U.S. patent application number 16/277824 was filed with the patent office on 2019-06-13 for devices and methods for treatment of heart failure via electrical modulation of a splanchnic nerve.
The applicant listed for this patent is Tamara Colette BAYNHAM, Mark GELFAND, Howard LEVIN. Invention is credited to Tamara Colette BAYNHAM, Mark GELFAND, Howard LEVIN.
Application Number | 20190175912 16/277824 |
Document ID | / |
Family ID | 65322629 |
Filed Date | 2019-06-13 |
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United States Patent
Application |
20190175912 |
Kind Code |
A1 |
GELFAND; Mark ; et
al. |
June 13, 2019 |
DEVICES AND METHODS FOR TREATMENT OF HEART FAILURE VIA ELECTRICAL
MODULATION OF A SPLANCHNIC NERVE
Abstract
Disclosed herein is a device, and method for treating heart
failure by electrically modulating a splanchnic nerve with an
implantable device.
Inventors: |
GELFAND; Mark; (New York,
NY) ; BAYNHAM; Tamara Colette; (Bowie, MD) ;
LEVIN; Howard; (Teaneck, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GELFAND; Mark
BAYNHAM; Tamara Colette
LEVIN; Howard |
New York
Bowie
Teaneck |
NY
MD
NJ |
US
US
US |
|
|
Family ID: |
65322629 |
Appl. No.: |
16/277824 |
Filed: |
February 15, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15293021 |
Oct 13, 2016 |
10207110 |
|
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16277824 |
|
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62240864 |
Oct 13, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/024 20130101;
A61B 5/1118 20130101; A61N 1/36135 20130101; A61B 5/02007 20130101;
A61B 5/029 20130101; A61B 5/4836 20130101; A61B 5/021 20130101;
A61B 5/4848 20130101; A61N 1/0556 20130101; A61B 2562/0219
20130101; G16H 20/40 20180101; A61B 5/4806 20130101; A61B 5/04001
20130101; A61B 5/686 20130101; A61B 5/1116 20130101; A61N 1/3627
20130101; G16H 40/63 20180101; A61B 5/1123 20130101; G16H 20/30
20180101; A61N 1/36114 20130101 |
International
Class: |
A61N 1/36 20060101
A61N001/36; A61N 1/05 20060101 A61N001/05; A61B 5/00 20060101
A61B005/00; A61N 1/362 20060101 A61N001/362 |
Claims
1. A method of selecting a patient for a greater splachnic nerve
blocking procedure to treat heart failure or symptoms associated
with heart failure in the patient, comprising: evaluating the
patient's splachnic vascular capacitance and determining whether or
not the splachnic vascular capacitance is below normal; if the
evaluated splachnic vascular capacitance is below normal,
identifying a target greater splachnic nerve for a blocking
procedure, wherein identifying the target greater splachnic nerve
comprises temporarily blocking the identified greater splachnic
nerve and measuring a physiological response to determine if the
temporarily blocking produced a desired clinical result; if the
temporary blocking produced the desired clinical result, performing
the blocking procedure on the identified greater splachnic
nerve.
2. The method of claim 1, wherein the evaluating step comprises
performing at least one of an orthostatic stress test, a fluid
challenge, an exercise test, and a drug challenge.
3. The method of claim 1, wherein the temporarily blocking step
comprises electrically stimulating a greater splachnic nerve.
4. The method of claim 1, wherein performing the blocking procedure
on the identified greater splachnic nerve comprises performing the
blocking procedure with an implanted device.
5. A nerve cuff adapted to deliver blocking therapy and further
adapted to confirm the the blocking therapy, comprising: a cuff
sized and configured to be positioned around a greater splanchnic
nerve; at least first, second, and third blocking therapy
electrodes secured to the cuff and axially spaced from one another;
at least one confirmation and stimulation electrode secured to the
cuff and axially spaced from the first, second and third blocking
therapy electrodes.
6. The nerve cuff of claim 5, wherein a distance between adjacent
pairs of the first, second, and third blocking therapy electrodes
is 1 to 2 mm.
7. The nerve cuff of claim 5, wherein the at least one confirmation
and stimulation electrode comprises first and second confirmation
and stimulation electrodes.
8. The nerve cuff of claim 7, wherein a distance between the first
and second confirmation and stimulation electrodes is 2-3 mm.
9. A method of using the nerve cuff in claim 5, comprising:
delivering blocking therapy with the first, second, and third
blocking therapy electrodes to the greater splanchnic nerve;
ceasing the delivery of blocking therapy; subsequent to the
cessation step, stimulating the greater splachnic nerve with the at
least one confirmation and stimulation electrode; and recording
extracellular action potentials resulting from the stimulating step
with at least one of the first, second, and third blocking therapy
electrodes.
10. A method of increasing exercise capacity in a patient by
blocking a greater splanchnic nerve, comprising: detecting that a
patient has started to exercise; and after detecting that the
patient has started to exercise and in response to the detection,
delivering blocking therapy to a greater splanchnic nerve to
increase the exercise capacity in a patient.
11. The method of claim 10, wherein delivering the blocking therapy
comprising deliverying the blocking therapy with an implanted nerve
cuff secured to the greater splanchnic nerve.
12. The method of claim 10, further comprising assessing the
effectiveness of the blocking therapy.
13. The method of claim 12, further comprising monitoring therapy
effectiveness by measuring physiological signals.
14. A method of treating heart failure or symptoms associated with
heart failure in a human patient, comprising: in a patient with
heart failure or symptoms associated with heart failure; surgically
accessing at least one thoracic nerve and optionally deflating the
lung proximate to that nerve; and affixing an implantable
neuromodulation device for applying nerve blocking therapy to said
at least one nerve, said device comprising a stimulus producer for
producing a nerve stimulus, and a delivery member for delivering
stimulus to said nerve, wherein said stimulus has parameters able
to cause a reversible blockage to the nerve conduction along the at
least one thoracic nerve.
15. The method of claim 14, wherein the implantable neuromodulation
device is affixed using a surgically implantable nerve cuff.
16. The method of claim 14, wherein said nerve is a greater
splanchnic nerve, and at least one of a left greater splanchnic
nerve and a right greater splanchnic nerve.
17. The method of claim 14, wherein surgically accessing is
selected from the group consisting of transthoracic,
transabdominal, percutaneous, access or any combination
thereof.
18. A method of treating heart failure or symptoms associated with
heart failure in a human patient, comprising: in a patient with
heart failure or symptoms associated with heart failure,
thoracoscopically accessing at least one greater splanchnic nerve
and optionally deflating the lung proximate to that nerve, affixing
an implantable neuromodulation device with a nerve cuff to said at
least one nerve, said device further comprising a pulse generator,
a detection member for detecting at least one physiological
parameter, and at least one lead for delivering stimulus to said
nerve through said nerve cuff, wherein said stimulus has parameters
able to cause a reversible blockage to the nerve conduction along
the at least one greater splanchnic nerve
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/293,021 filed Oct. 13, 2016 which claims
the benefit of the filing date of U.S. Provisional Application No.
62/240,864, filed Oct. 13, 2015, each of which application is
incorporated by reference in its entirety.
INCORPORATION BY REFERENCE
[0002] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
FIELD
[0003] The present disclosure is directed generally to devices,
systems and methods for treating patients suffering from heart
failure by electrically modulating a greater splanchnic nerve.
BACKGROUND
[0004] Heart failure (HF) is a medical condition that occurs when
the heart is unable to pump sufficiently to sustain the organs of
the body. Heart failure is a serious condition and affects millions
of patients in the United States and around the world.
[0005] In the United States alone, about 5.1 million people suffer
from heart failure and according to the Center for Disease Control,
the condition costs the nation over $30 billion in care,
treatments, medications, and lost production.
[0006] The normal healthy heart is a muscular pump that is, on
average, slightly larger than a fist. It pumps blood continuously
through the circulatory system to supply the body with oxygenated
blood. Under conditions of heart failure, the weakened heart cannot
supply the body with enough blood and results in cardiomyopathy
(heart muscle disease) characterized by fatigue and shortness of
breath, making even everyday activities such as walking very
difficult.
[0007] Oftentimes, in an attempt compensate for this dysfunction,
the heart and body undergo physiological changes that temporarily
mask the inability of the heart to sustain the body. These changes
include the enlargement of heart chamber, increased cardiac
musculature, increased heart rate, raised blood pressure, poor
blood flow, and imbalance of body fluids in the limbs and
lungs.
[0008] One common measure of heart health is left ventricular
ejection fraction (LVEF) or ejection fraction. By definition, the
volume of blood within a ventricle immediately before a contraction
is known as the end-diastolic volume (EDV). Likewise, the volume of
blood left in a ventricle at the end of contraction is end-systolic
volume (ESV). The difference between EDV and ESV represents the
stroke volume (SV). SV describes the volume of blood ejected from
the right and left ventricles with each heartbeat. Ejection
fraction (EF) is the fraction of the end-diastolic volume that is
ejected with each beat; that is, it is stroke volume (SV) divided
by end-diastolic volume (EDV). Cardiac Output (CO) is defined as
the volume of blood pumped per minute by each ventricle of the
heart. CO is equal to SV times the heart rate (HR). Cardiomyopathy,
in which the heart muscle becomes weakened, stretched, or exhibits
other structural problems, can be further categorized into systolic
and diastolic heart failure based on ventricular ejection
fraction.
[0009] Systolic dysfunction is characterized by a decrease in
myocardial contractility. A reduction in the left ventricular
ejection fraction (LVEF) results when myocardial contractility is
decreased throughout the left ventricle. CO is maintained in two
ways: left ventricular enlargement results in a higher stroke
volume and an increase in contractility as a result of the
increased mechanical advantage from stretching the heart. However,
these compensatory mechanisms are eventually exceeded by continued
weakening of the heart and CO decreases resulting in the
physiologic manifestations of heart failure. The left side of the
heart cannot pump with enough force to push a sufficient amount of
blood into the systemic circulation. This leads to fluid backing up
into the lungs and pulmonary congestion. In general terms, systolic
dysfunction is defined as an LVEF less than 40% and heart failure
in these patients can be broadly categorized as heart failure with
reduced ejection fraction (HFrEF).
[0010] On the other hand, diastolic dysfunction refers to cardiac
dysfunction in which left ventricular filling is abnormal and is
accompanied by elevated filling pressures. In diastole, while the
heart muscle is relaxed the filling of the left ventricle is a
passive process that depends on the compliance (defined by volume
changes over pressure changes), or distensibility, of the
myocardium or heart muscle. When the ventricles are unable to relax
and fill, the myocardium may strengthen in an effort to compensate
to poor stroke volume. This subsequent muscle hypertrophy leads to
even further inadequate filling. Diastolic dysfunction may lead to
edema or fluid accumulation, especially in the feet, ankles, and
legs. Furthermore, some patients may also have pulmonary congestion
as result of fluid buildup in the lungs. For patients with heart
failure but without systolic dysfunction, diastolic dysfunction is
the presumed cause. Diastolic dysfunction is characteristic of not
only hypertrophic cardiomyopathy (HCM) characterized by the
thickening of heart muscle, but also restrictive cardiomyopathy
(RCM) characterized by rigid heart muscle that cannot stretch to
accommodate passive filling. In general terms, diastolic
dysfunction is defined as an LVEF of greater than 40% and heart
failure in these patients can be broadly categorized as heart
failure with preserved ejection fraction (HFpEF).
[0011] While a number of drug therapies are successfully targeting
systolic dysfunction and heart failure with reduced ejection
fraction (HFrEF), drug therapies may have pervasive side effects in
some patients and are ineffective or dangerous to others. For the
large group of patients with diastolic dysfunction and heart
failure with preserved ejection fraction (HFpEF) no promising
therapies have yet been identified. The clinical course for
patients with both HFrEF and HFpEF is significant for recurrent
presentations of acute decompensated heart failure (ADHF) with
symptoms of dyspnea, decreased exercise capacity, peripheral edema
etc. Recurrent admissions for ADHF utilize the largest part of
current health care resources and could continue to generate
enormous costs.
[0012] While the physiology of heart failure is increasingly
becoming better understood, modern medicine has, thus far, failed
to develop new therapies for chronic management of HF or recurrent
ADHF episodes. Over the past few decades, strategies of ADHF
management and prevention have and continue to focus on the
classical paradigm that salt and fluid retention is the culprit of
intravascular fluid expansion and cardiac decompensation.
Increasing evidence suggests that fluid homeostasis and control of
intravascular fluid distribution is disrupted in patients with HF.
Deregulation of this key cardiovascular regulatory component could
not only explain findings in chronic HF but also in ADHF.
Consequently, blocking of the autonomic nervous system to alter
fluid distribution in the human body could be used as a therapeutic
intervention.
[0013] Additionally, the classical understanding of HF
pathophysiology emphasizes the mechanism of poor forward flow
(i.e., low cardiac output), resulting in neurohumoral, or
sympathetic nervous system (SNS) up-regulation. However, new
evidence emphasizes the concurrent role of backward failure (i.e.,
systemic congestion) in the pathophysiology and disease progression
of HF. Coexisting renal dysfunction with diuretic resistance often
complicates the treatment of HF and occurs more frequently in
patients with increased cardiac filling pressures. Chronic
congestive HF is characterized by longstanding venous congestion
and increased neurohumoral activation. Critically important has
been the identification of the splanchnic vascular bed as a major
contributor to blood pooling and cardiac physiology. Newly evolving
methods and devices involving sympathetic nervous system blocking
and manipulation of systems including the splanchnic vascular bed
have opened novel avenues to approach the treatment of heart
disease. In particular, the role of sympathetic nerves that
innervate smooth muscle in the walls of splanchnic veins have
become better known. In the case of hyperactivity of these nerves
they became a novel target in the treatment of CHF.
SUMMARY OF THE DISCLOSURE
[0014] In view of the foregoing, it would be desirable to provide
an apparatus and methods to affect neurohumoral activation for the
treatment of heart failure and particularly diastolic heart
failure, heart failure with preserved ejection fraction.
[0015] The present disclosure provides improved treatment options
for patients suffering from heart failure by blocking or inhibiting
the nerve activity of the splanchnic nerves (e.g., greater, lesser
and least) that innervate organs and vasculature of the abdominal
compartment and the greater splanchnic nerve (GSN) in particular.
By selectively blocking activity of specific nerves, the disclosure
provides methods and devices that can affect circulating blood
volume, pressure, blood flow and overall heart and circulatory
system functions. In this way, the present disclosure helps to
introduce solutions to treat HF and particularly heart failure with
preserved ejection fraction (HFpEF) based on the most contemporary
physiological theories regarding heart failure.
[0016] About 5% of the total body water is located within the
vasculature in the form of blood. The venous system contains
approximately 70% of total blood volume and is roughly 30 times
more compliant than the arterial system. Venous compliance is a
measure of the ability of a hollow organ or vessel to distend and
increase in volume with increasing internal pressure. A number of
mechanisms are involved in regulation of volume, most importantly
the neurohormonal system. On the arterial side, resistance vessels
regulate flow and resistance. The sympathetic nervous system plays
a major role in determining systemic vascular resistance
predominantly through activation and deactivation of
cardiopulmonary and arterial baroreflexes, as well as through
changes in circulating norepinephrine. Capacitance is a determinant
of the venous vascular function and higher vascular capacitance
means more blood can be stored in the respective vasculature. The
autonomic nervous system is the main regulatory mechanism of
vascular capacitance.
[0017] Circulating blood is distributed into two physiologically
but not anatomically separate compartments: the "venous reservoir"
and "effective circulatory volume". The term "venous reservoir" (or
"unstressed volume") refers to the blood volume that resides mainly
in the splanchnic vascular bed and does not contribute to the
effective circulating volume. The venous reservoir also referred to
as "unstressed volume" or "vascular capacitance" can be recruited
through a number of mechanisms like activation of the sympathetic
nervous system, drugs, or hormones. The term "effective circulatory
volume" (or "stressed volume") refers to blood that is present
mainly in the arterial system and in non-splanchnic venous vessels
and is one of the main determinants of preload of the heart. The
stressed blood volume and systemic blood pressure are regulated by
the autonomic nervous system part of which is the sympathetic
nervous system.
[0018] The unstressed volume of blood is mostly contained in the
splanchnic reservoir or "splanchnic vascular bed". The splanchnic
reservoir consists of vasculature of the visceral organs including
the liver, spleen, small and large bowel, stomach, as well as the
pancreas. Due to the low vascular resistance and high capacitance
the splanchnic vascular bed receives about 25% of the cardiac
output and the splanchnic veins contain anywhere from 20% to 50% of
the total blood volume. Consequently, the splanchnic vascular bed
serves as the major blood reservoir, which can take up or release,
actively and passively, the major part of any change in circulating
blood volume. While experimenting with cadavers and animals,
inventors were able to selectively block or stimulate the GSN to
artificially manipulate or modify the venous reservoir.
[0019] Splanchnic veins are considerably more compliant than veins
of the extremities. Animal and human studies demonstrate that the
splanchnic reservoir can not only store considerable amounts of
blood, but blood can also be actively or passively recruited from
it into the systemic circulation in response to variations of the
venous return to the heart. One of the main determinants of active
recruitment is sympathetic nerve activity (SNA), which through
hormones and a neurotransmitters epinephrine and norepinephrine
causes venoconstriction, thereby reducing splanchnic capacitance
and increasing effective circulatory volume. This can be explained
by a large numbers of adrenergic receptors in the splanchnic
vasculature that are sensitive to changes to the sympathetic
nervous system. Compared with arteries, splanchnic veins contain
more than 5 times the density of adrenergic terminals. The
consequence is a more pronounced venous vasomotor response in the
splanchnic system compared to other vascular regions.
[0020] The splanchnic vascular bed is well suited to accommodate
and store large amounts of blood as well as shift blood back into
active circulation, naturally acting in a temporary blood volume
storage capacity. The high vascular capacitance allows the
splanchnic vascular bed to maintain preload of the heart and
consequently arterial blood pressure and cardiac output over a wide
range of total body volume changes. Once the storage capacity of
the splanchnic vascular bed is reached, increases in total body
fluid express themselves as increased cardiac preload beyond
physiologic need and eventually extravascular edema and
particularly fluid accumulation in the lungs that is a symptom
common in heart failure.
[0021] Increased activation of the sympathetic nervous system and
the neurohormonal axis along with increases in body fluids and
salts have long been debated as causes versus effects of heart
failure. It has been previously suggested that in heart failure
redistribution of the splanchnic reservoir, driven by increased
sympathetic nerve activity to the splanchnic vascular bed leading
to decreased venous compliance and capacitance, is responsible for
increased intra-cardiac filling pressure (preload) in the absence
of increases in total body salt and water. Heart failure is marked
by chronic over-activity of the sympathetic nervous system and the
neurohormonal axis. It is now suggested that sympathetic nerve
activity and neurohormonal activation result in an increased
vascular tone and consequently in decreased vascular capacitance of
the splanchnic vascular bed. While peripheral vascular capacitance
is unchanged in HFpEF and HFrEF compared to controls, the
splanchnic vascular capacitance is decreased.
[0022] It is important to note that the so-called "acute heart
failure" is initiated by a combination of two pathways: cardiac and
vascular. The "cardiac pathway" is generally initiated by a low
cardiac contractility reserve, while the "vascular pathway" is
common to acute heart failure (AHF) that exhibits mild to moderate
decrease in cardiac contractility reserve.
[0023] Notably, in acute decompensated heart failure (ADHF), which
characterized by worsening of the symptoms: typically shortness of
breath (dyspnea), edema, and fatigue, in a patient with existing
heart disease, the cardiac filling pressures generally start to
increase more than 5 days preceding an admission. While this could
reflect a state of effective venous congestion following a build-up
of volume, nearly 50% of patients gain only an insignificant amount
of weight (<1 kg) during the week before admission. This means
that in about 50% of cases, decompensated HF is not caused by
externally added fluid, but rather symptoms and signs of congestion
can be entirely explained by redistribution of the existing
intravascular volume. Acute increases in sympathetic nervous tone
due to a variety of known triggers like cardiac ischemia,
arrhythmias, inflammatory activity and psychogenic stress and other
unknown triggers can disrupt the body's balance and lead to a fluid
shift from the splanchnic venous reservoir into the effective
circulation. This results ultimately in an increase in preload and
venous congestion. This explains the finding that in ADHF in both
HFrEF and HFpEF was preceded by a significant increase in diastolic
blood pressures.
[0024] In patients with HFpEF only small increases in diastolic
pressures/preload can result in decompensation due to impaired
relaxation of the ventricles. Thus patients with HFpEF are more
sensitive to intrinsic or extrinsic fluid shifts.
[0025] Chronic congestive heart failure is characterized by
longstanding venous congestion and increased neurohumoral
activation. Like in AHF, the splanchnic vascular bed has been
identified as a major contributor to HF physiology. Chronic
decrease in vascular compliance makes the human body more
susceptible for recurrent acute decompensation, making significant
the consequences of chronic congestion of the splanchnic
compartment. While the splanchnic vascular compartment is well
suited to accommodate acute fluid shifts (e.g., orthostasis,
exercise and dietary intake), the regulation of the splanchnic
vascular bed becomes maladaptive in chronic disease states
associated with increased total body volume and increased
splanchnic vascular pressure.
[0026] Clinically observed effects of heart failure drug regimens
like nitroglycerin and angiotension converting enzyme (ACE)
inhibitors exhibit their positive effects in the treatment of HF in
part through an increase in splanchnic capacitance subsequently
shifting blood into the venous reservoir thereby lowering left
ventricular diastolic pressure.
[0027] An orthostatic stress test (tilt test) can help to
distinguish high from low vascular capacitance. Orthostatic stress
causes blood shifts from the stressed volume into the unstressed
volume. Veins of the extremities are less compliant than splanchnic
veins, and therefore, their role as blood volume reservoirs is
relatively minimal. Less known is that blood goes mostly into the
splanchnic compartment, which results in a decreased preload to the
right and left heart. Stimulation of the atrial and carotid
baroreceptors results in an increased sympathetic tone causing
splanchnic vasoconstriction. This compensatory mechanism is
important, as it can rapidly shift volume from the unstressed
compartment back into active circulation. The hemodynamic response
to tilt in chronic congestive heart failure is atypical, as there
is no significant peripheral pooling in the upright posture. While
tolerance of orthostatic stress could be due to higher filling
volumes, filling status alone cannot explain this phenomenon.
[0028] Acute oral or intravenous fluid challenge can also serve as
a test of splanchnic vascular capacitance. The vascular capacitance
determines how "full" the unstressed volume reservoir (venous
reservoir) is and how much more fluid can be taken up to it in
order to buffer the effective circulation (stressed volume). A
fluid challenge could test the capacitance by measuring the effects
of a fluid bolus on cardiac filling pressures. Patients with a
"full tank", (low capacitance of venous reservoir), will not be
able to buffer the hemodynamic effects of the fluid bolus as well
as patients with a high capacitance in the venous reservoir.
Understandably patients with HF, HFpEF and patients with increased
sympathetic nerve activity will be more likely to respond to the
fluid challenge with a disproportional rise in cardiac filling
pressures. This could serve as a patient selection tool as well as
measure of therapeutic success.
[0029] In order to target the splanchnic nerves, primarily the
greater splanchnic nerve (GSN), the thoracic sympathetic trunk and
celiac plexus, several invasive and minimally invasive methods can
be used. Although not limited to these methods, access can be
transthoracic, transabdominal, percutaneous, or video-assisted
thoracoscopy.
[0030] Video-assisted thoracoscopic surgery (VATS) is a minimally
invasive surgical technique that may be used to target the
splanchnic nerves. The instrumentation for VATS includes the use of
a camera-linked 5 mm or 10 mm fiber-optic scope, with or without a
30-degree angle of visualization, and either conventional thoracic
instruments or laparoscopic instruments. Lung deflation, at least
partially, on the side of the chest where VATS is being performed
is a must to be able to visualize and pass instruments into the
thorax; this is usually achieved with a double-lumen endo-tracheal
tube that allows for single lung ventilation or a bronchial blocker
delivered via a standard single-lumen endotracheal tube. The use of
VATS provides direct visualization of the greater splanchnic nerve
as well as the placement of cuff electrodes.
[0031] Electrical modulation, specifically in the form of kilohertz
frequency range stimulation can provide the means to produce nerve
block. The term "electric nerve block" is used to describe the use
of electrical impulses to create a nerve block instead of the
traditional method of injecting an anesthetizing agent into the
site.
[0032] Electrodes can produce high frequency electrical impulses to
overstimulate or block a target area or nerve, but require careful
medical application to optimize outcomes. Nerves of the human body
can repolarize in a fraction of a second, thus, the minimum
blocking frequency is typically 1,000 to 20,000 Hz or more in some
cases at amplitudes of electric current above threshold of
stimulation or induced firing of the nerve. Current applied for
some duration at such frequencies prevent the nerves from
repolarizing and firing and instead achieve a neural blockade or
nerve block. It is to be understood that stimulation of a target or
target nerve is a term used to describe the modulation of nerve
activity.
[0033] In the context of this disclosure, modulation describes not
only stimulation to increase nerve activity, but also, more
notably, stimulation to create a nerve block. Conduction of the
blocking signal can be performed by a number of preferred
embodiments, as described in the examples, including single,
multiple, or multipole cuff electrodes that can be spiral or other
cuff configurations.
[0034] In light of the foregoing, it is desired that the present
disclosure provide treatment that is portable and implantable, yet
effective in reliably blocking target nerves, such as the greater
splanchnic nerve, to mobilize blood out of the effective
circulation (stressed volume) and shift it into splanchnic organs
or vasculature, and bed (venous reservoir) in order to temporarily
decrease cardiac preload and reduce venous congestion, relieve
pulmonary congestion, reduce pulmonary blood pressures and thus
sensation of dyspnea and to increase stroke volume, enhance blood
circulation and improve overall heart function. As such, use of the
present disclosure would grant patients suffering from heart
disease a return to a higher quality of living. This may be
especially important in patients with HFpEF that have normal
pulmonary blood pressures at rest but elevated ones when they
attempt to exercise and are thus unable to exercise or have modest
physical activity because of sensation of dyspnea that is believed
to be caused by an increase of pulmonary blood pressures.
[0035] Further, the present disclosure could be used in the therapy
of acute as well as chronic heart failure decompensation. Acute
heart failure decompensation would be prevented or its progression
halted by an offloading of the stressed volume and relieving venous
congestion, which believed to be a significant component of renal
dysfunction in heart failure. The disclosure can be used in support
of traditional medical therapy like diuretics as it can interrupt
or delay progression of cardiac decompensation.
[0036] In a chronic congestive heart failure state, the use of the
disclosure can be used on a long-term basis to improve fluid
distribution, thus improve symptoms of congestion like shortness of
breath and improve exercise capacity.
[0037] Compared to present methods of nerve blocking, the
disclosure aims to create reliable and consistent methods of nerve
blocking that are safe and cause no adverse effects, such as pain,
sensation or nerve damage. Additionally, the present disclosure
fulfills a long desired need to provide a treatment for heart
failure, especially for patients of diastolic or heart failure with
preserved ejection fraction (HFpEF) and particularly the need to
reduce or moderate the increase of pulmonary pressure and relieve
dyspnea (shortness of breath).
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] Other advantages of the disclosure are made apparent in the
following descriptions taken in conjunction with the provided
drawings wherein are set forth, by way of illustration and example,
certain exemplary embodiments of the present disclosure
wherein:
[0039] FIG. 1 is an anatomical representation of the supply of
sympathetic nerve fibers to organs of the human body.
[0040] FIG. 2 is a flow diagram showing the mechanisms of
decompensated heart failure
[0041] FIG. 3 is a partial flow diagram showing the role of
splanchnic compartment in blood volume distribution in heart
failure.
[0042] FIG. 4 is a partial flow diagram showing the role of the
therapeutic effects of disclosure to heart failure.
[0043] FIG. 5 is a graphical representation of pathophysiology of
acute decompensated heart failure.
[0044] FIGS. 6A, 6B and 6C are representations of the electrical
current in different cuff electrodes.
[0045] FIGS. 7A and 7B illustrate factors that determine minimal
electrical blocking parameter.
[0046] FIG. 8 is a schematic diagram of patient lying in the
lateral decubitus position having one camera port in the fifth
intercostal space at the mid-axillary line and one instrument port
placed at the anterior axillary line.
[0047] FIG. 9 is an axial cross section view of the upper thoracic
region including one visualization port and two instrument ports
accessing the paravertebral region where the thoracic splanchnic
nerves lie.
[0048] FIG. 10 is a plot of aortic and ventricular pressure in
response to electrical stimulation of a GSN in an animal study.
[0049] FIG. 11 is a schematic of the identification and exposure of
the greater splanchnic nerve.
[0050] FIGS. 12A and 12B are schematic diagrams of nerve cuff
configurations used to deliver blocking therapy.
[0051] FIG. 13 is a plot of mean arterial pressure over time
showing response to stimulation of a blocked nerve.
[0052] FIG. 14 is a flowchart illustrating the steps from patient
selection to permanent implantation.
[0053] FIG. 15 is a schematic diagram of IPG placement.
[0054] FIG. 16 is a functional block diagram that shows the
components and the respective signal flow of components housed in
an implantable pulse generator, or stimulus producer, for
neuromodulation and cardiac electrical modulation.
[0055] FIG. 17 is a flowchart illustrating the steps for blocking
therapy after exercise is detected.
[0056] FIG. 18 is a flowchart illustrating the steps for blocking
therapy.
DETAILED DESCRIPTION
[0057] The present disclosure relates to medical devices and
methods that offer treatment of heart disease, dysfunction and
heart failure, particularly HFpEF through the mechanism of
increased venous capacitance and relief of pulmonary congestion.
The treatments are provided through electrical block of at least a
portion of a splanchnic nerve (e.g., greater splanchnic nerve,
lesser splanchnic nerve, least splanchnic nerve, splanchnic nerve
roots, nerve fibers connected between the thoracic sympathetic
trunk and celiac plexus) with a nerve cuff electrode implanted to
impede or stop communication of a nerve signal along the blocked
nerve, which can affect physiological responses that are directly
or indirectly involved in the numerous factors of cardiovascular
health.
[0058] FIG. 1 is an anatomical representation of the supply of
sympathetic nerve fibers to organs of the human body. The SNS is
part of the autonomic nervous system, which also includes the
parasympathetic nervous system.
[0059] The SNS activates what is often termed the fight or flight
response. Like other parts of the nervous system, the sympathetic
nervous system operates through a series of interconnected neurons.
Sympathetic neurons are frequently considered part of the
peripheral nervous system, although there are many that lie within
the central nervous system.
[0060] Sympathetic neurons of the spinal cord (which is part of the
CNS) communicate with peripheral sympathetic neurons via a series
of sympathetic ganglia. Within the ganglia, spinal cord sympathetic
neurons join peripheral sympathetic neurons through chemical
synapses. Spinal cord sympathetic neurons are therefore called
presynaptic (or preganglionic) neurons, while peripheral
sympathetic neurons are called postsynaptic (or postganglionic)
neurons.
[0061] At synapses within the sympathetic ganglia, preganglionic
sympathetic neurons release acetylcholine, a chemical messenger
that binds and activates nicotinic acetylcholine receptors on
postganglionic neurons. In response to this stimulus,
postganglionic neurons principally release noradrenaline
(norepinephrine). Prolonged activation can elicit the release of
adrenaline from the adrenal medulla.
[0062] Once released, noradrenaline and adrenaline bind adrenergic
receptors on peripheral tissues. Binding to adrenergic receptors
causes the effects seen during the fight-or-flight response. These
include pupil dilation, increased sweating, increased heart rate,
and increased blood pressure.
[0063] Sympathetic nerves originate inside the vertebral column,
toward the middle of the spinal cord in the intermediolateral cell
column (or lateral horn), beginning at the first thoracic segment
of the spinal cord and are thought to extend to the second or third
lumbar segments. Because its cells begin in the thoracic and lumbar
regions of the spinal cord, the SNS is said to have a thoracolumbar
outflow. Thoracic splanchnic nerves (e.g., greater, lesser, or
least splanchnic nerves), which synapse in the prevertebral ganglia
are of particular interest for this disclosure.
[0064] FIG. 2 is a flow diagram showing the mechanisms of
decompensated heart failure. It illustrates the role of sympathetic
nerve activation 100 in the mobilization of venous reservoir 101
into the effective circulatory volume 102 leading to decompensation
103. Reversing, at least partially, by ablation of a greater
splanchnic nerve, the sympathetic activation of splanchnic nerves
is expected to relieve HF symptoms and reduce load on the failing
heart.
[0065] A particular area of interest in the body is the splanchnic
compartment, splanchnic vascular bed, or splanchnic reservoir,
which include the vasculature of the visceral organs including the
liver, spleen, small and large bowel, stomach as well as the
pancreas. The splanchnic venous vascular bed serves as the major
blood reservoir and can be affected by activation (e.g.,
stimulation) or deactivation (e.g., blocking or ablation) of
splanchnic nerves and particularly of the greater splanchnic nerve
(GSN) causing relaxation of veins, mobilization, release or uptake
of venous blood from or to splanchnic vascular beds, respectively,
and important changes in circulating blood volume.
[0066] The GSN may at least partially control splanchnic venous
compliance and capacitance. Capacitance is reduced in CHF patients
and particularly in some very hard to treat HFpEF patients as a
part of overall elevated sympathetic state. The sympathetic fibers
in the greater splanchnic nerve bundle that control contraction of
splanchnic veins are the particular target of the proposed blocking
therapy. In the context of this disclosure the GSN can mean right
or left greater splanchnic nerve and electrical block and
stimulation can be performed via an implanted nerve cuff
electrode(s) or a bilateral treatment can be performed from nerve
cuff electrodes implanted to access both right and left greater
splanchnic nerves. The splanchnic congestion and high venous
pressure is believed to adversely affect renal function and can be
illustrated by hepatorenal syndrome that causes diuretic
resistance. One theory is that the high portal vein pressure is
sensed by mechanoreceptors in the portal venous system and signaled
via neural reflex pathways to the kidney resulting in the retention
of sodium and fluid. It is believed by inventors that the proposed
block may at least partially reverse this phenomenon, improve renal
function and enable diuretics to work (restore diuretic
responsiveness
[0067] FIG. 3 and FIG. 4 show some of the interactions between
increases in sympathetic nervous system activity, including natural
activity (e.g. rate of firing) of the GSN, and the storage of blood
in the splanchnic bed. As illustrated by FIG. 3, increased central
SNA 114, can manifest, at least partially, in the elevated activity
of the GSN in all types of HF, resulting in a lower splanchnic
capacitance and possibly stiffened, less-compliant splanchnic bed
and regional effects including a decrease in the amount of blood
stored in the splanchnic veins perfusing and surrounding the
splanchnic organs (e.g., liver, spleen, pancreas, stomach, bowels)
110 and an increase in the amount of blood in central (and
pulmonary) veins 112. The volume of blood in splanchnic veins or
the splanchnic vascular bed 111 can be described as a "venous
reservoir", "unstressed volume" and refers to the blood volume that
does not contribute to the effective circulating volume and is
therefore hidden from circulation or the hemodynamically hidden
blood volume. The volume of blood in central veins 113 can be
termed "effective circulatory volume" or "stressed volume" and
refers to blood that is present mainly in the non-splanchnic veins
and is one of the main determinants of preload to the heart and in
CHF can contribute to venous congestion, high pulmonary circulation
pressures and sensation of dyspnea.
[0068] Conversely, as illustrated by FIG. 4, decreased sympathetic
nervous system activity or splanchnic bed normalized with GSN
blocking 120 may result in the compliance of the splanchnic bed,
which may be relaxed or normalized from the "stiff" or contracted
state. Blocking or inhibiting a target splanchnic nerve can result
in a decrease of efferent sympathetic tone to smooth muscle in the
walls of veins in the splanchnic vascular bed referred to as
splanchnic "venodilation" resulting in an increase 121 in the
volume of blood stored in the splanchnic bed 122 and a decrease 123
of volume of blood in the central veins 124 or in the overall
decrease in sympathetic nervous system activity. Other effects of
GSN blocking or inhibition may comprise reduction of pulmonary
vascular pressure and pulmonary capillary wedge pressure that is
index of left ventricular end-diastolic pressure, which important
measurable improvements in the treatment of HF. Understanding and
utilizing these interactions are some of the primary aims of
several embodiments disclosed herein. Specifically, the compliance
and capacitance of splanchnic vasculature is desired to be
increased.
[0069] FIG. 5 shows one possible clinical scenario in which the
sympathetic hyperactivity of the greater splanchnic 126 nerve leads
to the acceleration of fluid overload 127 and pulmonary venous
congestion in a HFpEF patient. Preventable hospital admission of
the HF patient is precipitated by the increase of pulmonary blood
pressures in response to exercise that causes "dyspnea upon
exertion". This sensation can be partially explained by the
patient's inability to buffer the sudden increase of venous blood
volume and pressure caused by exercise that is transmitted to the
pulmonary circulation and left atrium of the heart.
[0070] FIGS. 6A, 6B and 6C compares three different types of cuff
electrodes including monopolar (FIG. 6A), bipolar (FIG. 6B), and
tripolar (FIG. 6C). Electrical current paths of the compared types
are shown. During high frequency biphasic stimulation (HFBS), when
compared with a point electrode, the monopolar cuff electrode 130
(FIG. 6A) uses the electrical current more efficiently because the
cuff limits the current flow 131 in a 2-dimensional space along a
nerve. But, the electrical current coming into the monopolar cuff
might not be equal on each end 132 and 133 of the cuff electrode
130, which could cause unintended stimulation at one end of the
cuff. The current 131 on each side of the cuff is mainly determined
by the tissue resistance on each side of the cuff and by the
location of the remote reference electrode (not shown). In
addition, although the reference electrode is located remotely,
there is always a virtual anode 134 at each end of the cuff because
the current always flows into the nerve at the cuff ends. For HFBS,
the virtual anode is actually delivering HFBS at each end of the
cuff causing an excitation or block depending on the stimulation
intensity.
[0071] Similarly, a bipolar cuff electrode 135 (FIG. 6B) could
produce a virtual anodal 136 or cathodal 137 electrode at each end
of the cuff 135 depending on the tissue resistance within and
around the cuff. For HFBS, these virtual electrodes could produce
an unintended stimulation or blockade depending on stimulation
intensity. The virtual electrodes 136 and 137 could produce
variability and unpredictability in each clinical application
because the tissue resistance in and around the cuff 135 could
change with time. In acute animal experiments, this variability or
unpredictability presented as variable blocking effects, i.e.,
sometimes the nerve was blocked but other times the nerve block
failed depending on the blood or fluid accumulation in and around
the cuff or the position of the nerve in the cuff.
[0072] The tripolar cuff electrode 140 (FIG. 6C) effectively
eliminates the virtual electrode problems (e.g., associated with a
monopolar cuff or bipolar cuff) by connecting the two electrodes
142 at each end of the cuff thereby forcing the potentials at each
end of the cuff to be equal (i.e., no electrical current 141 can
flow outside the cuff). The tripolar cuff electrode may be an
efficient minimal electrode cuff configuration because it maximally
utilizes the current 141 for nerve stimulation when compared to the
monopolar or bipolar cuff electrode. In order to fully utilize the
efficiency, the inner diameter 143 of a tripolar cuff should
closely fit the diameter of a nerve it is fitted to so that less
current will flow in the space between the nerve and the electrode.
The electrode spacing 144 should be 1 to 2 mm in general because
the internodal distance of a nerve axon is about 100 times the axon
diameter. For axons of 1 to 20 .mu.m in diameter, the internodal
distances range from 0.1 mm to 2 mm. For electrical blocking of the
target nerve (e.g., GSN, lesser splanchnic nerve, least splanchnic
nerve, splanchnic nerve roots) that has an axon diameter less than
10 .mu.m, electrode spacing of 1 mm may be adequate.
[0073] Computational modeling results suggest that the minimum
frequency needed to block nerve activity is determined by potassium
channel kinetics. Since it is also known that at lower temperatures
ion channel kinetics become slower, the minimal blocking frequency
must decrease with temperature. FIG. 7A demonstrates how changes in
temperature affect the minimum electrical frequency required to
block axonal conduction for a nerve having an Axon diameter of 10
.mu.m. Thus, the minimum blocking frequency should be at least 6
kHz, due to the temperature of the human body (37.degree. C.). The
minimum stimulation intensity needed to block the nerve (i.e., the
block threshold) increases with increasing frequency for axons of
different diameter (5 to 20 .mu.m), see FIG. 7B.
[0074] A non-limiting example of placing a therapy delivery device
on a target site of the splanchnic nerves is described. FIG. 8 is a
schematic illustration of a view looking down on a patient 81 that
is positioned in a lateral decubitus position. Flexion of the table
allows some separation of the ribs by dropping the patient's hips
and therefore increasing the intercostal space 82 to work through.
The ipsilateral arm is abducted on an arm holder. Rotating the
table anteriorly and using reverse Trendelenburg positioning
further maximizes the exposure to the superior paravertebral area
by allowing the soon to be deflated lung 87 (FIG. 9) to fall away
from the apical posterior chest wall 88.
[0075] The following procedure is an example and it is understood
that a skilled thoracic surgeon can modify and improve it. The
procedure begins by placing patient under general anesthesia and
intubated via a double lumen endotracheal tube. The double lumen
endotracheal tube permits ventilation of one lung 89 and collapse
of the other lung 87 on the side of the thorax that is to be
operated upon without using carbon dioxide insuflation. One
incision is made in the midaxillary line seventh intercostal space
that is identified as port 204. Port 204 can be used for various
reasons, but it is preferred that port 204 is used as a telescopic
video port, which may provide video assistance during the
procedure. While under endoscopic observation, a second incision is
made in the fifth intercostal space at the anterior axillary line
that is identified as port 206. Port 206 is preferably used as an
instrument channel. A third incision is made at the posterior
axillary line in the sixth intercostal space that is identified as
port 202. Port 202 is preferably used as a second instrument
channel. Additional ports (or fewer) can be made as needed.
[0076] FIG. 9 is a schematic diagram of a transverse cross section
of the surgical site. The surgical exposure of an area of interest
207 and preparation of the relevant portion of the GSN for
treatment is described. Visualization during the procedure may be
provided by a camera introduced via a port, e.g., port 204. After
the lung 87 is collapsed, and if necessary, retracted down by a
fanning instrument via one of the instrument ports (e.g., port
202), the pleural cavity 208 is inspected. The entire intrathoracic
sympathetic chain (not shown) can be visualized under the parietal
pleura. The greater splanchnic nerve (not shown) can be visualized
through the parietal pleura from its first root to the
diaphragmatic recess. Before making an incision, identification of
the GSN can be confirmed. A needle or hook electrode can be
introduced through one of the instrument ports and manipulated to
penetrate the parietal pleura proximate to the GSN. After obtaining
the desired position proximate to the GSN, the hook electrode is
connected to an external electrical stimulator to deliver a
stimulation signal and monitor physiological response to confirm
GSN stimulation.
[0077] FIG. 10 illustrates a response to stimulation 146 of a GSN
at a level just above the diaphragm in an animal experiment
performed by the authors. The recognizable waveforms of increased
aortic and left ventricular pressure reflect the physiologic
response to electrical stimulation of the GSN. Similar increases
were observed in central venous pressure, right atrial pressure and
pulmonary artery pressure that can be measured and monitored in
real time in any well-equipped modern catheterization laboratory by
a trained cardiologist or surgeon.
[0078] After confirmation of GSN identification, the GSN 45 may be
exposed and dissected from the fascia. FIG. 11 is a diagram showing
exposure of a GSN 45. A pleural incision 70 from the level of T7 to
the diaphragm 52 along the medial aspect of the GSN 45 is shown
(FIG. 11). Electrocautery should not be used near the nerve, nerve
branches or the cuff electrode. Dissection of the pleura 70 and
tissue on both sides of the target nerve should be performed using
fine instruments. The optimal location for implantation of the cuff
electrode is as close the diaphragm 52 as possible. Prior to
implanting a nerve cuff electrode, the diameter 161 of the GSN
should be determined. A vessel loop of a known size should be used
to estimate nerve diameter. It is possible to have cuffs of several
diameters available to improve the cuff fit on the nerve.
[0079] In one embodiment, a nerve cuff electrode is tripolar in
configuration. It is envisioned that more than 3 electrodes can be
advantageous in some embodiments. The nerve cuff diameter will be
approximately the same diameter as the nerve to optimize nerve to
electrode contact but minimize nerve damage. Additionally, the
nerve cuff assembly may include additional cuffs (with or without
electrical contacts), proximal and/or distal to the active nerve
cuff. The additional cuffs may be used to serve as strain relief
for the active cuff electrode and aid in maintaining alignment of
the active nerve cuff.
[0080] A cuff 191 can be equipped with additional electrodes for
nerve recording designed to pick up extracellular potentials that
propagate along axons 190 (See FIGS. 12A and 12B). With the
electrode connected to a suitable recording amplifier that can be
part of the embedded electronics of the IPG (e.g., signal
conditioning circuit and DAQ, see FIG. 16), a signal can be
recorded whenever an action potential propagates along the nerve.
The amplitude V of the recorded potential is a function of the
extracellular action current amplitude, its wavelength and the
length the nerve portion that is between electrodes. Nerve
potentials can be recorded if a length of nerve encompassed by an
insulating cuff with electrodes placed inside the cuff. The
amplitude of the recorded signal depends non-linearly on the length
of the insulated portion. To obtain maximal signal amplitudes the
length of a nerve cuff should approximate wavelength to the extent
possible. Since a GSN in humans can be dissected and cuffed at 2 to
4 cm of length, it is feasible. There is no further advantage to
having the cuff length exceed wavelength. For large myelinated
axons, optimal length ranges between 30 and 40 mm. As a rule,
adequate signals are recorded during behavioral tasks when the cuff
length is about 10 times greater than the cuff inside diameter. An
essential prerequisite for recording nerve activity is to use an
insulating cuff comprising an electrically insulating layer 192. A
cuff wall permeable to electric current or an incompletely sealed
cuff will allow nerve currents to leak out and, additionally,
signals generated by structures outside the cuff by
electromyographic (EMG) noise originating from nearby muscles and
heart ECG may leak into the cuff and contaminate the recordings
with unwanted noise. Therefore, cuff-recording electrodes will not
be able to resolve nerve potentials from the noise unless the cuff
is well sealed along its entire length.
[0081] A possible side-effect of the HFBS therapy includes
undesired stimulation of muscle and pain nerves, for example,
intercostal nerves and innervated fascia. In one embodiment, an
isolating material may be inserted between the dissected nerve and
the intercostal space. The isolating material serves to limit
undesired stimulation, thus limiting possible pain associated with
HFBS.
[0082] Another possible side-effect of HFBS may be a result of the
initial nerve excitation during HFBS (or onset phenomenon). The
mechanism by which HFBS provides its blocking action is believed to
be through constantly activated potassium channels. HFBS generates
an initial action potential because the potassium channel is not
yet activated at the beginning of the HFBS. A possible means to
limit onset phenomenon is to use a cascade of electrodes to create
block of different strengths or gradually incremental partial
blocks. The length of GSN available for implantation of the cuff
electrode is approximately 3 to 4 cm long. Based on this, a nerve
cuff with 5 to 12 or more electrodes is possible. In one
embodiment, a 3 to 4 cm nerve cuff with 5 to 12 active electrodes
is implanted on the GSN. Gradual HFBS of different strengths could
be created. Each block could reduce conduction and onset would only
come from the virtual electrodes at the edges of the cuff. The
virtual electrodes proximate to the cuff edges would have less
intensity, thus limiting possible side-effects from the onset
phenomenon, especially on the afferent edge of the nerve where pain
fibers may be a concern
[0083] Regardless of the modality of nerve block, embodiments of a
device and method may further be configured to assist the blocking
procedure with a means to confirm safety and efficacy prior to and
following blocking. A means to confirm technical efficacy may
comprise identification of a target nerve before blocking and
absence of a target nerve signal transmission following the
blocking. A means to confirm procedural efficacy may comprise
temporarily blocking a target nerve to assess if a resulting
physiologic response is representative of a desired clinical effect
of the procedure.
[0084] Confirmation of efficacy may be assessed manually by a
practitioner by observing the parameter measurements in real time.
Alternatively, confirmation may be assessed automatically by the
computerized system console that takes input from the physiologic
monitoring equipment and compares it to a stimulation signal
profile. Confirmation may also be performed by the software
embedded in the IPG. Automatic changes to the block parameters
(e.g. current intensity) can be made by software based on the
results. Confirmation may include stimulation of the nerve
proximate to the block and measurement of nerve activity distal to
the block. Recording of nerve signals from nerve cuff electrodes is
known.
[0085] Confirmation of blocking therapy effectiveness may be
accomplished using nerve cuff designs shown in FIGS. 12A and 12B.
One exemplary embodiment is illustrated in FIG. 12A. A nerve 190
(e.g., GSN) positioned inside a cuff 191 having four active
electrodes is shown. The electrodes are embedded (or affixed) to an
insulating material 192 (elastomeric cuff). The electrodes are
numbered 1, 2, 3, and 4. This configuration provides a means to
deliver electrical nerve blocking therapy and tests the
effectiveness of the nerve block by recording stimulation-induced
extracellular action potentials post-block. Electrodes 2, 3, and 4
may be used to deliver blocking therapy. An example of
inter-electrode distance, d, between the electrodes to provide
blocking therapy is 1 to 2 mm. The effects of the electrical
blocking therapy is expected to last seconds to minutes after the
blocking signal ends. During the post-block period, electrodes 2, 3
and 4 may be used to record extracellular action potentials
generated by the proximal electrode 1 in a tri-polar recording
configuration that promotes cancelation of common noise. Electrodes
2, 3, and 4 may be switched from delivering a high frequency block
to recording extracellular potentials using embedded electronics
such as an embodiment of an electrode configuration switch shown in
FIG. 16. The DAQ and signal conditioning circuitry (FIG. 16) may
provide for acquisition of the extracellular potential as well as
filtering and amplification needed for recording. The stimulation
via proximal electrode 1 is unipolar with the return electrode in a
remote location (e.g., the IPG case). The electrodes may be
connected to the IPG using wired connections (see wire 193). The
connections provide communication between the nerve 190 and IPG for
delivery of HFBS, recording, and nerve stimulation.
[0086] In another exemplary embodiment, a nerve cuff 195 has 5
active electrodes (FIG. 12B). In this example, the high frequency
block therapy is delivered via electrodes 3, 4, and 5 in a tripolar
configuration with electrode 4 acting as a cathode. During the
post-block period, electrodes 3, 4, and 5 are used to record the
stimulation-induced extracellular action potential. The proximal
stimulus may be delivered via proximal electrodes 1 and 2 where the
stimulus is bipolar. An example of the inter-electrode distance, d,
between the bipolar stimulation electrodes is 2 to 3 mm.
[0087] To facilitate a clinically effective procedure, an
embodiment may involve confirming that a patient will experience
the desired physiologic effect of blocking before final
implantation. This may be achieved by electrically blocking the
nerve temporarily and observing a physiologic response (e.g.,
hemodynamic effect). If potential clinical success is assessed to
have a physiologic response as desired then permanent implantation
may proceed. Conversely, if the physiologic response to temporary
blocking is not as desired a physician may decide to not proceed
with implantation. Another option is to access the contralateral
GSN and evaluate the clinically efficacy.
[0088] To confirm this notion FIG. 13 illustrates an experiment
where the hemodynamic response to a greater splanchnic nerve
stimulation and block with locally injected lidocaine, a nerve
blocking agent, was tested in an animal. Time on the X-axis is in
minutes. The Y-axis represents mean arterial blood pressure in
mmHg. The first arrow 157 from the left indicates the time of
injection of lidocaine. The second arrow 158 indicates the time of
application of electrical stimulation to the greater splanchnic
nerve proximal to the blocked area of the nerve. The term
"proximal" as used herein with reference to a relative position on
a nerve denotes a location nearer to a point of origin, such as
brain, spinal cord, sympathetic chain or a midline of the body and
where the term "distal" is used to denote a location further away
from the point of origin and closer to the innervated peripheral
organ such as splanchnic vascular beds, liver and spleen. Following
the first stimulation 158 proximal to the nerve block 157, no or
very little physiologic response is observed on arterial blood
pressure, or other physiologic parameters that are omitted on this
graph for simplicity. The third arrow 159 illustrates electrical
stimulation of the greater splanchnic nerve for 30 seconds applied
distal to the lidocaine blocked area. The physiologic response
manifests by increase of mean arterial blood pressure and other
hemodynamic parameters as described in this application.
[0089] It is noted that MAP monitoring as mentioned above is an
example and hemodynamic monitoring does not necessarily need to be
invasive monitoring and may be accomplished with a less invasive
monitoring of blood pressure, for example using a Nexfin or
ClearSight device (Edwards) for continuous monitoring of
hemodynamics commonly used in hospitals. The ClearSight system
quickly connects to the patient by wrapping an inflatable cuff
around the finger. The ClearSight system provides noninvasive
access to automatic, up-to-the-minute hemodynamic information
including: SV, CO, SVR, or Continuous Blood Pressure (cBP). Such a
monitoring device may be hooked up to a computerized console to
communicate physiologic response to the computer, which may
determine stimulation or blocking parameters based on the
physiologic responses.
[0090] FIG. 14 is a flowchart that illustrates an example of a
process from patient selection to permanent device implantation for
blocking of the GSN to treat heart failure. One means for the
selection of patients 165 suitable for GSN blocking may include
evaluation of splanchnic vascular capacitance. An orthostatic
stress test (tilt table test), fluid challenge, exercise test or an
appropriate drug challenge can help distinguish low vascular
compliance from normal. Orthostatic stress causes blood shifts from
the stressed volume to the unstressed volume. In healthy patients,
to compensate for the shift, sympathetic tone increases resulting
in splanchnic vasoconstriction and rapid mobilization of blood from
the unstressed compartment to the active circulation. The
hemodynamic response to tilt in chronic CHF is atypical; as there
is significantly less peripheral pooling in the upright posture
indicating diminished splanchnic vascular capacitance. Acute oral
or intravenous fluid challenge is another test to assess splanchnic
vascular capacitance. A fluid challenge could test the capacitance
by measuring the effects of a fluid bolus on cardiac filling and
pulmonary pressures. Patients with low capacitance of the
splanchnic venous reservoir will be unable to compensate for the
hemodynamic effect of the fluid bolus. Patients with HF, HFPEF and
patients with increased SNA will be more likely to respond to the
fluid challenge with a disproportional rise in cardiac filing
pressure and other related and measurable physiologic parameters.
This response could indicate that the patient might be a candidate
for GSN ablation therapy. After the patient is identified as a
candidate for blocking therapy, the process of identifying the
appropriate nerve target 166 is implemented as the first step in
the implantation procedure. FIG. 10 illustrates a physiological
response to electrical stimulation to identify a target nerve
(GSN). After nerve target identification and selection, one means
of confirmation of procedural efficacy 167 is to temporarily block
the nerve target and evaluate 168 whether the physiological
response is consistent with the desired clinical effect. After
nerve target identification has been confirmed and procedural
efficacy has been confirmed permanent implant 169 be initiated.
Confirmation of the technical efficacy or success of the blocking
procedure may be accomplished by delivering electrical stimulation
proximal to the location of block where a physiological response
was elicited prior to electrical block. Absence or attenuation of
responses will indicate technical success of the blocking therapy
(see FIG. 13). If the blocking therapy is a success, no further
action is needed. If the blocking is not successful, the clinician
may opt to provide additional blocking 170 therapy at the same site
or repeat the procedure of identifying additional nerve targets
(e.g., contralateral GSN) and providing blocking therapy as
described previously.
[0091] In one exemplary embodiment, as illustrated in FIG. 15 a
portable and implantable device 175 with lead wires 176 is adapted
to terminate at a nerve cuff electrode 177 implanted around a
target GSN 45. The lead 176 is tunneled from the nerve cuff 177
implanted around the GSN 45 to the subcutaneous IPG 178 implant
site that can be on the patient's abdomen, flank or back. Another
lead 179 or leads may be implanted in the heart 180 via the veins
of cardiovascular system. The nerves are accessed as described in
FIGS. 8, 9, and 11.
[0092] The pulse generator 178 for electrical nerve stimulation in
an embodiment is implantable and programmable. Programmable pulse
generators can employ conventional microprocessors and other
standard electrical components. The pulse generators envisioned for
use in the present embodiments are able to generate charge
balanced, biphasic pulses. The biphasic pulse is repeated
continuously to produce the blocking stimulus waveform. The pulse
rate will vary depending on the duration of each phase, but will be
in the range of 0.5 Hz up to 10 kHz. When the stimulus is delivered
at the appropriate rate, typically around 6 kHz, the nerve membrane
is rendered incapable of transmitting an action potential. The
amplitude of the signal can vary between 0 and 20 mA. This type of
conduction block is immediately reversible by ceasing the
application of the waveform.
[0093] In a further embodiment, it is envisioned that the device
and IPG can both receive and transmit signals. For example, it is
envisioned that signals could be transmitted from the device to an
external programmer or display. Likewise, it is envisioned in a
further embodiment that patient or clinician input could be
received by the device to modulate the generated pulse, as needed.
The pulse generator can be battery operated or operated by a
radiofrequency device. Because the IPG, components, and power
source of the device may be implanted, it is envisioned that the
device is hermetically sealed.
[0094] A schematic of the implantable; pulse generator (IPG) that
may be part of system embodiment is shown in FIG. 16, which also
shows various functional components of an implantable device 175.
The components are typically contained in a case 215, which can be
electrically conductive and connected to the internal electronics
of the IPG, which is often referred to as the "can", "housing",
"encasing", or "case electrode", and may be programmably selected
to act as the return electrode for unipolar operational modes. The
case 215 may further be used as a return electrode alone, or in
combination with, one or more electrodes for stimulating or
blocking purposes. The case may also be used as one of the sensors
in determination of lead impedance, for example. The case 215 may
be made of a conductive metal, such as titanium, and the
implantable device hermetically sealed and leak rate tested.
[0095] The case further includes a connector (not shown, e.g., a
header or a connector block, made of polyurethane or other suitable
material), having a plurality of terminals shown schematically with
the names of the leads to which they are connected shown next to
the terminals, including: a nerve lead terminal 216, a cardiac lead
terminal 217, and a physiological sensor terminal 218 for
physiological sensors e.g., a blood pressure probe. The electrical
connection from the connector to the circuitry through the
hermetically sealed case are typically realized utilizing
feedthroughs made of an electrical conductor, such as platinum.
[0096] The implantable device 175 may include a programmable
microcontroller 219 that controls various operations of the
implantable neurostimulator device, including physiological
monitoring, nerve blocking therapy, electroneurogram sensing, and
cardiac sensing and stimulation therapy. Electroneurogram sensing
can be realized using the same cuff electrodes that are used for
stimulation and blocking (FIGS. 12A and 12B). The microcontroller
includes a microprocessor or equivalent control circuitry, RAM or
ROM memory, logic and timing circuitry, state machine circuitry,
and I/O circuitry.
[0097] The implantable device further includes a high frequency
blocking module 220, neurostimulation pulse generator 221, as well
as an optional cardiac pulse generator 222 that generate electrical
stimulation or blocking pulses for delivery by the neural lead 176
and cardiac lead(s) 179 via an electrode configuration switch. The
cardiac function of the device may be atrial or ventricular. The
electrode configuration switch 223 may include multiple switches
for connecting the desired electrodes to the appropriate I/O
circuits, thereby providing complete electrode programmability.
Accordingly, the switch, in response to a control signal from the
microcontroller 219, determines the polarity of the stimulation
pulses (e.g., unipolar, bipolar, etc.) by selectively closing the
appropriate combination of switches. The cardiac pulse generator
222 is capable of delivering a single electric pulse that excites
myocardium and generates an entire heart muscle contraction
(cardiac capture) and the neurostimulation pulse generator 221 is
capable of delivering trains of pulses that selectively excite an
approximate nerve creating series of action potentials in the nerve
fibers. The high frequency blocking 220 is capable of delivering
trains of pulses that selectively block the nerve creating
temporary blocking of nerve conduction.
[0098] The pulse generators and high frequency block module are
controlled by the microcontroller via appropriate control signals
used to trigger or inhibit the electrical pulses. The
microcontroller is illustrated as including timing control
circuitry 224 to control the timing of the electrical pulses (e.g.,
electrical nerve blocking frequency, neural stimulation frequency,
cardiac pacing rate, etc.). The timing control circuitry 224 may
also be used for the timing of the high frequency block therapy,
nerve stimulation periods (duty cycles, pulse widths), cardiac
refractory periods, noise detection windows, etc.
[0099] In another embodiment, GSN activity may be monitored to
control or modulate blocking therapy. GSN activity may be used as a
measure of therapy efficacy or as an indication for initiating
therapy. Signal conditioning circuits may be selectively coupled to
the nerve lead 216 through the switch 223 to detect the presence of
greater splanchnic nerve activity. The signal conditioning circuits
and may include dedicated sense amplifiers, multiplexed amplifiers,
or shared amplifiers. Each sensing circuit may employ one or more
low power precision amplifiers with programmable gain or automatic
gain control, bandpass filtering, and a threshold detection circuit
to selectively sense the nerve signal of interest.
[0100] In another embodiment, GSN activity may be monitored to
control or modulate blocking therapy. The DAQ module may be used to
acquire the electroneurograms. The electroneurograms may be saved
to memory and sent to an external system for signal processing.
Some processing, such as stimulus artifact reduction, may be
performed by the signal conditioning circuit of the IPG. The
external system my employ one or more sense amplifiers, multiplexed
amplifiers, or shared amplifiers. Each sensing circuit may employ
one or more low power precision amplifiers with programmable gain
or automatic gain control, bandpass filtering, and a threshold
detection circuit to selectively sense the nerve signal of
interest. After processing, the telemetry circuit can receive
information used to control or modulate blocking therapy.
[0101] The operating parameters of the implantable device may be
non-invasively programmed into the memory 225 through a telemetry
circuit 226 in telemetric communication via a communication link
with the external device, such as a clinician programmer or a
patient interface 227. In addition to telemetric communication,
communication may also be achieved using radio frequency or RF
(circuitry not shown). The microcontroller can activate the
telemetry circuit with a control signal. The telemetry circuit
allows the status information relating to the operation of the
device, as contained in the microcontroller 219 or memory 225, to
be sent to the external device through the established
communication link. The telemetry may be operated on demand by a
physician, a care provider who is not a physician, or the
patient.
[0102] The device additionally includes a battery 228 that provides
operating power to all of the components shown in FIG. 16. The
battery is capable of operating at low current drains for long
periods of time. The battery 228 also desirably has predictable
discharge characteristics so that elective replacement time can be
detected. The device can further include magnet detection circuitry
(not shown), coupled to the microcontroller 219, to detect when a
magnet is placed over the device. A magnet may be used by a
clinician to perform various test functions of the exemplary device
or to signal the microcontroller that a wand of an external
programmer is in place to receive or transmit data to the
microcontroller through the telemetry circuits. Communication
between the device and external devices (clinician programmer,
patient interface, sensors, etc.) may also be performed wirelessly
using RF communication protocols.
[0103] The device further includes an impedance measuring circuit
229 that is enabled by the microcontroller via a control signal.
The impedance measuring circuit is used for many purposes,
including: lead impedance surveillance during acute and chronic
phases for proper lead positioning or dislodgement; detecting
operable electrodes and automatically switching to an operable pair
if dislodgement occurs; measuring respiration rate, tidal volume or
minute ventilation; measuring thoracic impedance; detecting when
the device has been implanted; measuring cardiac stroke volume and
systolic and diastolic volume of blood in the heart; and so forth.
The impedance measuring circuit may be coupled to the switch so
that any desired electrode may be used.
[0104] In one configuration, the accelerometer output signal from
the activity/position sensor is bandpass-filtered, rectified, and
integrated at regular timed intervals. A processed accelerometer
signal can be used as a raw activity signal. The device derives an
activity measurement based on the raw activity signal at intervals
timed according to the cardiac cycle or at other suitable time
intervals. The activity signal alone can be used to indicate
whether a patient is active or resting. The activity measurement
can further be used to determine an activity variance parameter. A
large activity variance signal is indicative of a prolonged
exercise state. Low activity and activity variance signals are
indicative of a prolonged resting or inactivity state. The activity
variance can be monitored during day and night periods set by the
telemetry for the geographic area and time zone to detect the low
variance in the measurement corresponding to the sleep state.
[0105] In one embodiment as shown in FIG. 17, the activity signal
is used to provide responsive therapy. Patients with HFpEF
experience exercise limitations that have a tremendous effect on
quality of life. Upon detection of exercise 235, therapy is
initiated 236 to increase exercise capacity in these patients.
Patients may also initiate therapy prior to exercise. The efficacy
of therapy 237 can be derived from the calculation of the activity
variance parameter described above. The activity variance is
compared over time to indicate exercise time (or exercise capacity)
to create a measure of therapy efficacy. Once blocking therapy is
initiated 236, the effectiveness of the block may be determined
(see FIGS. 12A and 12B). If block is not effective, parameters will
be changed until successful blocking is confirmed. Once the
blocking is confirmed, physiological sensors will be monitored to
determine therapy effectiveness 234. The signal conditioning and
DAQ 230 modules in the IPG (FIG. 16) will be used to acquire the
physiological signal 238 used to determine therapy effectiveness
(Physiological Sensor Module, FIG. 16). High frequency block
parameters may be adjusted based on detection from physiological
sensors.
[0106] Another embodiment of the disclosure uses an accelerometer
239 to monitor position and provide therapy in response to
positional conditions. CHF patients may experience fluid back-up in
the lungs that results in difficulty breathing at rest or when
lying in bed. This results in altered sleep patterns, such as
sleeping in an upright position. This significantly reduces sleep
quality and results in deterioration of health and quality of life.
The accelerometer signal will be used to detect sleeping in upright
positions that are indicative of congestion. Detection of altered
sleeping patterns will trigger blocking therapy to relieve lung
congestion leading to improved sleep quality. The accelerometer
signal will be used to detect exercise 235 such as walking or
walking up the stairs and activate therapy in HFpEF patients that
experience dyspnea from exertion due to elevation of pulmonary
blood pressure in response to exercise induced mobilization of
splanchnic venous blood into the circulating volume (FIG. 17).
[0107] Another embodiment of the disclosure comprises a detection
device, a detection algorithm, a treatment device and a treatment
algorithm (FIG. 16). The detection and input of a variety of health
and heart health indicators (including venous capacitance,
unstressed volume, effective circulatory volume, pulmonary
pressure, dyspnea, as well as other factors described herein, etc.)
is envisioned to help determine the ranges in which the nerve block
is initiated, continued or terminated. These inputs, along with the
use of additional algorithms are envisioned to help streamline the
application of the present therapies. It is important and
envisioned that these algorithms are not only accurate and
effective for starting, continuing and stopping the generated
signal, but also that the system is tolerant of random or isolated
stimuli that do not require treatment. Further an algorithm may
incorporate information such as a feedback signal, sensor input, or
programmable input which may affect its output. In a further
embodiment, said device may be configured to receive signals from
sensors including fluid or blood pressure (BP) sensor and adjust
accordingly to modulate and deliver modified therapy, as needed or
desired. Sensors are envisioned to be comprised within the device
or separate from the device. Furthermore, it is also envisioned
that specifically the leads of the device may also comprises a
detector capable of sensing values (e.g., blood pressure, heart
rate, cardiac output, acceleration, fluid imbalance, fluid
impedance, etc.) and fine tuning delivery of the nerve block to
reduce venous congestion.
[0108] While automatic detection followed by the delivery of
therapy is envisioned to optimize the ease and convenience and
minimize risk of user error during operation, patient-initiated
therapy is also envisioned wherein the patient experiences
shortness of breath or other symptoms and initiates the therapy 244
for a set amount of time until benefit is achieved. In addition, it
is envisioned that the device may be remotely activated and
controlled, in coordination or independent of any
sensors/algorithms, in such a way that a user, emergency medical
personnel or medical practitioner could perform a manual override
and operation as required. One embodiment of operation of an
implantable system provides for blocking therapy initiation by a
clinician, a patient, programmed treatment algorithm, or via sensor
activation based on a detection algorithm (see FIG. 18). After
therapy is initiated 240, blocking effectiveness is assessed 241.
If blocking is not successful, high frequency blocking parameters
will be adjusted until blocking is successful. Once blocking
success is determined, therapy effectiveness may be assessed 242 by
monitoring physiological sensors 243. High frequency blocking
parameters may be modified to improve therapy effectiveness. In
addition, a programmer or patient programmer can be used to
remotely change stimulation parameters as required. For example,
maximum allowed stimulation energy may be reduced based on pain
sensation by the patient or increased based on medical tests.
[0109] While at least one exemplary embodiment of the present
invention(s) is disclosed herein, it should be understood that
modifications substitutions and alternatives may be apparent to one
of ordinary skill in the art and can be made without departing from
the scope of this disclosure. This disclosure is intended to cover
any adaptations or variations of the exemplary embodiment(s). In
addition, in this disclosure, the terms "comprise" or "comprising"
do not exclude other elements or steps, the terms "a" or "one" do
not exclude a plural number, and the term "or" means either or
both. Furthermore, characteristics or steps which have been
described may also be used in combination with other
characteristics or steps and in any order unless the disclosure or
context suggests otherwise. This disclosure hereby incorporates by
reference the complete disclosure of any patent or application from
which it claims benefit or priority.
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