U.S. patent application number 11/000538 was filed with the patent office on 2005-07-14 for methods and systems for providing therapies into the pericardial space.
This patent application is currently assigned to Medtronic, Inc.. Invention is credited to Morris, Mary M., Sigg, Daniel C., Ujhelyi, Michael R..
Application Number | 20050154370 11/000538 |
Document ID | / |
Family ID | 36048724 |
Filed Date | 2005-07-14 |
United States Patent
Application |
20050154370 |
Kind Code |
A1 |
Sigg, Daniel C. ; et
al. |
July 14, 2005 |
Methods and systems for providing therapies into the pericardial
space
Abstract
Methods and systems for transvenously accessing the pericardial
space via the vascular system and atrial wall, particularly through
the superior vena cava and right atrial wall, to deliver a
pharmacologic agent, particularly a NO-donor drug, to the heart are
disclosed. A proximal connector of an infusion catheter is coupled
to an infusion pump, and a distal catheter segment having a distal
infusion catheter lumen end opening is disposed in the pericardial
space. The implantable infusion pump is operable in conjunction
with an implantable ischemia monitor to monitor the ischemic state
and trigger delivery or regulate the periodic delivery of the
pharmacologic agent to optimally treat ischemia. The patient may
operate a patient activator that the patient when feeling ischemia
symptoms to transmit a signal that is received by the implantable
infusion pump and triggers delivery of a bolus and/or continuous
infusion.
Inventors: |
Sigg, Daniel C.; (St. Paul,
MN) ; Ujhelyi, Michael R.; (Maple Grove, MN) ;
Morris, Mary M.; (Mounds View, MN) |
Correspondence
Address: |
MEDTRONIC, INC.
710 MEDTRONIC PARKWAY NE
MS-LC340
MINNEAPOLIS
MN
55432-5604
US
|
Assignee: |
Medtronic, Inc.
|
Family ID: |
36048724 |
Appl. No.: |
11/000538 |
Filed: |
December 1, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11000538 |
Dec 1, 2004 |
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10606908 |
Jun 26, 2003 |
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10606908 |
Jun 26, 2003 |
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09430096 |
Oct 29, 1999 |
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6613062 |
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Current U.S.
Class: |
604/503 |
Current CPC
Class: |
A61B 2017/349 20130101;
A61B 2017/3488 20130101; A61B 2018/00392 20130101; A61M 2005/1405
20130101; A61B 17/3417 20130101; A61B 2017/3484 20130101; A61B
18/1492 20130101; A61B 2017/22077 20130101; A61B 17/3478 20130101;
A61M 5/1723 20130101; A61M 2205/3523 20130101; A61B 2017/00247
20130101; A61B 17/00234 20130101; A61B 2017/003 20130101; A61B
2018/00357 20130101; A61B 2018/00291 20130101; A61M 5/14276
20130101 |
Class at
Publication: |
604/503 |
International
Class: |
A61M 031/00 |
Claims
What is claimed is:
1. A method of accessing the pericardial space between a heart and
its pericardium to deliver a pharmacologic agent to the heart, the
method comprising the steps of: advancing an infusion catheter to
dispose a distal catheter segment having a distal infusion catheter
lumen end opening in the pericardial space; attaching a proximal
connector of the infusion catheter to an infusion pump having a
reservoir containing the pharmacologic agent; detecting an ischemic
state of the heart; and delivering the pharmacologic agent from the
reservoir into the pericardial space to counter the detected
ischemic state.
2. The method of claim 1, further comprising: detecting a remotely
transmitted therapy delivery command; and delivering a bolus of the
pharmacologic agent.
3. The method of claim 2, wherein the pharmacologic agent comprises
NO-donor drugs selected from the group consisting of nitroglycerin,
isosorbide mononitrate, sodium nitroprusside, a diazenium diolate,
an NO aspirin, an S-Nitrosothiol, and morpholinosydnonimime or any
other NO-generating, NO-donor or NO-precursor drug (e.g.
L-arginin).
4. The method of claim 1, wherein the detecting step comprises:
sensing a feature of the EGM of the heart; and detecting a
characteristic of the sensed feature indicative of the ischemic
state.
5. The method of claim 4, wherein the pharmacologic agent comprises
NO-donor drugs selected from the group consisting of nitroglycerin,
isosorbide mononitrate, sodium nitroprusside, a diazenium diolate,
an NO aspirin, an S-Nitrosothiol, and morpholinosydnonimime or any
other NO-generating, NO-donor or NO-precursor drug (e.g.
L-arginin).
6. The method of claim 1, wherein the detecting step comprises:
sensing blood pH; and detecting a value of the sensed blood pH
indicative of the ischemic state.
7. The method of claim 5, wherein the pharmacologic agent comprises
NO-donor drugs selected from the group consisting of nitroglycerin,
isosorbide mononitrate, sodium nitroprusside, a diazenium diolate,
an NO aspirin, an S-Nitrosothiol, and morpholinosydnonimime or any
other NO-generating, NO-donor or NO-precursor drug (e.g.
L-arginin).
8. The method of claim 1, wherein the detecting step comprises:
sensing blood oxygen saturation; and detecting a value of the
sensed oxygen saturation indicative of the ischemic state.
9. The method of claim 7, wherein the pharmacologic agent comprises
NO-donor drugs selected from the group consisting of nitroglycerin,
isosorbide mononitrate, sodium nitroprusside, a diazenium diolate,
an NO aspirin, an S-Nitrosothiol, and morpholinosydnonimime or any
other NO-generating, NO-donor or NO-precursor drug (e.g.
L-arginin).
10. The method of claim 1, wherein the detecting step comprises:
sensing one or both of blood pressure and flow in the heart; and
detecting a value of the sensed one or both of blood pressure and
flow indicative of the ischemic state.
11. The method of claim 10, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
12. A system for delivering a pharmacologic agent into the
pericardial space surrounding the heart to treat an ischemic state:
an infusion pump having a reservoir adapted to receive a
pharmacologic agent to be delivered into the pericardial space; and
an infusion catheter coupled a proximal catheter end to the
infusion pump and adapted to be routed to dispose a distal catheter
segment having a distal infusion catheter lumen end opening in the
pericardial space; and wherein the infusion pump further comprises:
means for detecting an ischemic state of the heart; and means for
delivering a bolus of the pharmacologic agent into the pericardial
space to counter the detected ischemic state.
13. The system of claim 12, wherein the infusion pump further
comprises means responsive to a remotely transmitted therapy
delivery command for delivering a bolus of the pharmacologic
agent.
14. The system of claim 13, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
15. The system of claim 12, wherein the detecting means comprises:
means for sensing a feature of the EGM of the heart; and means for
detecting a characteristic of the sensed feature indicative of the
ischemic state.
16. The system of claim 15, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
17. The system of claim 12, wherein the detecting means comprises:
means for sensing blood pH; and means for detecting a value of the
sensed blood pH indicative of the ischemic state.
18. The system of claim 17, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
19. The system of claim 12, wherein the detecting means comprises:
means for sensing blood oxygen saturation; and means for detecting
a value of the sensed oxygen saturation indicative of the ischemic
state.
20. The system of claim 19, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
21. The system of claim 12, wherein the detecting means comprises:
means for sensing one or both of blood pressure and flow in the
heart; and means for detecting a value of the sensed one or both of
blood pressure and flow indicative of the ischemic state.
22. The system of claim 21, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
23. A method of transvenously accessing the pericardial space
between a heart and its pericardium to deliver a pharmacologic
agent to the heart to treat an ischemic state, the method
comprising the steps of: passing a fixation catheter having a
fixation catheter lumen extending between proximal and distal
fixation catheter lumen openings and a distal tissue fixation
mechanism through a selected peripheral vein and one of the
inferior vena cava and the superior vena cava to establish a
transvenous route into the right atrium of the heart; disposing the
distal fixation mechanism and distal fixation catheter lumen
opening proximate the right atrial wall; affixing the distal
fixation mechanism to the right atrial wall; passing an infusion
catheter through the fixation catheter lumen out of the distal
fixation catheter lumen opening and through the stabilized atrial
wall to dispose a distal catheter segment having a distal infusion
catheter lumen end opening in the pericardial space; and delivering
a pharmacologic agent through the infusion catheter to treat an
ischemic state.
24. The method of claim 23, wherein the delivering step comprises:
attaching a proximal connector of the infusion catheter to an
infusion pump; subcutaneously implanting the infusion pump in the
thoracic region; and operating the infusion pump to deliver the
pharmacologic agent into the pericardial space.
25. The method of claim 24, wherein the operating step comprises:
detecting a remotely transmitted therapy delivery command; and
delivering a bolus of the pharmacologic agent.
26. The method of claim 25, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
27. The method of claim 24, wherein the operating step comprises:
detecting an ischemic state of the heart; and regulating the
delivery of the pharmacologic agent to counter the detected
ischemic state.
28. The method of claim 27, wherein the detecting step comprises:
sensing a feature of the EGM of the heart; and detecting a
characteristic of the sensed feature indicative of the ischemic
state.
29. The method of claim 28, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
30. The method of claim 27, wherein the detecting step comprises:
sensing blood pH; and detecting a value of the sensed blood pH
indicative of the ischemic state.
31. The method of claim 30, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
32. The method of claim 27, wherein the detecting step comprises:
sensing blood oxygen saturation; and detecting a value of the
sensed oxygen saturation indicative of the ischemic state.
33. The method of claim 32, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
34. The method of claim 27, wherein the detecting step comprises:
sensing one or both of blood pressure and flow in the heart; and
detecting a value of the sensed one or both of blood pressure and
flow indicative of the ischemic state.
35. The method of claim 34, wherein the pharmacologic agent
comprises NO-donor drugs selected from the group consisting of
nitroglycerin, isosorbide mononitrate, sodium nitroprusside, a
diazenium diolate, an NO aspirin, an S-Nitrosothiol, and
morpholinosydnonimime or any other NO-generating, NO-donor or
NO-precursor drug (e.g. L-arginin).
36. A method of transvenously accessing the pericardial space
between a heart and its pericardium to deliver a NO-donor drug to
the heart, the method comprising the steps of: advancing an
infusion catheter to dispose a distal catheter segment having a
distal infusion catheter lumen end opening in the pericardial
space; attaching a proximal connector of the infusion catheter to
an infusion pump; detecting a condition of the heart; and
delivering a bolus of NO-donor drug.
37. The method of claim 36, further comprising: detecting a
remotely transmitted therapy delivery command; and delivering a
bolus of the NO-donor drug.
38. The method of claim 36, wherein the detecting step comprises:
sensing a feature of the EGM of the heart; and detecting a
characteristic of the sensed feature indicative of an ischemic
state.
39. The method of claim 36, wherein the detecting step comprises:
sensing blood pH; and detecting a value of the sensed blood pH
indicative of an ischemic state.
40. The method of claim 36, wherein the detecting step comprises:
sensing blood oxygen saturation; and detecting a value of the
sensed oxygen saturation indicative of an ischemic state.
41. The method of claim 36, wherein the detecting step comprises:
sensing one or both of blood pressure and flow in the heart; and
detecting a value of the sensed one or both of blood pressure and
flow indicative of an ischemic state.
42. The method of claim 36, wherein the advancing step comprises:
passing a fixation catheter having a fixation catheter lumen
extending between proximal and distal fixation catheter lumen
openings and a distal tissue fixation mechanism through a selected
peripheral vein and one of the inferior vena cava and the superior
vena cava to establish a transvenous route into the right atrium of
the heart disposing the distal fixation mechanism and distal
fixation catheter lumen opening proximate the right atrial wall;
affixing the distal fixation mechanism to the right atrial wall;
passing an infusion catheter through the fixation catheter lumen
out of the distal fixation catheter lumen opening and through the
stabilized atrial wall to dispose a distal catheter segment having
a distal infusion catheter lumen end opening in the pericardial
space.
43. The method of claim 36, wherein the advancing step comprises
advancing the distal catheter segment from the right atrium through
the right atrial wall.
44. The method of claim 36, wherein the NO-donor drug is selected
from the group consisting of nitroglycerin, isosorbide mononitrate,
sodium nitroprusside, a diazenium diolate, an NO aspirin, an
S-Nitrosothiol, and morpholinosydnonimime or any other
NO-generating, NO-donor or NO-precursor drug (e.g. L-arginin).
45. A system for delivering a NO-donor drug into the pericardial
space surrounding the heart to treat an ischemic state: an infusion
pump having a reservoir adapted to receive a NO-donor drug; an
infusion catheter coupled a proximal catheter end to the infusion
pump and adapted to be routed from the infusion pump to dispose a
distal catheter segment having a distal infusion catheter lumen end
opening in the pericardial space; and wherein the infusion pump
further comprises: means for detecting a condition of the heart;
and means for delivering a bolus of the NO-donor drug from the
reservoir into the pericardial space to counter the detected
condition.
46. The system of claim 45, wherein the infusion pump further
comprises means for regulating the delivery of the NO-donor drug
into the pericardial space to counter the detected condition.
47. The system of claim 45, wherein the infusion pump further
comprises means responsive to a remotely transmitted therapy
delivery command for delivering a bolus of the NO-donor drug.
48. The system of claim 45, wherein the detecting means comprises:
means for sensing a feature of the EGM of the heart; and means for
detecting a characteristic of the sensed feature indicative of an
ischemic state.
49. The system of claim 45, wherein the detecting means comprises:
means for sensing blood pH; and means for detecting a value of the
sensed blood pH indicative of an ischemic state.
50. The system of claim 45, wherein the detecting means comprises:
means for sensing blood oxygen saturation; and means for detecting
a value of the sensed oxygen saturation indicative of an ischemic
state.
51. The system of claim 45, wherein the detecting means comprises:
means for sensing one or both of blood pressure and flow in the
heart; and means for detecting a value of the sensed one or both of
blood pressure and flow indicative of an ischemic state.
52. The system of claim 45, further comprising: a fixation catheter
having a fixation catheter lumen extending between proximal and
distal fixation catheter lumen openings and a distal tissue
fixation mechanism adapted to be advanced through a selected
peripheral vein and one of the inferior vena cava and the superior
vena cava to establish a transvenous route into the right atrium of
the heart means for disposing the distal fixation mechanism and
distal fixation catheter lumen opening proximate the right atrial
wall; and means for affixing the distal fixation mechanism to the
right atrial wall, whereby the infusion catheter is adapted to be
advanced through the fixation catheter lumen out of the distal
fixation catheter lumen opening and through the stabilized atrial
wall to dispose the distal catheter segment having the distal
infusion catheter lumen end opening in the pericardial space.
53. The system of claim 45, wherein the NO-donor drug is selected
from the group consisting of nitroglycerin, isosorbide mononitrate,
sodium nitroprusside, a diazenium diolate, an NO aspirin, an
S-Nitrosothiol, and morpholinosydnonimime or any other
NO-generating, NO-donor or NO-precursor drug (e.g. L-arginin).
Description
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/606,908, filed Jun. 26, 2003, published as
Published Patent Application No. 2004/0087938 A1, which is a
division of U.S. patent application Ser. No. 09/430,096, filed Oct.
29, 1999, now U.S. Pat. No. 6,613,062.
FIELD OF THE INVENTION
[0002] This invention relates generally to methods and systems for
delivering a pharmacologic agent into the pericardial space to
treat the heart, e.g., methods and systems that deliver a
pharmacologic agent into the pericardial space upon detection of
symptoms of ischemia.
BACKGROUND OF THE INVENTION
[0003] The human heart wall consists of an inner layer of simple
squamous epithelium, referred to as the endocardium, overlying a
variably thick heart muscle or myocardium and is enveloped within a
multi-layer tissue structure referred to as the pericardium. The
innermost layer of the pericardium, referred to as the visceral
pericardium or epicardium, clothes the myocardium. The epicardium
reflects outward at the origin of the aortic arch to form an outer
tissue layer, referred to as the parietal pericardium, which is
spaced from and forms an enclosed sac extending around the visceral
pericardium of the ventricles and atria. An outermost layer of the
pericardium, referred to as the fibrous pericardium, attaches the
parietal pericardium to the sternum, the great vessels and the
diaphragm so that the heart is confined within the middle
mediastinum. Normally, the visceral pericardium and parietal
pericardium lie in close contact with each other and are separated
only by a thin layer of a serous pericardial fluid that enables
friction free movement of the heart within the sac. The space
(really more of a potential space) between the visceral and
parietal pericardia is referred to as the pericardial space. In
common parlance, the visceral pericardium is usually referred to as
the epicardium, and epicardium will be used hereafter. Similarly,
the parietal pericardium is usually referred to as the pericardium,
and pericardium will be used hereafter in reference to parietal
pericardium.
[0004] Access to the pericardial space is desirable in order to
provide a variety of cardiac therapies, including delivery of
therapeutic agents (defined herein as including genetic agents,
biologic agents, and pharmacologic agents), placement of electrical
medical leads for pacing, cardioversion, defibrillation or EGM
monitoring, removal of pericardial fluid for diagnostic analysis,
or other purposes (e.g. placement of chemical sensors). A variety
of mechanisms have been developed for accessing the pericardial
space, ranging from a simple puncture by means of a large bore
needle to intricate catheter or cannula based systems provided with
sealing and anchoring mechanisms.
[0005] Access to the pericardial space may be accomplished from
outside the body by making a thoracic or sub-xiphoid incision to
access and cut or pierce the pericardial sac. Access to the
pericardial space from the exterior of the body, accomplished by
passing a cannula or catheter type device through the chest wall
and thereafter passing the cannula or catheter or a further
instrument through the pericardium into the pericardial space, is
disclosed in U.S. Pat. Nos. 5,827,216, 5,900,433, and 6,162,195
issued to Igo, U.S. Pat. No. 5,336,252 issued to Cohen, and U.S.
Pat. Nos. 5,972,013, 6,206,004, 6,592,552 by Schmidt, for example.
In certain cases the pericardial sac is cut by a cutting instrument
as disclosed in U.S. Pat. Nos. 5,931,810, 6,156,009, and 6,231,518
issued to Grabek et al.
[0006] Alternatively, an elongated perforating instrument device is
introduced from a skin incision or puncture by a transvenous or
transarterial approach into the right or left heart chambers,
respectively, and a cutting or piercing or penetrating mechanism at
the distal end of the elongated perforating instrument is operated
to penetrate through the atrial or ventricular wall of the right or
left heart chamber into the surrounding pericardial space without
perforating the pericardial sac. For example, a transvenous
catheter provided with a hollow helical needle adapted to rotated
and pierce through the wall of a right or left heart chamber to
access the pericardial space to deliver pharmacologic agents is
disclosed in U.S. Pat. Nos. 5,797,870 issued to March et al. A
transvenous catheter introduced into the right ventricular chamber
to provide access through the right ventricular wall to enable
passage of an electrical medical lead into the pericardial space is
disclosed in, U.S. Pat. No. 4,991,578 issued to Cohen, and U.S.
Pat. No. 5,330,496 issued to Alferness, for example. It has also
been proposed that a preferred site of penetration of catheters or
electrical medical leads through the atrial wall into the
pericardial space is within the right atrial appendage as disclosed
in U.S. Pat. No. 5,269,326 issued to Verrier, U.S. Pat. No.
6,200,303 issued to Verrier et al and U.S. Pat. No. 5,968,010
issued to Waxman et al. Transvenous approaches through either of
the inferior vena cava or the superior vena cava are disclosed in
these patents.
[0007] It would be particularly desirable to facilitate access to
the pericardial space to enable chronic delivery of pharmacologic
agents to the heart as suggested in the above-referenced '326,
'303, and '010 patents. In particular it is noted that the
pericardial fluid provides an excellent medium for delivery of
pharmacologic agents to the cardiac muscles and coronary vessels
without distribution to other organs. Among the clinically
significant pharmacologic agents (i.e., drugs) which could
advantageously be delivered to the heart via the pericardial fluid
are those that improve cardiac contractility (e.g., digitalis
drugs, adrenergic agonists, etc.), that suppress arrhythmias (e.g.,
class I, II, III, and IV agents and specialized drugs such as
amiodarone, which is particularly potent but has severe systemic
side effects), that dilate coronary arteries (e.g., nitroglycerin,
calcium channel blockers, etc.), that lyse clots in the coronary
circulation (e.g., thrombolytic agents such as streptokinase or
tissue-type plasminogen activator (TPA)) or that reverse symptoms
of heart failure (e.g. beta-adrenergic blockers).
[0008] Examples of other pharmacologic agents which may be
administered into the pericardial space include: agents to protect
the heart pharmacologically from the toxic effects of drugs
administered to the body generally for other diseases, such as
cancer; antibiotics, steroidal and non-steroidal medications for
the treatment of certain pericardial diseases; and growth factors
to promote angiogenesis or neovascularization of the heart.
[0009] The delivery of further pharmacologic agents into the
pericardial space is disclosed in the above-referenced '433 patent,
wherein cardio-active or cardio-vascular active drugs are selected
from vasodilator, antiplatelet, anticoagulant, thrombolytic,
anti-inflammatory, antiarrhythmic, initropic, antimitotic,
angiogenic, antiatherogenic and gene therapy bioactive agents. The
approaches to the pericardial space include those disclosed in the
above-referenced '326 patent or transthoracically, e.g., under the
xiphoid process, i.e., by a sub-xiphoid surgical approach.
[0010] It is proposed in the '433 patent to deliver the
pharmacologic agents into the pericardial space to treat or to
prevent vascular thrombosis and angioplasty restenosis,
particularly coronary vascular thrombosis and angioplasty
restenosis, thereby to decrease incidence of vessel rethrombosis,
unstable angina, myocardial infarction, and sudden death. In
particular, it is proposed to deliver a congener of an
endothelium-derived bioactive agent, more particularly a
nitrovasodilator, representatively the nitric oxide donor agent
sodium nitroprusside, to the pericardial space at a therapeutically
effective dosage rate to abolish cyclic coronary flow reductions
(CFR's) while reducing or avoiding systemic effects such as
suppression of platelet function and bleeding. Particular congeners
of an endothelium-derived bioactive agent include prostacyclin,
prostaglandin E.sub.1, and a nitrovasodilator agent.
Nitrovasodilater agents include nitric oxide (NOX) and NOX donor
agents, including L-arginine, sodium nitroprusside and
nitroglycycerine. The so-administered nitrovasodilators are
effective to provide one or more of the therapeutic effects of
promotion of vasodilation, inhibition of vessel spasm, inhibition
of platelet aggregation, inhibition of vessel thrombosis, and
inhibition of platelet growth factor release, at the treatment
site, without inducing systemic hypotension or anticoagulation. The
administration of nitroglycerin intravenously has been demonstrated
to reduce infarct size, expansion and complications in patients
(Circulation. 1988 October;78(4): 906-19).
[0011] As set forth in commonly assigned U.S. Pat. No. 6,115,630 to
Stadler et al, myocardial ischemia is a leading cause of human
morbidity and mortality in developed countries. Myocardial ischemia
involves oxygen starvation of the myocardium, particularly in the
bulky left ventricular wall, which can lead to myocardial
infarction and/or the onset of malignant arrhythmias if the oxygen
starvation is not alleviated. Although myocardial ischemia is
associated with the symptom of angina pectoris, the majority of
episodes of myocardial ischemia are asymptomatic or "silent."
Myocardial ischemia is caused by an imbalance of oxygen supply and
oxygen demand. The diseased arteries are pathohistologically
characterized by constriction in one or more section of a cardiac
artery that is caused by vessel thrombosis, platelet aggregation,
vessel spasm, angioplasty restenosis, and other conditions. This
can cause to decreased oxygen supply, while exercise, stress or
other conditions leading to increased tone of the sympathetic
nervous system and/or increased blood levels of catecholamines can
increase myocardial oxygen demand. As noted in the '630 patent,
accurate and rapid detection of myocardial ischemia is the first
essential step toward reducing morbidity and mortality from this
often silent but deadly condition. Without the knowledge of the
condition, it cannot be treated.
[0012] An ischemic event often causes the performance of the heart
to be impaired and manifests itself through changes in the
electrical (e.g. the electrocardiogram or EGM signal), functional
(e.g., pressure, flow, etc.) or metabolic (e.g. blood or tissue
oxygen, pH, etc.) parameters of the cardiac function. An ischemic
event results in changes in the electrophysiological properties of
the heart muscle that eventually manifest themselves as changes in
the external ECG or internal EGM. The conventional approach to the
detection of ischemia and infarction relies on analysis and
interpretation of features of the ECG or EGM, e.g., the ST-segment,
the T-wave or the Q-wave, to detect deviations from normal.
Computer-based technology has been employed to monitor, display,
and semi-automatically or automatically analyze the ischemic ECG
changes. The above-referenced '630 patent sets forth improved
methods of detecting ischemia from the EGM sensed across a
plurality of sense electrodes.
[0013] In commonly assigned U.S. Pat. No. 5,199,428 to Obel et al,
it is proposed that the detection of myocardial ischemia can be
accomplished by sensing the patient's coronary sinus blood pH
and/or oxygen saturation and comparing each to preset, normal
thresholds. Blood pH or oxygen saturation sensors are located in
the coronary sinus or a coronary vein to measure the dissolved
oxygen and/or the lactic acid level of myocardial venous return
blood. The measured blood oxygen saturation and/or blood pH and the
ST segment deviation are compared to respective programmable
thresholds reflecting clinical risk levels. When ischemia is
confirmed, the disclosed system triggers burst stimulation of
selected nerves until the measured blood gas and/or blood pH and/or
ST segment returns to non-clinical risk levels.
[0014] For example, it has been proposed, as described in commonly
assigned, co-pending U.S. patent application Ser. No. 10/002,338
filed Oct. 30, 2001, and Publication No. 2003/0083702 to employ
various types of sensors including accelerometers, magnets, and
sonomicrometers typically located in a blood vessel or heart
chamber that respond to or move with mechanical heart function to
derive a metric that changes in value over the heart cycle in
proportion to the strength, velocity or range of motion of one or
more of the heart chambers or valves. Such a mechanical function
metric would complement the measurement of blood pressure and the
EGM to more confidently determine the degree of change in a heart
failure (HF) condition of the heart.
[0015] An implantable EGM monitor for recording the cardiac
electrogram from electrodes remote from the heart as disclosed in
commonly assigned U.S. Pat. No. 5,331,966 and PCT publication WO
98/02209 is embodied in the Medtronic.RTM. REVEAL.RTM. Insertable
Loop Recorder having spaced housing EGM electrodes. More elaborate
implantable hemodynamic monitors (IHMs) for recording the EGM from
electrodes placed in or about the heart and other physiologic
sensor derived signals, e.g., one or more of blood pressure, blood
gases, temperature, electrical impedance of the heart and/or chest,
and patient activity have also been proposed. In particular, the
Medtronic.RTM. CHRONICLE.RTM. Implantable Hemodynamic Monitor (IHM)
system comprises a CHRONICLE.RTM. Model 9520 IHM of the type
described in commonly assigned U.S. Pat. No. 5,368,040 coupled with
a Model 4328A pressure sensor lead that monitors the EGM of the
heart and senses blood pressure within a heart chamber using a
pressure sensing transducer of the type disclosed in commonly
assigned U.S. Pat. No. 5,564,434. The CHRONICLE.RTM. Model 9520 IHM
measures absolute blood pressure, and the patient is also provided
with an externally worn Medtronic.RTM. Model No. 2955HF atmospheric
pressure reference monitor of the type described in commonly
assigned U.S. Pat. No. 5,810,735 to record contemporaneous
atmospheric pressure values.
[0016] A further IHM is disclosed in commonly assigned U.S. Pat.
No. 6,438,408 that measures a group of parameters indicative of the
state of HF employing EGM signals, measures of blood pressure
including absolute pressure P, developed pressure DP (DP=systolic
P-diastolic P), and/or dP/dt, and measures of heart chamber volume
(V) over one or more cardiac cycles. These parameters include: (1)
relaxation or contraction time constant tau (.tau.); (2) mechanical
restitution (MR), i.e., the mechanical response of a heart chamber
to premature stimuli applied to the heart chamber; (3)
recirculation fraction (RF), i.e., the rate of decay of PESP
effects over a series of heart cycles; and (4) end systolic
elastance (E.sub.ES), i.e., the ratios of end systolic blood
pressure P to volume V. These HF state parameters are determined
periodically regardless of patient posture and activity level.
However, certain of the parameters are only measured or certain of
the data are only stored when the patient heart rate is regular and
within a normal sinus range between programmed lower and upper
heart rates. The parameter data is associated with a date and time
stamp and with other patient data, e.g., patient activity level,
and the associated parameter data is stored in IMD memory for
retrieval at a later date employing conventional telemetry systems.
Incremental changes in the parameter data over time, taking any
associated time of day and patient data into account, provide a
measure of the degree of change in the HF condition of the
heart.
[0017] Methods and apparatus for developing estimates of the
ventricular afterload derived from ventricular pressure
measurements employing the CHRONICLE.RTM. Model 9520 IHM coupled
with a Model 4328A pressure sensor lead are described in commonly
assigned, co-pending U.S. patent application Ser. No. 10/376,064
filed Feb. 26, 2003. The estimates of the ventricular afterload can
be used to quantify the current state of cardiovascular function,
to discern changes in the state of cardiovascular function over
time, and to select or alter a therapy delivered by an IMD to
optimize cardiovascular function of patients experiencing HF,
hypertension, and other clinical pathologies.
[0018] A system and method are disclosed in commonly assigned
co-pending U.S. patent application Ser. No. 10/368,278 filed Feb.
18, 2003, for detecting mechanical pulsus alternans (MPA) as well
as associated electrical alternans and other MPA episode data from
ventricular pressure and EGM measurements employing the
CHRONICLE.RTM. Model 9520 IHM coupled with a Model 4328A pressure
sensor lead. The collected MPA episode trend data provides indicia
related to the mechanical performance of the HF patient's heart so
that the response of the heart to drug or electrical stimulation
therapies prescribed to reduce HF symptoms can be assessed.
[0019] It has also been proposed to detect ischemic conditions of
the heart from EGM characteristics, particularly, ST segment
elevation, and mechanical heart motion as measured by an
accelerometer or changes in measured blood pressure, for example,
as described in commonly assigned, co-pending U.S. Patent
Application Publication Nos. U.S. 2003/0045805 and U.S.
2002/0120205.
[0020] It is therefore desirable to provide a system and method
that detects an ischemic state and delivers a pharmacologic agent
into the pericardial space to treat the ischemic state in an
efficient manner.
[0021] It would also be desirable to provide a system and method
that delivers NO-donors into the pericardial space to treat
detected conditions of the heart.
BRIEF SUMMARY OF THE INVENTION
[0022] Accordingly, the present invention provides systems and
methods that access the pericardial space and deliver a
pharmacologic agent into the pericardial space to counter a
detected ischemic state or other cardiac condition.
[0023] In preferred embodiments, the methods and systems of the
present invention provide for transvenously accessing the
pericardial space between a heart and its pericardium to deliver a
pharmacologic agent to the heart from an implantable infusion pump
(IIP). A proximal connector of an infusion catheter is coupled to
the IIP, and a distal catheter segment having a distal infusion
catheter lumen end opening is disposed in the pericardial space.
The IIP delivers a bolus the pharmacologic agent into the
pericardial space to treat or counter symptoms of a cardiac
condition.
[0024] In one preferred embodiment, the infusion catheter is routed
transvenously into the right atrium and through the right atrial
wall in the atrial appendage to dispose the distal infusion
catheter lumen end opening in the pericardial space. The routing
may be effected employing a fixation catheter attached to the right
atrial wall.
[0025] Preferably, the IIP is operable to detect a remotely
transmitted therapy delivery command and to deliver a bolus of the
pharmacologic agent. Advantageously, the patient may be provided
with a "patient activator" that the patient can operate when
feeling cardiac symptoms, e.g., ischemia symptoms, to transmit a
signal that is received by the IIP and triggers delivery of the
bolus.
[0026] In a further embodiment, the IIP is operable in conjunction
with an implantable ischemia monitor to monitor the ischemic state
and regulate the periodic delivery of the pharmacologic agent to
optimally treat ischemia.
[0027] Preferably, the IIP is preferably programmable by the
treating physician, and a baseline dosage correlated to a detected
baseline ischemic state is programmed by the physician at
implantation and from time to time during patient work-ups. The
baseline dosage frequency of delivery may be intermittent at
specified intervals or continuous. A dosage adjustment from
baseline dosage, e.g., a dosage adjustment in bolus volume or
frequency of delivery, takes place as a function of the difference
between a currently measured ischemic state and the baseline
ischemic state. A weighting or scale factor can be programmed by
the physician into memory to adjust the function. A maximum dosage
adjustment (positive and negative) from baseline dosage may also be
programmed by the physician.
[0028] Preferably, the pharmacologic agent comprises NO-releasing
or NO-donor drugs selected from the group consisting of nitric
oxide (NOX) and NOX donor agents, preferably selected among
nitroglycerin (also known as glyceryltrinitrate or GTN), isosorbide
mononitrate (ISMN), sodium nitroprusside (SNP), a diazenium diolate
(e.g. DETA/NO), NO Aspirins (NCX 4016 and nCX 4215), an
S-Nitrosothiol (SNAP), and morpholinosydnonimime (SIN-1) or any
other compound which either induces increased nitric oxide levels
(e.g. L-arginine, other NO-donors) The delivery of NO-donor drugs
advantageously treats a number of cardiac conditions, including but
not limited to ischemia.
[0029] The detection may be accomplished by sensing a feature of
the EGM of the heart, and detecting a characteristic of the sensed
feature indicative of the ischemic state. Alternatively or
additionally, the detection may be accomplished by use of sensors
sensing one or more of blood pH and blood oxygen saturation in the
coronary sinus or blood pressure and blood flow in the heart and
detecting a value indicative of the ischemic state. The ischemic
state can be determined as a composite of the detected sensor and
EGM signals.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] These and other advantages and features of the present
invention will be more readily understood from the following
detailed description of the preferred embodiments thereof, when
considered in conjunction with the drawings, in which like
reference numerals indicate identical structures throughout the
several views, and wherein:
[0031] FIG. 1 is a schematic illustration of an IIP implanted
subcutaneously within the patient's body coupled to an infusion
catheter to deliver a bolus and/or continuous infusion of a
pharmacologic agent, the bolus and/or continuous infusion
programmed through use of an external programmer, into the
pericardial space in response to an external patient activator
trigger signal to counter an ischemic state detected by the
patient;
[0032] FIG. 2 is a schematic illustration of the operating system
of the IIP of FIG. 1 in relation to the external programmer and
patient activator;
[0033] FIG. 3 is a schematic illustration of an exemplary infusion
catheter usable in the practice of the present invention;
[0034] FIG. 4 is a simplified flow chart illustrating the operation
of the system of FIGS. 1 and 2;
[0035] FIG. 5 is a schematic illustration of a combined IIP and
ischemia monitor, programmed through use of an external programmer,
implanted subcutaneously within the patient's body, coupled to an
ischemia detection lead enabling detection of an ischemic state and
an infusion catheter to deliver a bolus of a pharmacologic agent
upon detection of the ischemic state or in response to an external
patient activator trigger signal into the pericardial space to
counter the ischemic state;
[0036] FIG. 6 is a schematic illustration of the operating system
of the IIP of FIG. 4 in relation to the external programmer and
patient activator with the infusion catheter extending through the
right atrial wall into the pericardial space;
[0037] FIG. 7 is a schematic illustration of an exemplary ischemia
monitoring lead usable in the practice of the present
invention;
[0038] FIG. 8 is a simplified flow chart illustrating the operation
of the system of FIGS. 5 and 6;
[0039] FIG. 9 is a schematic illustration of the exemplary and
optional use of a fixation catheter to route the infusion catheter
into the pericardial space; and
[0040] FIG. 10 is a schematic illustration of the operating system
of the IIP of FIG. 4 in relation to the external programmer and
patient activator with the infusion catheter extending through
pericardial sac into the pericardial space.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE
INVENTION
[0041] In the following detailed description, references are made
to illustrative embodiments of methods and apparatus for carrying
out the invention. It is understood that other embodiments can be
utilized without departing from the scope of the invention.
[0042] Implantable drug pumps having drug reservoirs that can be
refilled through ports accessed transcutaneously and coupled with
catheters extending from the reservoir to a delivery site have been
developed or proposed to deliver a variety of drugs. The
Medtronic.RTM. SynchroMed.RTM. Infusion System approved for certain
clinical uses comprises an Implantable Infusion Pump (IIP) coupled
to a catheter. The battery powered IIP can be advantageously
programmed to frequently or continuously deliver drug boluses of
drugs that have a short duration of activity directly to an
efficacious site. The IIP is surgically implanted subcutaneously
under the skin such that the refill port is directed outward. The
IIP reservoir can be refilled as necessary. Adverse side effects
are reduced and the mental and physical states of many patients are
improved by the automatically administered drug therapy. It is not
necessary to rely upon the patient to comply with the prescribed
regimen.
[0043] One embodiment of an exemplary IIP system in which the
present invention can be implemented is depicted in FIGS. 1 and 2
comprising an IIP 50 and infusion catheter 40 implanted in the
patient's body 10 and an external programmer 80 and patient
activator 90 operated by the patient. The IIP 50 communicates with
the external programmer 80 through uplink telemetry (UT) and
downlink telemetry (DT) transmissions through the patient's skin
12. The patient activator 90 can be operated by the patient to send
a trigger (TRIG) signal through the patient's skin 12 to cause the
IIP 50 to deliver a bolus of the pharmacologic agent.
[0044] In FIG. 1, the IIP 50 includes the infusion catheter 40
coupled at a proximal end to a fitting or connector 52 of the IIP
housing 58 and extending into the pericardial space PS of heart 30
enclosed by pericardial sac or pericardium 28. The heart 30 and the
surrounding pericardial sac 28 are cut away in part to expose the
epicardium and the right heart chambers or the right atrium (RA)
and the right ventricle (RV) (separated by the tricuspid valve).
Venous blood drains into the RA through the superior vena cava
(SVC) and the inferior vena cava (not shown). The RA appendage 32
extends somewhat laterally of the axis of the RA between the SVC
and tricuspid valve.
[0045] The infusion catheter 40 is illustrated in greater detail in
FIG. 4 and comprises an elongated therapeutic catheter body 44
extending between a proximal fluid connector 42 and a therapeutic
catheter body distal end 46. The fluid connector 42 is shaped and
adapted to be coupled to the fluid connector 52 of the IIP 50 for
chronic dispensation of drugs or agents from a reservoir of an IIP
50 into the pericardial space PS. A fluid transmitting lumen 48
extends from a proximal lumen end opening at the fluid connector 42
and one or more delivery lumen exit ports 49 at or near the
therapeutic catheter body distal end 46. Fluid transmitting lumen
48 may function as a through lumen for over the wire advancement of
the therapeutic catheter body 44 over a guidewire that is first
passed through the atrial wall if a delivery lumen exit port 49 is
axially aligned with fluid transmitting lumen 48.
[0046] The infusion catheter 40 is preferably advanced via the
venous system draining through the superior vena cava into the
right atrium, then deflected into the atrial appendage and through
the right atrial wall to dispose the delivery lumen exit ports 49
in the pericardial space PS. The instruments and techniques
disclosed in commonly assigned Published Patent Application No.
2004/0087938 A1 and U.S. Pat. No. 6,613,062 to Leckrone et al may
be employed to dispose the distal segment of the infusion catheter
40 in the pericardial space PS.
[0047] As depicted in commonly assigned U.S. Patent Application
Publication No. 2003/0204181, the IIP housing 58 encloses an
electronic control or operating system depicted in FIG. 2 including
a control module 200 and associated electrical and mechanical
components. The external programmer 80 and the patient activator 90
are also shown schematically in FIG. 2 disposed outside the
patient's skin 12.
[0048] The mechanical components include a drug reservoir 240
associated with a resealable drug fill port 56 in the housing 58
and an outlet to a peristaltic roller pump 244. A bellows (not
shown), associated with a gas-filled pressure chamber (not shown),
applies a constant pressure against the drug reservoir 240 and the
volume of drug within the drug reservoir 240. The catheter port 246
is coupled to the output of the peristaltic roller pump 246, and
the roller pump 246 is periodically energized by an output signal
of the circuit module 200 to deliver a dosage of the pharmacologic
agent into the pericardial space through the infusion catheter 40.
After subcutaneous implantation, a hypodermic needle is inserted
through the patient's skin 12 and then through the resealable
membrane of port 56 to fill the drug reservoir 240 with the
pharmacologic agent.
[0049] The control module 200 is also coupled to a battery or
batteries 208, an RF telemetry antenna 234, and a piezoelectric
crystal 210. The control module 200 has a system architecture that
is constructed about a microcomputer-based control and timing
system 202 that varies in sophistication and complexity depending
upon the type and functional features incorporated therein. The
micro-computer-based IIP control and timing system 202 can be
similar to the microcomputer circuit 114 of the IHM 52 described
above with respect to FIG. 3. The functions of microcomputer-based
IIP control and timing system 202 are controlled by firmware and
programmed software algorithms stored in RAM and ROM including PROM
and EEPROM and are carried out using a CPU, ALU, etc., of a typical
microprocessor core architecture.
[0050] Power levels and signals are derived from battery 208 by the
power supply/POR circuit 226 having power-on-reset (POR) capability
to power the roller pump 244 and the other components of the
circuit module 200. The power supply/POR circuit 226 provides one
or more low voltage power Vlo and one or more VREF sources. Not all
of the conventional interconnections of these voltage sources and
signals with the circuitry of the IIP control module 200 are shown
in FIG. 2.
[0051] In certain IIPs, an audible patient alert warning or message
can be generated by a transducer when driven by a patient alert
driver to advise of device operations, e.g., confirmed delivery of
a bolus or dosage of pharmacologic agent, or the battery depletion
level to warn of a depleted battery state or depletion of the
pharmacologic agent in reservoir 240.
[0052] Current electronic IIP circuitry of control module 200
employs clocked CMOS digital logic ICs that require a clock signal
CLK provided by a piezoelectric crystal 210 and system clock 238
coupled thereto. In FIG. 2, each CLK signal generated by system
clock 238 is routed to all applicable clocked logic of the
microcomputer-based control and timing system 202 and to the
telemetry transceiver I/O circuit 224 and the circadian or real
time clock 236. The crystal oscillator 238 provides one or more
fixed frequency system clock or CLK signal that is independent of
the battery voltage over an operating battery voltage range for
system timing and control functions and in formatting uplink
telemetry signal transmissions in the telemetry I/O circuit 224.
The real-time or circadian clock 134 driven by system clock 238
that provides a time of day signal to the microcomputer-based
timing and control system 202.
[0053] The telemetry transceiver 224 coupled to the RF telemetry
antenna 234 enables UT and DT telemetry capabilities with a
remotely located external medical device, e.g., programmer 80, or a
more proximal external medical device carried on the patient's body
10, or another IMD in the patient's body 10. During an UT
transmission, the external RF telemetry antenna 82 of programmer 80
operates as a telemetry receiver antenna, and the IIP RF telemetry
antenna 234 operates as a telemetry transmitter antenna.
Conversely, during a DT transmission, the external RF telemetry
antenna 82 operates as a telemetry transmitter antenna, and the IIP
RF telemetry antenna 234 operates as a telemetry receiver
antenna.
[0054] In general terms, the operation of the roller pump 244 can
controlled through resident software and firmware in the
microcomputer-based control and timing system 202 in a general
manner similar to that described in commonly assigned U.S. Pat. No.
4,692,147. The frequency and volume of each bolus or dosage of
pharmacologic agent delivered into the pericardial space can be
governed by DT transmitted dosage commands that are stored in RAM.
Data related to the delivery of dosages of pharmacologic agent can
be stored in RAM within the microcomputer-based control and timing
system 202 and UT transmitted to the programmer 80 in a telemetry
session initiated by a medical care provider.
[0055] There are a number of ways that the IIP 50 can employed to
dispense pharmacologic agent into the pericardial space PS in
accordance with the various aspects of the invention. First, a
fixed amount or bolus or dosage can be dispensed at predetermined
timed intervals over the entire 24 hour day, that is once a day or
more than once a day to maintain a relatively uniform level of
pharmacologic agent in the pericardial space. Or, a bolus or dosage
of pharmacologic agent into the pericardial space PS may be
delivered at specific times as timed out by the circadian clock
236.
[0056] It is expected that the patient's physician would develop a
conservative delivery regimen and use the programmer 80 to DT
transmit the delivery times or delivery delay and bolus or dosage
quantities. The symptoms of ischemia or pathologies associated with
ischemia would be monitored, and the physician would periodically
adjust the bolus or dosage depending upon the observed response or
lack of response.
[0057] Optionally, the patient can be provided with the patient
activator 90 to command the delivery of a bolus pharmacologic agent
into the pericardial space PS. Suitable patient activators can
communicate with IMDs, e.g., IIP 50, through the use of digitally
encoded RF telemetry, infrared, acoustic pulsed, or magnetic
signals that pass through the patient's skin 12. Preferably, the
patient activator 90 is of the type disclosed in commonly assigned
U.S. Pat. No. 5,755,737 or in U.S. Pat. Nos. 5,674,249 and
4,263,679 that communicate with the IIP 50 via RF DT transmissions
through the patient's skin 12 between the patient activator antenna
92 and the IIP RF antenna 234.
[0058] For simplicity, the depicted exemplary patient activator 90
includes a battery powered RF telemetry transmitter conforming to
the RF telemetry protocol employed in RF telemetry between the RF
telemetry transceiver 224 and the telemetry transceiver within the
programmer 80. The patient activator 90 preferably includes a
button 94 to be depressed by the patient to cause an RF activation
or TRIG signal to be emitted from the RF antenna 92 that is
received by the RF telemetry transceiver 224. A first light, e.g.,
an LED 96, lights up when the TRIG signal is transmitted. A second
light, e.g., LED 98, may be provided to indicate patient activator
battery status.
[0059] The TRIG signal is received via RF antenna 234 and
transmitted through RF telemetry transceiver 224 to the
microcomputer-based control and timing system 202. In accordance
with this aspect of the present invention, a motivated and
competent patient provided with a patient activator 90 can transmit
the TRIG signal and command the control and timing system 202 to
deliver a bolus or dosage of pharmacologic agent when the patient
experiences symptoms or preceding an activity that might cause
symptoms, e.g., angina pectoris.
[0060] The frequency of delivery or discharge of dosages of
pharmacologic agent can be limited within a delivery delay time
window started by any delivery earlier initiated by the patient. In
other words, the receipt of a TRIG command from the patient
activator 90 would initiate delivery of the bolus of pharmacologic
agent and also start a delivery delay timer that would have to time
out before the control and timing system 202 can respond to any
further TRIG commands initiated by the patient's use of the magnet
patient activator 90.
[0061] The delivery of pharmacologic agent into the pericardial
space (PS) is alternatively controlled in a variety of ways. The
general operation of a drug delivery system including the IIP 50,
the programmer 80, and the patient activator 90 is set forth in
FIG. 3. During normal operation, the drug dosage is programmed or
set by the physician and stored in memory of the
microcomputer-based timing and control system 202. Thus, a revised
or adjusted dosage that is received from external programmer 80 is
stored in memory of the microcomputer-based timing and control
system 202 in step S106 when such a dosage command is received as
determined in step S104. The adjusted dosage is then employed in
steps S108 and S10 until a further adjusted dosage is received and
stored in steps S104 and S106. The dosage delivery algorithm
determines if dosage delivery criteria are met in step S108, and
the dosage is delivered in step S110 when the dosage delivery
criteria are met. The baseline dosage frequency of the dosage
delivery criteria can be continuous or intermittent.
[0062] If the patient is competent, the physician enables the
patient activation function within programmed limits, e.g., how
frequently a dosage may be delivered, both automatically and in
response to patient activation, and the maximum dosage volume or
bolus that can be delivered in a given time period. A drug dosage
is delivered in step S110 when the patient activation is detected
in step S100 and patient activation is so enabled as determined in
step S102.
[0063] Thus, the drug dosage is delivered in step S110 from time to
time or continuously, depending upon the programmed or adjusted
delivery frequency, when the delivery criteria are met in step S108
in the absence of either a patient activation or a received dosage
command in steps S100-S106. In the simplest operating mode and
embodiment of the invention, only steps S108 and S110 are performed
between refills of the drug dispenser reservoir and patient
work-ups by the attending physician.
[0064] As noted above, a variety of implantable hemodynamic
monitors (IHMs) for recording the EGM from electrodes placed in or
about the heart and other physiologic sensor derived signals, e.g.,
one or more of blood pressure, blood gases, temperature, electrical
impedance of the heart and/or chest, and patient activity have been
proposed in the prior art. The present invention contemplates
monitoring of the ischemic state of the patient employing any
appropriate monitoring system and technology and modulating or
regulating the delivery of the pharmacologic agent into the
pericardial space PS.
[0065] Thus, a still further exemplary IIP system in which the
present invention can be implemented is depicted in FIGS. 5 and 6
comprising a combined ischemia monitor (IM) and IIP 100 coupled via
connector 160 to the infusion catheter 40 and to an ischemia
monitoring lead 60 implanted in the patient's body 10. The IM/IIP
250 communicates by RF telemetry with external programmer 80 via UT
and DT transmissions as described above. The IM/IIP 250 optionally
communicates with the patient activator 90 operated by the patient
as described above with respect to FIGS. 1-3. An exemplary ischemia
monitoring lead 60, depicted in greater detail in FIG. 7, supports
a physiologic sensor and one or more sense electrode for sensing
the EGM that are adapted to be disposed in the coronary sinus CS as
shown in FIG. 5. The IM/IIP 250 operates in accordance with the
method depicted in FIG. 8 to dispense a bolus of pharmacologic
agent into the PS through the delivery lumen of the infusion
catheter 40. The pharmacologic agent is dispensed from a reservoir
within housing 158, and the reservoir is refilled through port 156
in the manner described above.
[0066] In this embodiment, the IM/IIP 100 further comprises
electrical circuitry and components for deriving near field and/or
far field EGM signals and one or more physiologic sensor signal and
processing the signals in the manner depicted in FIG. 8 to
determine an ischemic state to trigger or modulate the delivery of
pharmacologic agent through the infusion catheter 40 into the PS
surrounding heart 30. For example, the IM/IIP housing 158 supports
sense electrodes 162, 164, 166 arranged in an orthogonal array. The
far field EGM can be detected from selected pairs of the electrodes
162, 164, 166 so that ST segment changes indicative of ischemia can
be detected by sense circuitry of the operating system in the
manner disclosed in the above-referenced '630 patent, for example.
Moreover, the operating system responds to physiologic signals
and/or near field EGM signals detected, for example, in the
coronary sinus CS and conducted through the ischemia monitoring
lead 60 to the operating system depicted in FIG. 6.
[0067] Turning to FIG. 7, an exemplary ischemia monitoring lead 60
is formed of an elongated lead body 66 extending between a proximal
lead connector comprising a connector ring 62 and a connector pin
64 and a distal tip sense electrode 74. The proximal lead connector
is shaped and adapted to be inserted into a bore of the connector
160 of the subcutaneously implanted IM/IIP 100. A proximal ring
shaped sense electrode 72 and a physiologic sensor 70 are disposed
along the elongated lead body 66 proximal to the distal tip sense
electrode 64.
[0068] As shown in FIG. 5, the lead body 66 is adapted to be
advanced through the venous system, the SVC, the RA, and the ostium
of the CS to dispose the distal segment of the lead body 66
supporting the physiologic sensor 70 and the sense electrodes 72
and 74 in the CS or a vein branching from the CS. A lead lumen 68
extends from a proximal lumen end opening axially through connector
pin 64 through the length of the lead body 66 and either terminates
at extends axially through tip pace/sense electrode 64 to function
as a stylet lumen to receive a stylet to advance the distal segment
of the lead body into the CS or a through lumen for over the wire
advancement of the lead body 66 over a guidewire placed in the
CS.
[0069] In this location, the physiologic sensor 70 may comprise one
or more chemical/biochemical sensor selected from the group
consisting of a blood/extracellular tissue gas saturation sensor
sensitive to changes in pCO.sub.2 and pO.sub.2 signifying ischemia,
a blood pH sensor sensitive to pH and lactate changes signifying
ischemia, and sensors capable of detecting myocardial enzyme
leakage-troponin isoforms or creatine kinase or lactate
dehydrogenase that are indicative of ischemia. Lead conductors
extend within lead body between the proximal connector ring 62 and
pin 64 and the sense electrodes 72 and 74, respectively, and the
physiologic sensor 70. The signals on the lead conductors may be
multiplexed in time to enable readout of the sensor and EGM
signals.
[0070] It should be understood that the depicted physiologic sensor
70 disposed in the CS in FIG. 5 is merely exemplary of one location
of a chemical/biochemical or chemical sensor in deriving sensor
signals indicative of an ischemic state. The ischemia monitoring
lead 60 can alternatively be routed into the pericardial space PS
to dispose the EGM sense electrodes 72 and/or 74 and the
chemical/biochemical physiologic sensor 70 therein. It will be
understood that the ischemia monitoring lead 60 and the infusion
catheter may be combined to so dispose the sense electrodes 72
and/or 74 and/or physiologic sensor 70 in the pericardial space
PS.
[0071] It will also be understood that a pO.sub.2 sensor can be
disposed into the myocardium to detect blood gas changes indicative
of ischemia state and other cardiac conditions. Furthermore, other
ischemia or cardiac condition sensors on sensor leads and disposed
in use elsewhere in or about the heart may be substituted for
physiologic sensor 70.
[0072] For example, a blood pressure sensor can be disposed in the
right or left ventricular chamber to develop right ventricular
pressure (RVP) signals or left ventricular pressure (LVP) signals,
respectively, from which +dP/dt and/or an acute fall in RVP or LVP
can be detected that is indicative of a worsening ischemic state.
Alternatively, the blood pressure sensor may be disposed in the
right atrial chamber to detect changes in right atrial pressure
(RAP) indicative of a higher filling pressure. The physiologic
sensor 70 and the sense electrode 72 may be combined so that
ischemia monitoring lead 60 functions in the manner of the combined
EGM and pressure sensing lead disclosed in commonly assigned U.S.
Pat. No. 5,564,434 to Halperin et al.
[0073] Alternatively, the EGM sense electrodes 72 and/or 74 and/or
physiologic sensor 70 may be located in any suitable cardiac vessel
or chamber and be configured to develop blood flow signals
indicative in ischemia state and other cardiac conditions.
[0074] Moreover, it will be understood that changes in heart
volume, ejection fraction and segment shortening indicative of an
ischemic state or other cardiac condition may be derived from the
output signals of a plurality of accelerometers, magnets or
sonomicrometers arrayed about the heart as described in the
above-referenced commonly assigned, co-pending U.S. patent
application Ser. No. 10/002,338 filed Oct. 30, 2001, and
Publication No. 2003/0100925. Such mechanical heart function
sensors respond to or move with mechanical heart function to derive
a metric that changes in value over the heart cycle in proportion
to the strength, velocity or range of motion of one or more of the
heart chambers or valves. Such a mechanical function metric would
complement the measurement of blood pressure and the EGM to more
confidently determine the degree of change in an ischemic state or
HF condition of the heart.
[0075] Turning to FIG. 6, the depicted external programmer 80,
patient activator 90, and the drug reservoir, roller pump 244,
catheter port 246, and operating system 200 correspond to and
function as described above in regard to FIG. 2. Thus, the IM/IIP
250 incorporates the physical structure of the IIP 50 but further
includes the input/output circuit 112 of an IHM for receiving and
processing EGM signals from one or more of the sense electrodes 72,
74, 162, 164, 166 and powering and processing the ischemia signal
of the ischemia monitor 70. It would be expected that the selected
EGM electrodes would be programmable by the physician. A patient
activity sensor 106 may also be provided in housing 158 to develop
an activity signal. The micro-computer-based timing and control
system 202 and the input/output circuit 112 perform the dosage
adjustment and delivery algorithm depicted in the steps of FIG. 8.
In this embodiment, the micro-computer-based timing and control
system 202 processes the signals developed in the input output
circuit 112 received through data communication bus 130 to perform
the steps of FIG. 8.
[0076] The general operation of the IHM 50 in performing a dosage
adjustment algorithm and communicating an adjusted dosage to the
external drug dispenser (or a discrete IIP or IIP function
incorporated into a combined IHM and IIP) is set forth in the steps
of FIG. 5. The physiologic sensor 70 and the activity sensor 106
are periodically powered to develop sensor output signals and the
near field and/or far field EGM signals are periodically sampled by
the input/output circuit 112 and provided by bus 130 to the
micro-computer-based timing and control system 202. The sensor
output and EGM signals are processed in step S200 to calculate the
adjusted dosage. The adjusted dosage is compared to the current
dosage, that is the most recently determined dosage, and to
programmed dosage limits in step S202.
[0077] The adjusted dosage is substituted for the current dosage in
step S208 if the adjusted dosage differs from the current dosage as
determined in step S204 and the adjusted dosage is within
programmed limits as determined in step S206. The adjusted dosage
that is stored in step S210 with related data for UT transmission
to the external programmer 80 may be limited to one of the upper or
lower dosage limits in step S208 if the adjusted dosage satisfying
step S204 is determined to beyond the programmed limits in step
S206.
[0078] Thus, the adjusted dosage is stored in RAM for use as the
current dosage and for UT transmission upon receipt of a DT
transmitted interrogation command from programmer 80. The
micro-computer-based timing and control system 202 performs the
steps S212 and S214 in the same fashion as steps S100 and S102 of
FIG. 4 as described above. Similarly, the micro-computer-based
timing and control system 202 performs the steps S216 and S218 in
the same fashion as steps S108 and S10 of FIG. 4 as described
above. The dosage is delivered in step S218 in the manner of step
S10 of FIG. 4 as described above.
[0079] It has also been proposed to implant multiple implantable
medical devices (IMDs) in the same patient, and to enable
communication between the IMDs, whereby the multiple IMDs function
cooperatively as disclosed, for example, in commonly assigned U.S.
Pat. Nos. 4,987,897 to Funke. The multiple IMDs include tissue
stimulators, e.g., cardiac pacemakers, implantable
cardioverter-defibrillators (ICDs), gastrointestinal stimulators,
deep brain stimulators, and spinal cord stimulators, IlPs,
implantable physiologic sensors, and activity sensors.
Consequently, it will be appreciated that the system and method of
the embodiment of FIGS. 6-8 can be alternatively realized employing
IIP 50 coupled to infusion catheter 40 and a separately housed and
implanted IM having an array of far field sense electrodes 162,
164, 166 and coupled with the ischemia monitoring lead 60. In this
case, steps S200-S210 of FIG. 8 would be performed in the IM, and
the resulting adjusted dosage would be transmitted to the IIP 50,
where it would be stored in IIP RAM for use in performing steps
S212-S218.
[0080] A variety of patient worn external drug delivery systems
have been developed that obviate the problems that arise from
patient non-compliance with the prescribed drug regimen, that are
convenient to use and enable more precise dosage titration, and
that reduce side effects as a result of the dosage titration and
because the drug can, in certain cases, be delivered to an optimal
delivery site rather than being injected into the blood stream or
ingested. Consequently, it will be appreciated that the present
invention may be practiced employing an externally worn drug pump
in place of the IIP 50 and coupled to infusion catheter 50
extending through a skin incision. It will be further appreciated
that the system and method of the embodiment of FIGS. 6-8 can be
alternatively realized employing such an external drug pump coupled
to infusion catheter 40 and a separately housed and implanted IM
having an array of far field sense electrodes 162, 164, 166 and
coupled with the ischemia monitoring lead 60. In this case, steps
S200-S210 of FIG. 8 would be performed in the IM, and the resulting
adjusted dosage would be transmitted to the external drug pump,
where it would be stored in IIP RAM for use in performing steps
S212-S218.
[0081] FIG. 9 illustrates a preferred manner of passing the
infusion catheter 40 through the right atrial wall to transvenously
accessing the pericardial space PS involves passing a fixation
catheter 120 having a fixation catheter lumen 122 extending between
proximal and distal fixation catheter lumen openings and a distal
tissue fixation mechanism 124 through a selected peripheral vein
and one of the inferior vena cava and the SVC to establish a
transvenous route into the RA. The distal fixation mechanism 124
and distal fixation catheter lumen opening are disposed proximate
the right atrial wall 34 in the atrial appendage 36, and the distal
fixation mechanism 124 is affixed to the right atrial wall 34. The
infusion catheter 40 is passed through the fixation catheter lumen
122 out of the distal fixation catheter lumen opening and through
the stabilized atrial wall 34 to dispose the distal catheter
segment having the distal infusion catheter exit ports in the
pericardial space PS.
[0082] FIG. 10 illustrates an alternative routing of the infusion
catheter 40 through an incision made in the pericardial sac 28 to
dispose the exit ports 49 in the pericardial space 49. Access to
the pericardial sac 28 may take any form, e.g., those disclosed in
the above-referenced '433 patent, and the infusion catheter 40 is
routed subcutaneously to the subcutaneously implanted IM/IIP.
[0083] Preferably, the pharmacologic agent delivered into the
pericardial space as described above comprises NO-releasing or
NO-donor drugs preferably selected from the group consisting of
nitroglycerin (also known as glyceryltrinitrate or GTN), isosorbide
mononitrate (ISMN), sodium nitroprusside (SNP), a diazenium diolate
(DETA/NO), NO Aspirins (NCX 4016 and nCX 4215), an S-Nitrosothiol
(SNAP), and morpholinosydnonimime (SIN-1). The identification and
function of these NO-donor drugs is set forth in "Nitric Oxide
Donors" by T. Yamamoto and R. Bing, published in Proc Soc Exp Biol
Med. 2000 (Dec;225(3): 200-6) and papers referenced therein.
Certain pre-cursers that induce NO production by endothelia NO
synthase, e.g., L-arginine, may alternatively be delivered into the
pericardial space.
[0084] The delivery of the above NO-donor drugs in accordance with
the systems and methods of the present invention can be
precipitated by a number of events and delivery can be regulated in
accordance with a number of scenarios as follows:
[0085] 1. Acute reversible myocardial ischemia: signs of ischemia
via sensor->release of NO-donor until ischemia reverses.
[0086] 2. Chronic therapy refractory Angina pectoris->signs of
ischemia: release of NO-donor until ischemia reverses (effect may
be via angiogenesis).
[0087] 3. Chronic therapy refractory Angina pectoris->patient
has angina at rest and activates pump to release of NO-donor until
pain reverses.
[0088] 4. Chronic therapy refractory Angina pectoris->patient is
prepared to undergo physical activity and activates release of
NO-donor to prevent activity induced angina attacks. The release is
timed and so depending on activity duration the patient may need to
activate release several times. The release duration is
programmable.
[0089] 5. Acute, subacute myocardial infarction: sensor:
biochemical (key=enzyme leakage-prolonged lactate elevation>30
minutes continuously).->infusion of NO-donor during ischemia and
reperfusion, possibly up to days to weeks after infarction.
[0090] 6. If stenting: continuous high-dose NO-donor delivery for
days to weeks to prevent in stent restenosis.
[0091] 7. If TPA treatment: continuous NO-donor delivery to treat
ischemia/reperfusion related complications (arrhythmias, stunning,
accelerated cell death, infarct expansion).
[0092] 8. Silent ischemia: ischemia sensor senses ischemia: release
of NO-donor until ischemia subsides.
[0093] 9. Vasospastic Angina: ischemia sensor (typically via ST
segment changes) triggers release of NO-donor until ischemia
subsides.
[0094] Thus, a variety of embodiments are presented that facilitate
detecting symptoms of pathologies associated with ischemia and
triggering delivery of a pharmacologic agent to a pericardial space
site to alleviate such symptoms and otherwise treat ischemia and
pathologies associated with ischemia. Moreover, systems and methods
for detecting and responding to cardiac conditions by delivering
NO-donor drugs into he pericardial space are disclosed.
[0095] All patents and publications referenced herein are hereby
incorporated by reference in their entireties.
[0096] It will be understood that certain of the above-described
structures, functions and operations of the above-described
preferred embodiments are not necessary to practice the present
invention and are included in the description simply for
completeness of an exemplary embodiment or embodiments.
[0097] In addition, it will be understood that specifically
described structures, functions and operations set forth in the
above-referenced patents can be practiced in conjunction with the
present invention, but they are not essential to its practice.
[0098] It is to be understood, that within the scope of the
appended claims, the invention may be practiced otherwise than as
specifically described without actually departing from the spirit
and scope of the present invention. The disclosed embodiments are
presented for purposes of illustration and not limitation, and the
present invention is limited only by the claims that follow.
* * * * *