the present invention provides methods and devices for
immediate relief of acute symptoms associated with bronchial
constriction such as asthma attacks, COPD exacerbations and/or
anaphylactic reactions.
[0049] For convenience, the remaining disclosure will be directed
specifically to the treatment in or around the carotid sheath with
devices introduced through a percutaneous penetration in a
patient's neck or through the esophagus or through the trachea of a
patient, but it will be appreciated that the systems and methods of
the present invention can be applied equally well to other tissues
and nerves of the body, including but not limited to other
parasympathetic nerves, sympathetic nerves, spinal or cranial
nerves. In addition, the present invention can be used to directly
or indirectly stimulate or otherwise modulate nerves that innervate
bronchial smooth muscle.
[0050] While the exact physiological causes of asthma, COPD and
anaphylaxis have not been determined, the present invention
postulates that the direct mediation of the smooth muscles of the
bronchia is the result of activity in one or more nerves near or in
the carotid sheath. In the case of asthma, it appears that the
airway tissue has both (i) a hypersensitivity to the allergen that
causes the overproduction of the cytokines that stimulate the
cholinergic receptors of the nerves and/or (ii) a baseline high
parasympathetic tone or a high ramp up to a strong parasympathetic
tone when confronted with any level of cholenergic cytokine. The
combination can be lethal. Anaphylaxis appears to be mediated
predominantly by the hypersensitivity to an allergen causing the
massive overproduction of cholenergic receptor activating cytokines
that overdrive the otherwise normally operating vagus nerve to
signal massive constriction of the airways. Drugs such as
epinephrine drive heart rate up while also relaxing the bronchial
muscles, effecting temporary relief of symptoms from these
conditions. Experience has shown that severing the vagus nerve (an
extreme version of reducing the parasympathetic tone) has an effect
similar to that of epinephrine on heart rate and bronchial diameter
in that the heart begins to race (tachycardia) and the bronchial
passageways dilate.
[0051] In accordance with the present invention, the delivery, in a
patient suffering from severe asthma, COPD or anaphylactic shock,
of an electrical impulse sufficient to stimulate, block and/or
modulate transmission of signals will result in relaxation of the
bronchi smooth muscle, dilating airways and/or counteract the
effect of histamine on the vagus nerve. Depending on the placement
of the impulse, the stimulating, blocking and/or modulating signal
can also raise the heart function.
[0052] Stimulating, blocking and/or modulating the signal in
selected nerves to reduce parasympathetic tone provides an
immediate emergency response, much like a defibrillator, in
situations of severe asthma or COPD attacks or anaphylactic shock,
providing immediate temporary dilation of the airways and
optionally an increase of heart function until subsequent measures,
such as administration of epinephrine, rescue breathing and
intubation can be employed. Moreover, the teachings of the present
invention permit immediate airway dilation and/or heart function
increase to enable subsequent life saving measures that otherwise
would be ineffective or impossible due to severe constriction or
other physiological effects. Treatment in accordance with the
present invention provides bronchodilation and optionally increased
heart function for a long enough period of time so that
administered medication such as epinephrine has time to take effect
before the patient suffocates.
[0053] In a preferred embodiment, a method of treating bronchial
constriction comprises stimulating selected nerve fibers
responsible for reducing the magnitude of constriction of smooth
bronchial muscle to increase the activity of the selected nerve
fibers. Certain signals of the parasympathetic nerve fibers cause a
constriction of the smooth muscle surrounding the bronchial
passages, while other signals of the parasympathetic nerve fibers
carry the opposing signals that tend to open the bronchial
passages. Specifically, it should be recognized that certain
signals, such as cholinergic fibers mediate a response similar to
that of histamine, while other signals (e.g., nonadrenergic,
noncholinergic or iNANC nerve fibers) generate an effect similar to
epinephrine. Given the postulated balance between these signals,
stimulating the iNANC nerve fibers and/or blocking or removing the
cholinergic signals should create an imbalance emphasizing
bronchodilation.
[0054] In one embodiment of the present invention, the selected
nerve fibers are inhibitory nonadrenergic noncholinergic (iNANC)
nerve fibers which are generally responsible for bronchodilation.
Stimulation of these iNANC fibers increases their activity, thereby
increasing bronchodilation and facilitating opening of the airways
of the mammal. The stimulation may occur through direct stimulation
of the efferent iNANC fibers that cause bronchodilation or
indirectly through stimulation of the afferent sympathetic or
parasympathetic nerves which carry signals to the brain and then
back down through the iNANC nerve fibers to the bronchial
passages.
[0055] In certain embodiments, the iNANC nerve fibers are
associated with the vagus nerve and are thus directly responsible
for bronchodilation. Alternatively, the iNANC fibers may be
interneurons that are completely contained within the walls of the
bronchial airways. These interneurons are responsible for
modulating the cholinergic nerves in the bronchial passages. In
this embodiment, the increased activity of the iNANC interneurons
will cause inhibition or blocking of the cholinergic nerves
responsible for bronchial constriction, thereby facilitating
opening of the airways.
[0056] As discussed above, certain parasympathetic signals mediate
a response similar to histamine, thereby causing a constriction of
the smooth muscle surrounding the bronchial passages. Accordingly,
the stimulating step of the present invention is preferably carried
out without substantially stimulating the parasympathetic nerve
fibers, such as the cholinergic nerve fibers associated with the
vagus nerve, that are responsible for increasing the magnitude of
constriction of smooth muscle. In this manner, the activity of the
iNANC nerve fibers are increased without increasing the activity of
the adrenergic fibers which would otherwise induce further
constriction of the smooth muscle. Alternatively, the method may
comprise the step of actually inhibiting or blocking these
cholinergic nerve fibers such that the nerves responsible for
bronchodilation are stimulated while the nerves responsible for
bronchial constriction are inhibited or completely blocked. This
blocking signal may be separately applied to the inhibitory nerves;
or it may be part of the same signal that is applied to the iNANC
nerve fibers.
[0057] While it is believed that there are little to no direct
sympathetic innervations of the bronchial smooth muscle in most
individuals, recent evidence has suggested asthma patients do have
such sympathetic innervations within the bronchial smooth muscle.
In addition, the sympathetic nerves may have an indirect effect on
the bronchial smooth muscle. Accordingly, alternative embodiments
of the prevent invention contemplate a method of stimulating
selected efferent sympathetic nerves responsible for mediating
bronchial passages either directly or indirectly. The selected
efferent sympathetic nerves may be nerves that directly innervate
the smooth muscles, nerves that release systemic bronchodilators or
nerves that directly modulate parasympathetic ganglia transmission
(by stimulation or inhibition of preganglionic to postganglionic
transmissions).
[0058] Method and devices of the present invention are particularly
useful for providing substantially immediate relief of acute
symptoms associated with bronchial constriction such as asthma
attacks, COPD exacerbations and/or anaphylactic reactions. One of
the key advantages of the present invention is the ability to
provide almost immediate dilation of the bronchial smooth muscle in
patients suffering from acute bronchoconstriction, opening the
patient's airways and allowing them to breathe and more quickly
recover from an acute episode (i.e., a relatively rapid onset of
symptoms that are typically not prolonged or chronic).
[0059] The magnitude of bronchial constriction in a patient is
typically expressed in a measurement referred to as the Forced
Expiratory Volume in 1 second (FEV.sub.1). FEV.sub.1 represents the
amount of air a patient exhales (expressed in liters) in the first
second of a pulmonary function test, which is typically performed
with a spirometer. The spirometer compares the FEV.sub.1 result to
a standard for the patient, which is based on the predicted value
for the patient's weight, height, sex, age and race. This
comparison is then expressed as a percentage of the FEV.sub.1 as
predicted. Thus, if the volume of air exhaled by a patient in the
first second is 60% of the predicted value based on the standard,
the FEV.sub.1 will be expressed in both the actual liters exhaled
and as a percentage of predicted (i.e., 60% of predicted).
[0060] As will be discussed in more detail in the experiments
below, applicants have disclosed a system and method for increasing
a patient's FEV.sub.1 in a relatively short period of time.
Preferably, the electrical impulse applied to the patient is
sufficient to increase the FEV.sub.1 of the patient by a clinically
significant amount in a period of time less than about 6 hours,
preferably less than 3 hours and more preferably less than 90
minutes. In an exemplary embodiment, the clinically significant
increase in FEV.sub.1 occurs in less than 15 minutes. A clinically
significant amount is defined herein as at least a 12% increase in
the patient's FEV.sub.1 versus the FEV.sub.1 prior to application
of the electrical impulse.
[0061] FIG. 1 is a schematic diagram of a nerve modulating device
300 for delivering electrical impulses to nerves for the treatment
of bronchial constriction or hypotension associated with
anaphylactic shock, COPD or asthma. As shown, device 300 may
include an electrical impulse generator 310; a power source 320
coupled to the electrical impulse generator 310; a control unit 330
in communication with the electrical impulse generator 310 and
coupled to the power source 320; and electrodes 340 coupled to the
electrical impulse generator 310 for attachment via leads 350 to
one or more selected regions of a nerve (not shown). The control
unit 330 may control the electrical impulse generator 310 for
generation of a signal suitable for amelioration of the bronchial
constriction or hypotension when the signal is applied via the
electrodes 340 to the nerve. It is noted that nerve modulating
device 300 may be referred to by its function as a pulse generator.
U.S. Patent Application Publications 2005/0075701 and 2005/0075702,
both to Shafer, both of which are incorporated herein by reference,
relating to stimulation of neurons of the sympathetic nervous
system to attenuate an immune response, contain descriptions of
pulse generators that may be applicable to the present
invention.
[0062] FIG. 2 illustrates an exemplary electrical voltage/current
profile for a stimulating, blocking and/or modulating impulse
applied to a portion or portions of selected nerves in accordance
with an embodiment of the present invention. As shown, a suitable
electrical voltage/current profile 400 for the blocking and/or
modulating impulse 410 to the portion or portions of a nerve may be
achieved using pulse generator 310. In a preferred embodiment, the
pulse generator 310 may be implemented using a power source 320 and
a control unit 330 having, for instance, a processor, a clock, a
memory, etc., to produce a pulse train 420 to the electrode(s) 340
that deliver the stimulating, blocking and/or modulating impulse
410 to the nerve via leads 350. For percutaneous, esophageal or
endotracheal use, the nerve modulating device 300 may be available
to the surgeon as external emergency equipment. For subcutaneous
use, device 300 may be surgically implanted, such as in a
subcutaneous pocket of the abdomen. Nerve modulating device 300 may
be powered and/or recharged from outside the body or may have its
own power source 320. By way of example, device 300 may be
purchased commercially. Nerve modulating device 300 is preferably
programmed with a physician programmer, such as a Model 7432 also
available from Medtronic, Inc.
[0063] The parameters of the modulation signal 400 are preferably
programmable, such as the frequency, amplitude, duty cycle, pulse
width, pulse shape, etc. In the case of an implanted pulse
generator, programming may take place before or after implantation.
For example, an implanted pulse generator may have an external
device for communication of settings to the generator. An external
communication device may modify the pulse generator programming to
improve treatment.
[0064] In addition, or as an alternative to the devices to
implement the modulation unit for producing the electrical
voltage/current profile of the stimulating, blocking and/or
modulating impulse to the electrodes, the device disclosed in U.S.
Patent Publication No.: 2005/0216062 (the entire disclosure of
which is incorporated herein by reference), may be employed. U.S.
Patent Publication No.: 2005/0216062 discloses a multi-functional
electrical stimulation (ES) system adapted to yield output signals
for effecting, electromagnetic or other forms of electrical
stimulation for a broad spectrum of different biological and
biomedical applications. The system includes an ES signal stage
having a selector coupled to a plurality of different signal
generators, each producing a signal having a distinct shape such as
a sine, a square or a saw-tooth wave, or simple or complex pulse,
the parameters of which are adjustable in regard to amplitude,
duration, repetition rate and other variables. The signal from the
selected generator in the ES stage is fed to at least one output
stage where it is processed to produce a high or low voltage or
current output of a desired polarity whereby the output stage is
capable of yielding an electrical stimulation signal appropriate
for its intended application. Also included in the system is a
measuring stage which measures and displays the electrical
stimulation signal operating on the substance being treated as well
as the outputs of various sensors which sense conditions prevailing
in this substance whereby the user of the system can manually
adjust it or have it automatically adjusted by feedback to provide
an electrical stimulation signal of whatever type he wishes and the
user can then observe the effect of this signal on a substance
being treated.
[0065] The electrical leads 350 and electrodes 340 are preferably
selected to achieve respective impedances permitting a peak pulse
voltage in the range from about 0.2 volts to about 20 volts.
[0066] The stimulating, blocking and/or modulating impulse signal
410 preferably has a frequency, an amplitude, a duty cycle, a pulse
width, a pulse shape, etc. selected to influence the therapeutic
result, namely stimulating, blocking and/or modulating some or all
of the transmission of the selected nerve. For example the
frequency may be about 1 Hz or greater, such as between about 15 Hz
to 50 Hz, more preferably around 25 Hz. The modulation signal may
have a pulse width selected to influence the therapeutic result,
such as about 20 .mu.S or greater, such as about 20 .mu.S to about
1000 .mu.S. The modulation signal may have a peak voltage amplitude
selected to influence the therapeutic result, such as about 0.2
volts or greater, such as about 0.2 volts to about 20 volts.
[0067] In a preferred embodiment of the invention, a method of
treating bronchial constriction comprises applying one or more
electrical impulse(s) of a frequency of about 15 Hz to 50 Hz to a
selected region of the vagus nerve to reduce a magnitude of
constriction of bronchial smooth muscle. As discussed in more
detail below, applicant has made the unexpected discovered that
applying an electrical impulse to a selected region of the vagus
nerve within this particular frequency range results in almost
immediate and significant improvement in bronchodilation, as
discussed in further detail below. Applicant has further discovered
that applying electrical impulses outside of the selected frequency
range (15 Hz to 50 Hz) does not result in immediate and significant
improvement in bronchodilation. Preferably, the frequency is about
25 Hz. In this embodiment, the electrical impulse(s) are of an
amplitude of between about 0.75 to 12 volts (depending on the size
and shape of the electrodes and the distance between the electrodes
and the selected nerve(s)) and have a pulsed on-time of between
about 50 to 500 microseconds, preferably about 200-400
microseconds.
[0068] In accordance with one embodiment, nerve modulating device
300 is provided in the form of a percutaneous or subcutaneous
implant that can be reused by an individual. In accordance with
another embodiment, devices in accordance with the present
invention are provided in a "pacemaker" type form, in which
electrical impulses 410 are generated to a selected region of the
nerve by device 300 on an intermittent basis to create in the
patient a lower reactivity of the nerve to upregulation
signals.
[0069] FIG. 3 illustrates an exemplary nerve modulating device 500
for use in the esophagus of a patient. As shown, device 500
includes a signal source 501 that operates to apply at least one
electrical signal to an NG tube 504 (via lead 540). As discussed
above, signal source 501 preferably includes an impulse generator
510, a control unit 530 and a power source 520 in communication
with impulse generator 510. NG tube 504 includes an internal
conductor 512 that couples lead 540 to an electrode assembly 502 at
the distal portion of NG tube 504. In this embodiment, device 500
further includes a return electrode 550 coupled to impulse
generator 510 via lead 540. Return electrode 550 is typically
placed on an outer skin surface of the patient (not shown), as is
well known in the art.
[0070] In use, electrode assembly 502 is inserted into the
esophagus of a patient past a cricoid cartilage of the patient, an
electromagnetic field emanates from the electrode assembly 502 to
the anatomy of the patient in the vicinity of the esophagus to
achieve the therapeutic result. In the exemplary embodiment,
electrode assembly 502 comprises a balloon electrode device that is
described in more detail in commonly assigned co-pending U.S.
patent application Ser. No. 12/338,191, filed Dec. 18, 2008, the
complete disclosure of which is incorporated herein by reference.
It will be recognized by those skilled in the art, however, that a
variety of different electrode assemblies may be used with the
present invention.
[0071] Referring now to FIG. 4, an alternative embodiment is
illustrated for treatment of selected nerves within a patient's
neck with a device 800 introduced through the trachea 802 of a
patient. As shown, device 800 includes an endotracheal tube 803
that is inserted into the patient under intubation as is well known
in the art. Tube 803 comprises a flexible shaft 805 with an inner
lumen 806, and a distal electrode assembly 808. As in the previous
embodiment, electrode assembly 502 comprises a balloon electrode
device that is described in more detail in U.S. patent application
Ser. No. 12/338,191 but it should be understood that a variety of
different electrode assemblies may be used with the present
invention. Electrode assembly 808 may be an integral part of tube
803 or it may be a separate device that is inserted through the
inner lumen 806 of a standard endotracheal tube. Many types of
conventional endotracheal tubes may be used, such as oral
un-cuffed, oral cuffed, Rae tube, nasal tube, reinforced tube,
double-lumen tubes and the like. Tube 803 also includes a fluid
passage 804 fluidly coupling the inner lumen 806 with a source of
electrically conductive fluid (not shown) and a proximal port 810
for coupling to a source of electrical energy (also not shown).
Tube 802 may also include an aspiration lumen (not shown) for
aspirating the conductive fluid and/or other bodily fluids as is
well known in the art.
[0072] Prior to discussing experimental results, a general approach
to treating bronchial constriction in accordance with one or more
embodiments of the invention may include a method of (or apparatus
for) treating bronchial constriction associated with anaphylactic
shock, COPD or asthma, comprising applying at least one electrical
impulse to one or more selected nerve fibers of a mammal in need of
relief of bronchial constriction. The method may include:
introducing one or more electrodes to the selected regions near or
adjacent to the selected nerve fibers, such as certain fibers near
or around the carotid sheath; and applying one or more electrical
stimulation signals to the electrodes to produce the at least one
electrical impulse, wherein the one or more electrical stimulation
signals are of a frequency between about 15 Hz to 50 Hz.
[0073] The one or more electrical stimulation signals may be of an
amplitude of between about 1-12 volts, depending on the size and
shape of the electrodes and the distance between the electrodes and
the selected nerve fibers. The one or more electrical stimulation
signals may be one or more of a full or partial sinusoid, square
wave, rectangular wave, and/or triangle wave. The one or more
electrical stimulation signals may have a pulsed on-time of between
about 50 to 500 microseconds, such as about 100, 200 or 400
microseconds. The polarity of the pulses may be maintained either
positive or negative. Alternatively, the polarity of the pulses may
be positive for some periods of the wave and negative for some
other periods of the wave. By way of example, the polarity of the
pulses may be altered about every second.
[0074] In one particular embodiment of the present invention,
electrical impulses are delivered to one or more portions of the
vagus nerve. The vagus nerve is composed of motor and sensory
fibers. The vagus nerve leaves the cranium and is contained in the
same sheath of dura matter with the accessory nerve. The vagus
nerve passes down the neck within the carotid sheath to the root of
the neck. The branches of distribution of the vagus nerve include,
among others, the superior cardiac, the inferior cardiac, the
anterior bronchial and the posterior bronchial branches. On the
right side, the vagus nerve descends by the trachea to the back of
the root of the lung, where it spreads out in the posterior
pulmonary plexus. On the left side, the vagus nerve enters the
thorax, crosses the left side of the arch of the aorta, and
descends behind the root of the left lung, forming the posterior
pulmonary plexus.
[0075] In mammals, two vagal components have evolved in the
brainstem to regulate peripheral parasympathetic functions. The
dorsal vagal complex (DVC), consisting of the dorsal motor nucleus
(DMNX) and its connections, controls parasympathetic function below
the level of the diaphragm, while the ventral vagal complex (VVC),
comprised of nucleus ambiguus and nucleus retrofacial, controls
functions above the diaphragm in organs such as the heart, thymus
and lungs, as well as other glands and tissues of the neck and
upper chest, and specialized muscles such as those of the
esophageal complex.
[0076] The parasympathetic portion of the vagus innervates
ganglionic neurons which are located in or adjacent to each target
organ. The VVC appears only in mammals and is associated with
positive as well as negative regulation of heart rate, bronchial
constriction, bronchodilation, vocalization and contraction of the
facial muscles in relation to emotional states. Generally speaking,
this portion of the vagus nerve regulates parasympathetic tone. The
VVC inhibition is released (turned off) in states of alertness.
This in turn causes cardiac vagal tone to decrease and airways to
open, to support responses to environmental challenges.
[0077] The parasympathetic tone is balanced in part by sympathetic
innervations, which generally speaking supplies signals tending to
relax the bronchial muscles so overconstriction does not occur.
Overall, airway smooth muscle tone is dependent on several factors,
including parasympathetic input, inhibitory influence of
circulating epinephrine, iNANC nerves and sympathetic innervations
of the parasympathetic ganglia. Stimulation of certain nerve fibers
of the vagus nerve (upregulation of tone), such as occurs in asthma
or COPD attacks or anaphylactic shock, results in airway
constriction and a decrease in heart rate. In general, the
pathology of severe asthma, COPD and anaphylaxis appear to be
mediated by inflammatory cytokines that overwhelm receptors on the
nerve cells and cause the cells to massively upregulate the
parasympathetic tone.
[0078] The methods described herein of applying an electrical
impulse to a selected region of the vagus nerve may further be
refined such that the at least one region may comprise at least one
nerve fiber emanating from the patient's tenth cranial nerve (the
vagus nerve), and in particular, at least one of the anterior
bronchial branches thereof, or alternatively at least one of the
posterior bronchial branches thereof. Preferably the impulse is
provided to at least one of the anterior pulmonary or posterior
pulmonary plexuses aligned along the exterior of the lung. As
necessary, the impulse may be directed to nerves innervating only
the bronchial tree and lung tissue itself. In addition, the impulse
may be directed to a region of the vagus nerve to stimulate, block
and/or modulate both the cardiac and bronchial branches. As
recognized by those having skill in the art, this embodiment should
be carefully evaluated prior to use in patients known to have
preexisting cardiac issues.
[0079] Experiments were performed to identify exemplary methods of
how electrical signals can be supplied to the peripheral nerve
fibers that innervate and/or control the bronchial smooth muscle to
(i) reduce the sensitivity of the muscle to the signals to
constrict, and (ii) to blunt the intensity of, or break the
constriction once it has been initiated. In particular, specific
signals were applied to the selected nerves in guinea pigs to
produce selective stimulation, interruption or reduction in the
effects of nerve activity leading to attenuation of
histamine-induced bronchoconstriction.
[0080] Male guinea pigs (400 g) were transported to the lab and
immediately anesthetized with an i.p. injection of urethane 1.5
g/kg. Skin over the anterior neck was opened and the carotid artery
and both jugular veins were cannulated with PE50 tubing to allow
for blood pressure/heart rate monitoring and drug administration,
respectively. The trachea was cannulated and the animal ventilated
by positive pressure, constant volume ventilation followed by
paralysis with succinylcholine (10 ug/kg/min) to paralyze the chest
wall musculature to remove the contribution of chest wall rigidity
from airway pressure measurements.
[0081] Guanethidine (10 mg/kg i.v.) was given to deplete
norepinephrine from nerve terminals that may interfere with the
nerve stimulation. In these experiments, vagus nerves were exposed
and connected to electrodes to allow selective stimuli of these
nerves. Following 15 minutes of stabilization, baseline hemodynamic
and airway pressure measurements were made before and after the
administration of repetitive doses of i.v. histamine.
[0082] Following the establishment of a consistent response to i.v.
histamine, nerve stimulation was attempted at variations of
frequency, voltage and pulse duration to identity parameters that
attenuate responses to i.v. histamine. Bronchoconstriction in
response to i.v. histamine is known to be due both to direct airway
smooth muscle effects and to stimulation of vagal nerves to release
acetylcholine.
[0083] At the end of vagal nerve challenges, atropine was
administered i.v. before a subsequent dose of histamine to
determine what percentage of the histamine-induced
bronchoconstriction was vagal nerve induced. This was considered a
100% response. Success of electrical interruption in vagal nerve
activity in attenuating histamine-induced bronchoconstriction was
compared to this maximum effect. Euthanasia was accomplished with
intravenous potassium chloride.
[0084] In order to measure the bronchoconstriction, the airway
pressure was measured in two places. The blood pressure and heart
rate were measured to track the subjects' vital signs. In all the
following graphs, the top line BP shows blood pressure, second line
AP1 shows airway pressure, third line AP2 shows airway pressure on
another sensor, the last line HR is the heart rate derived from the
pulses in the blood pressure.
[0085] In the first animals, the signal frequency applied was
varied from less than 1 Hz through 2,000 Hz, and the voltage was
varied from 1V to 12V. Initial indications seemed to show that an
appropriate signal was 1,000 Hz, 400 .mu.s, and 6-10V.
[0086] FIG. 5 graphically illustrates exemplary experimental data
on guinea pig #2. More specifically, the graphs of FIG. 5 show the
effect of a 1000 Hz, 400 .mu.S, 6V square wave signal applied
simultaneously to both left and right branches of the vagus nerve
in guinea pig #2 when injected with 12 .mu.g/kg histamine to cause
airway pressure to increase. The first peak in airway pressure is
histamine with the electric signal applied to the vagus, the next
peak is histamine alone (signal off), the third peak is histamine
and signal again, fourth peak is histamine alone again. It is
clearly shown that the increase in airway pressure due to histamine
is reduced in the presence of the 1000 Hz, 400 .mu.S and 6V square
wave on the vagus nerve. The animal's condition remained stable, as
seen by the fact that the blood pressure and heart rate are not
affected by this electrical signal.
[0087] After several attempts on the same animal to continue to
reproduce this effect with the 1,000 Hz signal, however, we
observed that the ability to continuously stimulate and suppress
airway constriction was diminished, and then lost. It appeared that
the nerve was no longer conducting. This conclusion was drawn from
the facts that (i) there was some discoloration of the nerve where
the electrode had been making contact, and (ii) the effect could be
resuscitated by moving the lead distally to an undamaged area of
the nerve, i.e. toward the organs, but not proximally, i.e., toward
the brain. The same thing occurred with animal #3. It has been
hypothesized that the effect seen was, therefore, accompanied by a
damaging of the nerve, which would not be clinically desirable.
[0088] To resolve the issue, in the next animal (guinea pig #4), we
fabricated a new set of electrodes with much wider contact area to
the nerve. With this new electrode, we started investigating
signals from 1 Hz to 3,000 Hz again. This time, the most robust
effectiveness and reproducibility was found at a frequency of 25
Hz, 400 .mu.s, 1V.
[0089] FIG. 6 graphically illustrates exemplary experimental data
on guinea pig #5. The graphs of FIG. 6 show the effect of a 25 Hz,
400 .mu.s, 1V square wave signal applied to both left and right
vagus nerve in guinea pig #5 when injected with 8 .mu.g/kg
histamine to cause airway pressure to increase. The first peak in
airway pressure is from histamine alone, the next peak is histamine
and signal applied. It is clearly shown that the increase in airway
pressure due to histamine is reduced in the presence of the 25 Hz,
400 .mu.S, 1V square wave on the vagus nerve.
[0090] FIG. 7 graphically illustrates additional exemplary
experimental data on guinea pig #5. The graphs of FIG. 7 show the
effect of a 25 Hz, 200 .mu.S, 1V square wave signal applied to both
of the left and right vagus nerves in guinea pig #5 when injected
with 8 .mu.g/kg histamine to cause airway pressure to increase. The
second peak in airway pressure is from histamine alone, the first
peak is histamine and signal applied. It is clearly shown that the
increase in airway pressure due to histamine is reduced in the
presence of the 25 Hz, 200 .mu.S, 1V square wave on the vagus
nerve. It is clear that the airway pressure reduction is even
better with the 200 .mu.S pulse width than the 400 .mu.S
signal.
[0091] FIG. 8 graphically illustrates further exemplary
experimental data on guinea pig #5. The graphs of FIG. 8 show
repeatability of the effect seen in the previous graph. The animal,
histamine and signal are the same as the graphs in FIG. 7.
[0092] It is significant that the effects shown above were repeated
several times with this animal (guinea pig #5), without any loss of
nerve activity observed. We could move the electrodes proximally
and distally along the vagus nerve and achieve the same effect. It
was, therefore, concluded that the effect was being achieved
without damaging the nerve.
[0093] FIG. 9 graphically illustrates subsequent exemplary
experimental data on guinea pig #5. The graphs of FIG. 9 show the
effect of a 25 Hz, 100 .mu.S, 1V square wave that switches polarity
from + to - voltage every second. This signal is applied to both
left and right vagus nerve in guinea pig #5 when injected with 8
.mu.g/kg histamine to cause airway pressure to increase. From left
to right, the vertical dotted lines coincide with airway pressure
events associated with: (1) histamine alone (large airway
spike--followed by a very brief manual occlusion of the airway
tube); (2) histamine with a 200 .mu.S signal applied (smaller
airway spike); (3) a 100 .mu.S electrical signal alone (no airway
spike); (4) histamine with a 100 uS signal applied (smaller airway
spike again); (5) histamine alone (large airway spike); and (6)
histamine with the 100 .mu.S signal applied.
[0094] This evidence strongly suggests that the increase in airway
pressure due to histamine can be significantly reduced by the
application of a 25 Hz, 100 .mu.S, 1V square wave with alternating
polarity on the vagus nerve.
[0095] FIG. 10 graphically illustrates exemplary experimental data
on guinea pig #6. The graphs in FIG. 10 show the effect of a 25 Hz,
200 .mu.S, 1V square wave that switches polarity from + to -
voltage every second. This signal is applied to both left and right
vagus nerve in guinea pig #6 when injected with 16 .mu.g/kg
histamine to cause airway pressure to increase. (Note that this
animal demonstrated a very high tolerance to the effects of
histamine, and therefore was not an ideal test subject for the
airway constriction effects, however, the animal did provide us
with the opportunity to test modification of other signal
parameters.)
[0096] In this case, the first peak in airway pressure is from
histamine alone, the next peak is histamine with the signal
applied. It is clearly shown that the increase in airway pressure
due to histamine is reduced moderately in its peak, and most
definitely in its duration, when in the presence of the 25 Hz, 200
.mu.S, 1V square wave with alternating polarity on the vagus
nerve.
[0097] FIG. 11 graphically illustrates additional exemplary
experimental data on guinea pig #6. As mentioned above, guinea pig
#6 in the graphs of FIG. 10 above needed more histamine than other
guinea pigs (16-20 .mu.g/kg vs 8 .mu.g/kg) to achieve the desired
increase in airway pressure. Also, the beneficial effects of the 1V
signal were less pronounced in pig #6 than in #5. Consequently, we
tried increasing the voltage to 1.5V. The first airway peak is from
histamine alone (followed by a series of manual occlusions of the
airway tube), and the second peak is the result of histamine with
the 1.5V, 25 Hz, 200 .mu.S alternating polarity signal. The
beneficial effects are seen with slightly more impact, but not
substantially better than the 1V.
[0098] FIG. 12 graphically illustrates further exemplary
experimental data on guinea pig #6. Since guinea pig #6 was losing
its airway reaction to histamine, we tried to determine if the 25
Hz, 200 .mu.S, 1V, alternating polarity signal could mitigate the
effects of a 20V, 20 Hz airway pressure stimulating signal that has
produced a simulated asthmatic response. The first airway peak is
the 20V, 20 Hz stimulator signal applied to increase pressure, then
switched over to the 25 Hz, 200 .mu.S, 1V, alternating polarity
signal. The second peak is the 20V, 20 Hz signal alone. The first
peak looks modestly lower and narrower than the second. The 25 Hz,
200 .mu.S, 1V signal may have some beneficial airway pressure
reduction after electrical stimulation of airway constriction.
[0099] FIG. 13 graphically illustrates subsequent exemplary
experimental data. On guinea pig #6 we also investigated the effect
of the 1V, 25 Hz, and 200 .mu.S alternating polarity signal. Even
after application of the signal for 10 minutes continuously, there
was no loss of nerve conduction or signs of damage.
[0100] FIG. 14 graphically illustrates exemplary experimental data
on guinea pig #8. The graph below shows the effect of a 25 Hz, 200
.mu.S, 1V square wave that switches polarity from + to - voltage
every second. This signal is applied to both left and right vagus
nerve in guinea pig #8 when injected with 12 .mu.g/kg histamine to
cause airway pressure to increase. The first peak in airway
pressure is from histamine alone, the next peak is histamine with
the signal applied. It is clearly shown that the increase in airway
pressure due to histamine is reduced in the presence of the 25 Hz,
200 .mu.S, 1V square wave with alternating polarity on the vagus
nerve. We have reproduced this effect multiple times, on 4
different guinea pigs, on 4 different days.
[0101] The airway constriction induced by histamine in guinea pigs
can be significantly reduced by applying appropriate electrical
signals to the vagus nerve.
[0102] We found at least 2 separate frequency ranges that have this
effect. At 1000 Hz, 6V, 400 .mu.S the constriction is reduced, but
there is evidence that this is too much power for the nerve to
handle. This may be mitigated by different electrode lead design in
future tests. Different types of animals also may tolerate
differently differing power levels.
[0103] With a 25 Hz, 1V, 100-200 .mu.S signal applied to the vagus
nerve, airway constriction due to histamine is significantly
reduced. This has been repeated on multiple animals many times.
There is no evidence of nerve damage, and the power requirement of
the generator is reduced by a factor of between 480
(40.times.6.times.2) and 960 (40.times.6.times.4) versus the 1000
Hz, 6V, 400 .mu.S signal.
[0104] In addition to the exemplary testing described above,
further testing on guinea pigs was made by applicant to determine
the optimal frequency range for reducing bronchoconstriction. These
tests were all completed similarly as above by first establishing a
consistent response to i.v. histamine, and then performing nerve
stimulation at variations of frequency, voltage and pulse duration
to identity parameters that attenuate responses to i.v. histamine.
The tests were conducted on over 100 animals at the following
frequency values: 1 Hz, 10 Hz, 15 Hz, 25 Hz, 50 Hz, 250 Hz, 500 Hz,
1000 Hz, 2000 Hz and 3000 Hz at pulse durations from 0.16 ms to 0.4
ms with most of the testing done at 0.2 ms. In each of the tests,
applicant attempted to achieve a decrease in the histamine
transient. Any decrease was noted, while a 50% reduction in
histamine transient was considered a significant decrease.
[0105] The 25 Hz signal produced the best results by far with about
68% of the animals tested (over 50 animals tested at this
frequency) achieving a reduction in histamine transient and about
17% of the animals achieving a significant (i.e., greater than 50%)
reduction. In fact, 25 Hz was the only frequency in which any
animal achieved a significant decrease in the histamine transient.
About 30% of the animals produced no effect and only 2% (one
animal) resulted in an increase in the histamine transient.
[0106] The 15 Hz signal was tested on 18 animals and showed some
positive effects, although not as strong as the 25 Hz signal. Seven
of the animals (39%) demonstrated a small decrease in histamine
transient and none of the animals demonstrated an increase in
histamine transient. Also, none of the animals achieved a
significant (greater than 50%) reduction as was seen with the 25 Hz
signal.
[0107] Frequency ranges below 15 Hz had little to no effect on the
histamine transient, except that a 1 Hz signal had the opposite
effect on one animal (histamine transient actually increased
indicating a further constriction of the bronchial passages).
Frequency ranges at or above 50 Hz appeared to either have no
effect or they increased the histamine transient and thus increased
the bronchoconstriction.
[0108] These tests demonstrate that applicant has made the
surprising and unexpected discovery that a signal within a small
frequency band will have a clinically significant impact on
reducing the magnitude of bronchial constriction on animals subject
to histamine. In particular, applicant has shown that a frequency
range of about 15 Hz to about 50 Hz will have some positive effect
on counteracting the impact of histamine, thereby producing
bronchodilation. Frequencies outside of this range do not appear to
have any impact and, in some case, make the bronchoconstriction
worse. In particular, applicant has found that the frequency signal
of 25 Hz appears to be the optimal and thus preferred frequency as
this was the only frequency tested that resulted in a significant
decrease in histamine transient in at least some of the animals and
the only frequency tested that resulted in a positive response
(i.e., decrease in histamine transient) in at least 66% of the
treated animals.
[0109] FIGS. 15-18 graphically illustrate exemplary experimental
data obtained on five human patients in accordance with multiple
embodiments of the present invention. In the first patient (see
FIGS. 15 and 16), a 34 year-old, Hispanic male patient with a four
year history of severe asthma was admitted to the emergency
department with an acute asthma attack. He reported self treatment
with albuterol without success. Upon admission, the patient was
alert and calm but demonstrated bilateral wheezing, elevated blood
pressure (BP) (163/92 mmHg) related to chronic hypertension, acute
bronchitis, and mild throat hyperemia. All other vital signs were
normal. The patient was administered albuterol (2.5 mg), prednisone
(60 mg PO), and zithromax (500 mg PO) without improvement. The
spirometry assessment of the lung function revealed a Forced
Expiratory Volume in 1 second (FEV.sub.1) of 2.68 l/min or 69% of
predicted. Additional albuterol was administered without benefit
and the patient was placed on supplemental oxygen (2 l/min).
[0110] A study entailing a new investigational medical device for
stimulating the selected nerves near the carotid sheath was
discussed with the patient and, after review, the patient completed
the Informed Consent. Following a 90 minute observational period
without notable improvement in symptoms, the patient underwent
placement of a percutaneous, bipolar electrode to stimulate the
selected nerves (see FIG. 16). Using anatomical landmarks and
ultrasound guidance, the electrode was inserted to a position near
the carotid sheath, and parallel to the vagus nerve.
[0111] The electrode insertion was uneventful and a sub-threshold
test confirmed the device was functioning. Spirometry was repeated
and FEV.sub.1 remained unchanged at 2.68 l/min. Stimulation (25 Hz,
300 us pulse width signal) strength was gradually increased until
the patient felt a mild muscle twitch at 7.5 volts then reduced to
7 volts. This setting achieved therapeutic levels without
discomfort and the patient was able to repeat the FEV.sub.1 test
without difficulty. During stimulation, the FEV.sub.1 improved
immediately to 3.18 l/min and stabilized at 3.29 l/min (85%
predicted) during 180 minutes of testing. The benefit remained
during the first thirty minutes after terminating treatment, then
decreased. By 60 minutes post stimulation, dyspnea returned and
FEV.sub.1 decreased to near pre-stimulation levels (73% predicted)
(FIG. 2). The patient remained under observation overnight to
monitor his hypertension and then discharged. At the 1-week
follow-up visit, the exam showed complete healing of the insertion
site, and the patient reported no after effects from the
treatment.
[0112] This was, to the inventor's knowledge, the first use of
nerve stimulation in a human asthma patient to treat
bronchoconstriction. In the treatment report here, invasive surgery
was not required. Instead a minimally invasive, percutaneous
approach was used to position an electrode in close proximity to
the selected nerves. This was a relatively simple and rapid
procedure that was performed in the emergency department and
completed in approximately 10 minutes without evidence of bleeding
or scarring.
[0113] FIG. 17 graphically illustrates another patient treated
according to the present invention. Increasing doses of
methacholine were given until a drop of 24% in FEV.sub.1 was
observed at 1 mg/ml. A second FEV.sub.1 was taken prior to
insertion of the electrode. The electrode was then inserted and
another FEV.sub.1 taken after electrode insertion and before
stimulation. The stimulator was then turned on to 10 V for 4
minutes, the electrode removed and a post-stimulation FEV.sub.1
taken showing a 16% increase. A final rescue albuterol treatment
restored normal FEV.sub.1.
[0114] FIG. 18 is a table summarizing the results of all five human
patients. In all cases, FEV.sub.1 values were measured prior to
administration of the electrical impulse delivery to the patient
according to the present invention. In addition, FEV.sub.1 values
were measures at every 15 minutes after the start of treatment. A
12% increase in FEV.sub.1 is considered clinically significant. All
five patients achieved a clinically significant increase in
FEV.sub.1 of 12% or greater in 90 minutes or less, which represents
a clinically significant increase in an acute period of time. In
addition, all five patients achieved at least a 19% increase in
FEV.sub.1 in 150 minutes or less.
[0115] As shown, the first patient initially presented with an
FEV.sub.1 of 61% of predicted. Upon application of the electrical
impulse described above, the first patient achieved at least a 12%
increase in FEV.sub.1 in 15 minutes or less and achieved a peak
increase in FEV.sub.1 of 43.9% after 75 minutes. The second patient
presented with an FEV.sub.1 of 51% of predicted, achieved at least
a 12% increase in FEV.sub.1 in 30 minutes or less and achieved a
peak increase in FEV.sub.1 of 41.2% after 150 minutes. The third
patient presented with an FEV.sub.1 of 16% of predicted, achieved
at least a 12% increase in FEV.sub.1 in 15 minutes or less and
achieved a peak increase in FEV.sub.1 of about 131.3% in about 150
minutes. However, it should be noted that this patient's values
were abnormal throughout the testing period. The patient was not
under extreme duress as a value of 16% of predicted would indicate.
Therefore, the exact numbers for this patient are suspect, although
the patient's symptoms clearly improved and the FEV.sub.1 increased
in any event. The fourth patient presented with an FEV.sub.1 of
predicted of 66%, achieved at least a 12% increase in FEV.sub.1 in
90 minutes or less and achieved a peak increase in FEV.sub.1 of
about 19.7% in 90 minutes or less. Similarly, the fifth patient
presented with an FEV.sub.1 of predicted of 52% and achieved a
19.2% peak increase in FEV.sub.1 in 15 minutes or less. The
electrode in the fifth patient was unintentionally removed around
30 minutes after treatment and, therefore, a true peak increase in
FEV.sub.1 was not determined.
[0116] In U.S. patent application Ser. No. 10/990,938 filed Nov.
17, 2004 (Publication Number US2005/0125044A1), Kevin J. Tracey
proposes a method of treating many diseases including, among
others, asthma, anaphylactic shock, sepsis and septic shock by
electrical stimulation of the vagus nerve. However, the examples in
the Tracey application use an electrical signal that is 1 to 5V, 1
Hz and 2 mS to treat endotoxic shock, and no examples are shown
that test the proposed method on an asthma model, an anaphylactic
shock model, or a sepsis model. The applicants of the present
application performed additional testing to determine if Tracey's
proposed method has any beneficial effect on asthma or blood
pressure in the model that shows efficacy with the method used in
the present application. The applicants of the present application
sought to determine whether Tracey's signals can be applied to the
vagus nerve to attenuate histamine-induced bronchoconstriction and
increase in blood pressure in guinea pigs.
[0117] Male guinea pigs (400 g) were transported to the lab and
immediately anesthetized with an i.p. injection of urethane 1.5
g/kg. Skin over the anterior neck was opened and the carotid artery
and both jugular veins are cannulated with PE50 tubing to allow for
blood pressure/heart rate monitoring and drug administration,
respectively. The trachea was cannulated and the animal ventilated
by positive pressure, constant volume ventilation followed by
paralysis with succinylcholine (10 ug/kg/min) to paralyze the chest
wall musculature to remove the contribution of chest wall rigidity
from airway pressure measurements.
[0118] Guanethidine (10 mg/kg i.v.) was given to deplete
norepinephrine from nerve terminals that may interfere with vagal
nerve stimulation. Both vagus nerves were exposed and connected to
electrodes to allow selective stimuli of these nerves. Following 15
minutes of stabilization, baseline hemodynamic and airway pressure
measurements were made before and after the administration of
repetitive doses of i.v. histamine.
[0119] Following the establishment of a consistent response to i.v.
histamine, vagal nerve stimulation was attempted at variations of 1
to 5 volts, 1 Hz, 2 mS to identity parameters that attenuate
responses to i.v. histamine. Bronchoconstriction in response to
i.v. histamine is known to be due to both direct airway smooth
muscle effects and due to stimulation of vagal nerves to release
acetylcholine.
[0120] At the end of vagal nerve challenges atropine was
administered i.v. before a subsequent dose of histamine to
determine what percentage of the histamine-induced
bronchoconstriction was vagal nerve induced. This was considered a
100% response. Success of electrical interruption in vagal nerve
activity in attenuating histamine-induced bronchoconstriction was
compared to this maximum effect. Euthanasia was accomplished with
intravenous potassium chloride.
[0121] In order to measure the bronchoconstriction, the airway
pressure was measured in two places. The blood pressure and heart
rate were measured to track the subjects' vital signs. In all the
following graphs, the top line BP (red) shows blood pressure,
second line AP1 shows airway pressure, third line AP2 shows airway
pressure on another sensor, the last line HR is the heart rate
derived from the pulses in the blood pressure.
[0122] FIG. 19 graphically illustrates exemplary experimental data
from a first experiment on another guinea pig. The graph shows the
effects of Tracey's 1V, 1 Hz, 2 mS waveform applied to both vagus
nerves on the guinea pig. The first peak in airway pressure is from
histamine alone, after which Tracey's signal was applied for 10
minutes as proposed in Tracey's patent application. As seen from
the second airway peak, the signal has no noticeable effect on
airway pressure. The animal's vital signs actually stabilized, seen
in the rise in blood pressure, after the signal was turned off.
[0123] FIG. 20 graphically illustrates exemplary experimental data
from a second experiment on the guinea pig in FIG. 19. The graph
shows the effects of Tracey's 1V, 1 Hz, 2 mS waveform with the
polarity reversed (Tracey did not specify polarity in the patent
application) applied to both vagus nerves on the guinea pig. Again,
the signal has no beneficial effect on airway pressure. In fact,
the second airway peak from the signal and histamine combination is
actually higher than the first peak of histamine alone.
[0124] FIG. 21 graphically illustrates exemplary experimental data
from a third experiment on the guinea pig in FIG. 19. The graph
shows the effects of Tracey's 1V, 1 Hz, 2 mS waveform applied to
both vagus nerves on the guinea pig. Again, the signal has no
beneficial effect on airway pressure. Instead, it increases airway
pressure slightly throughout the duration of the signal
application.
[0125] FIG. 22 graphically illustrates additional exemplary
experimental data from an experiment on a subsequent guinea pig.
The graph shows, from left to right, application of the 1.2V, 25
Hz, 0.2 mS signal disclosed in the present application, resulting
in a slight decrease in airway pressure in the absence of
additional histamine. The subsequent three electrical stimulation
treatments are 1V, 5V, and 2.5V variations of Tracey's proposed
signal, applied after the effects of a histamine application
largely had subsided. It is clear that the Tracey signals do not
cause a decrease in airway pressure, but rather a slight increase,
which remained and progressed over time.
[0126] FIG. 23 graphically illustrates further exemplary
experimental data from additional experiments using signals within
the range of Tracey's proposed examples. None of the signals
proposed by Tracey had any beneficial effect on airway pressure.
Factoring in a potential range of signals, one experiment used
0.75V, which is below Tracey's proposed range, but there was still
no beneficial effect on airway pressure.
[0127] FIG. 24 graphically illustrates exemplary experimental data
from subsequent experiments showing the effect of Tracey's 5V, 1
Hz, 2 mS signal, first without and then with additional histamine.
It is clear that the airway pressure increase is even greater with
the signal, as the airway pressure progressively increased during
the course of signal application. Adding the histamine after
prolonged application of the Tracey signal resulted in an even
greater increase in airway pressure.
[0128] The full range of the signal proposed by Tracey in his
patent application was tested in the animal model of the present
application. No reduction in airway pressure was seen. Most of the
voltages resulted in detrimental increases in airway pressure and
detrimental effects to vital signs, such as decreases in blood
pressure.
[0129] In International Patent Application Publication Number WO
93/01862, filed Jul. 22, 1992, Joachim Wernicke and Reese Terry
(hereinafter referred to as "Wernicke") propose a method of
treating respiratory disorders such as asthma, cystic fibrosis and
apnea by applying electric signals to the patient's vagus nerve.
However, Wernicke specifically teaches to apply a signal that
blocks efferent activity in the vagus nerve to decrease the
activity of the vagus nerve to treat asthma. Moreover, the example
disclosed in Wernicke for the treatment of asthma is an electrical
impulse having a frequency of 100 Hz, a pulse width of 0.5 ms, an
output current of 1.5 mA and an OFF time of 10 seconds for every
500 seconds of ON time (see Table 1 on page 17 of Wernicke). The
applicants of the present application performed additional testing
to determine if Wernicke's proposed method has any beneficial
effect on bronchodilation or blood pressure in the model that shows
efficacy with the method used in the present application. The
applicants of the present application sought to determine whether
Wernicke's signal can be applied to the vagus nerve to attenuate
histamine-induced bronchoconstriction and increase in blood
pressure in guinea pigs.
[0130] Similar to the Tracey testing, male guinea pigs (400 g) were
transported to the lab and immediately anesthetized with an i.p.
injection of urethane 1.5 g/kg. Skin over the anterior neck was
opened and the carotid artery and both jugular veins are cannulated
with PE50 tubing to allow for blood pressure/heart rate monitoring
and drug administration, respectively. The trachea was cannulated
and the animal ventilated by positive pressure, constant volume
ventilation followed by paralysis with succinylcholine (10
ug/kg/min) to paralyze the chest wall musculature to remove the
contribution of chest wall rigidity from airway pressure
measurements.
[0131] Guanethidine (10 mg/kg i.v.) was given to deplete
norepinephrine from nerve terminals that may interfere with vagal
nerve stimulation. Both vagus nerves were exposed and connected to
electrodes to allow selective stimuli of these nerves. Following 15
minutes of stabilization, baseline hemodynamic and airway pressure
measurements were made before and after the administration of
repetitive doses of i.v. histamine.
[0132] Following the establishment of a consistent response to i.v.
histamine, vagal nerve stimulation was attempted at variations of
100 Hz, 0.5 ms and 1.5 mA output current to identity parameters
that attenuate responses to i.v. histamine. Bronchoconstriction in
response to i.v. histamine is known to be due to both direct airway
smooth muscle effects and due to stimulation of vagal nerves to
release acetylcholine.
[0133] At the end of vagal nerve challenges atropine was
administered i.v. before a subsequent dose of histamine to
determine what percentage of the histamine-induced
bronchoconstriction was vagal nerve induced. This was considered a
100% response. Success of electrical interruption in vagal nerve
activity in attenuating histamine-induced bronchoconstriction was
compared to this maximum effect. Euthanasia was accomplished with
intravenous potassium chloride.
[0134] In order to measure the bronchoconstriction, the airway
pressure was measured in two places. The blood pressure and heart
rate were measured to track the subjects' vital signs. In all the
following graphs, the top line BP (red) shows blood pressure,
second line AP1 shows airway pressure, third line AP2 shows airway
pressure on another sensor, the last line HR is the heart rate
derived from the pulses in the blood pressure.
[0135] FIGS. 25 and 26 graphically illustrate exemplary
experimental data from the experiment on another guinea pig. The
graph shows the effects of Wernicke's 100 Hz, 1.5 mA, 0.5 mS
waveform applied to both vagus nerves on the guinea pig. FIG. 25
illustrates two peaks in airway pressure (AP) from histamine alone
with no treatment (the first two peaks) and a third peak at the
right of the graph after which Wernicke's signal was applied at 1.2
mA. As shown, the results show no beneficial result on the
histamine-induced airway pressure increase or the blood pressure at
1.2 mA. In FIG. 26, the first and third peaks in airway pressure
(AP) are from histamine along with no treatment and the second peak
illustrates airway pressure after Wernicke's signal was applied at
1.8 mA. As shown, the signal actually increased the
histamine-induced airway pressure at 2.8 mA, making it clinically
worse. Thus, it is clear the Wernicke signals do not cause a
decrease in airway pressure.
[0136] Although the invention herein has been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of the principles and
applications of the present invention. It is therefore to be
understood that numerous modifications may be made to the
illustrative embodiments and that other arrangements may be devised
without departing from the spirit and scope of the present
invention as defined by the appended claims.
* * * * *