U.S. patent application number 09/057060 was filed with the patent office on 2001-11-22 for cardiac drug delivery system and method for use.
Invention is credited to ALTMAN, PETER A..
Application Number | 20010044619 09/057060 |
Document ID | / |
Family ID | 22008265 |
Filed Date | 2001-11-22 |
United States Patent
Application |
20010044619 |
Kind Code |
A1 |
ALTMAN, PETER A. |
November 22, 2001 |
CARDIAC DRUG DELIVERY SYSTEM AND METHOD FOR USE
Abstract
Implantable cardiac drug delivery systems. The systems are
installed endocardially into a chamber in the heart, and are
variously capable of delivering anti-arrhythmia agents into the
heart wall, and into the epicardial space outside the heart, and
into other chambers in the heart through the septa of the
heart.
Inventors: |
ALTMAN, PETER A.; (SAN
FRANCISCO, CA) |
Correspondence
Address: |
CROCKETT & CROCKETT
24012 CALLE DE LA PLATA
SUITE 400
LAGUNA HILLS
CA
92653
US
|
Family ID: |
22008265 |
Appl. No.: |
09/057060 |
Filed: |
April 8, 1998 |
Current U.S.
Class: |
604/539 ;
604/264 |
Current CPC
Class: |
A61N 1/0587 20130101;
A61M 2210/125 20130101; A61N 1/0568 20130101; A61M 25/0084
20130101; A61M 2025/0089 20130101; A61N 1/0563 20130101; A61M
5/14276 20130101; A61N 1/3621 20130101 |
Class at
Publication: |
604/539 ;
604/264 |
International
Class: |
A61M 025/00 |
Claims
I claim:
1. A method of treating the heart of a human patient comprising:
providing a catheter with a fluid port on the distal tip of the
catheter, and a lumen extending from the distal tip to the proximal
end of the catheter, and a fluid source in communication with the
lumen at the proximal end of the catheter; inserting the catheter
into the endocardial space of the heart, and penetrating the heart
wall with the distal tip of the catheter to place the distal tip of
the catheter in the epicardial space outside the heart; delivering
fluid through the catheter into the epicardial space.
2. A method of treating the heart of a human patient comprising:
providing a catheter with a fluid port on the digital tip of the
catheter, and a lumen extending from the distal tip to the proximal
end of the catheter, and a fluid source in communication with the
lumen at the proximal end of the catheter; inserting the catheter
into the endocardial space of a first chamber of the heart, and
penetrating a septum of the heart with the distal tip of the
catheter to place the distal tip of the catheter in the endocardial
space in a second chamber of the heart; delivering fluid through
the catheter into the endocardial space in a second chamber of the
heart.
3. A catheter for use in treating the heart of a patient, capable
of insertion into the endocardial space of the right atrium and
subsequent insertion into the atrial wall and penetration of the
atrial wall, said catheter comprising: a catheter tube with a
distal section in the epicardial space outside the right atrium, a
proximal section in fluid communication with a fluid source located
in chest of the patient, and an intermediate section extending from
the proximal section, into the vena cava, through the endocardial
space of the right atrium, and penetrating the wall of the right
atrium; a flange on the catheter at the point where the catheter
penetrates the atrial wall, said flange secured to the atrial
wall.
4. The catheter of claim 3 wherein the distal section of the
catheter extends around the heart and forms a helical coil
surrounding the heart.
5. A method of treating arrhythmia in a chamber of the heart, said
method comprising: creating at least two linear lesion of slow
conducting tissue in the wall of the chamber of the heart;
delivering an anti-arrhythmia agent into the wall of the heart in
the vicinity of the long linear lesion(s), creating a region of
slow conducting tissue effectively joining two or more linear
lesions together.
Description
FIELD OF THE INVENTION
[0001] The inventions described below relate to the field of
cardiovascular drug delivery, including systems and methods for
providing local transient pharmacological therapy to the
myocardium.
BACKGROUND OF THE INVENTION
[0002] Atrial fibrillation is a form of heart disease that afflicts
millions of people. It is a condition in which the normal
contraction of the heart is interrupted, primarily by abnormal and
uncontrolled action of the atria of the heart. The heart has four
chambers: the right atrium, right ventricle, the left ventricle,
the left atrium. The right atrium pumps de-oxygenated blood from
the vena cava to the right ventricle, which pumps the blood to the
lungs, necessary for return flow of de-oxygenated blood from the
body. The right atrium contracts to squeeze blood into the right
ventricle, and expands to such blood from the vena cava. The
contractions normally occur in a controlled sequence with the
contractions of the other chambers of the heart. When the right
atrium fails to contract, contracts out of sequence, or contracts
ineffectively, blood flow within the heart is disrupted. The
disruption of the normal rhythm of contraction is referred to as an
arrhythmia. The arrhythmia known as atrial fibrillation can cause
weakness due to reduced ventricular filling and reduced cardiac
output, stroke due to clot formation in a poorly contracting atria
(which may lead to brain damage and death), and even other life
threatening ventricular arrhythmias.
[0003] A therapy being developed for atrial fibrillation is the
atrial defibrillator. Atrial defibrillators are typically
implantable electrical therapy devices which deliver defibrillating
energy to the atrium to terminate arrhythmias. They sense the
electrical activity of the atrium and deliver an electrical shock
to the atrium when the electrical activity indicates that the
atrium is in fibrillation. Electrical defibrillation has two major
problems: the therapy causes substantial pain, and has the
potential to initiate a life threatening ventricular arrhythmias.
The pain associated with the electrical shock is severe and
unacceptable for many patients. Unlike electrical ventricular
defibrillators, where the patient loses consciousness prior to
receiving therapy, the patient who suffers an atrial arrhythmia is
conscious and alert when the device delivers electrical
therapy.
[0004] The potential for inappropriate induction of ventricular
fibrillation by the shock intended to defibrillate the atrium
exists. The induction of ventricular fibrillation has great
potential to result in death in just a few minutes if no
intervening therapy is provided. Careful algorithms to deliver
shocks to the periods in the ventricular contraction cycle when the
heart is not susceptible to shock induced ventricular fibrillation
have been developed to reduce the potential of this risk. If the
problem of patient pain can be overcome, atrial defibrillators
could be used in a large portion of the patient population that
suffers from atrial fibrillation.
[0005] Pharmacological Atrial Defibrillators
[0006] For some time, doctors have treated atrial fibrillation with
drugs injected intravenously or administered orally. Recent
literature describes the potential for the delivery of drugs to the
heart on demand to terminate arrhythmias. The concept has been
suggested for use in the atrium to treat atrial fibrillation.
Arzbaecher, Pharmacologic Atrial Defibrillator and Method, U.S.
Pat. No. 5,527,344 (Jun. 18, 1996) describes a pharmacological
atrial defibrillator and method for automatically delivering a
defibrillating drug into the bloodstream of a patient upon
detection of atrial arrhythmias in order to terminate the atrial
arrhythmias. Arzbaecher teaches that unspecified defibrillating
drugs should be injected into the bloodstream with a large initial
dose followed by delivery of a continuous smaller dose (this is the
"two-compartment pharmacokinetic model" discussed in the Arzbaecher
patent). By delivering agents to a blood vessel and maintaining a
therapeutic level of drugs in the blood stream, Arzbaecher requires
systemic effects to be achieved in order to terminate atrial
arrhythmias. In other words, if drugs injected according to
Arzbaecher are to have any effective concentrations within the
heart, a large amount must be injected in the blood stream to
ensure that an adequate dose will be delivered to the affected area
of the heart. While the drugs are in the blood stream, they are
available throughout the body to cause side effects on all other
organs.
[0007] There are several disadvantages to the transient
introduction of systemic drug levels by an implantable device.
Systemic effects resulting from such delivery may result in
detrimental effects to ventricular cardiac conduction. These
detrimental effects could be life threatening. The large amount of
drugs required for systemic delivery of therapeutic doses demands a
larger, less comfortable device than smaller dosages would allow.
The large quantity of drug in the implantable reservoir of such a
system is potentially more dangerous if it develops a leak or is
ruptured. Such a large single dosage will require a reservoir that
requires frequent follow ups for refilling post therapy by a
clinician. Lastly, the large quantities of drug required to obtain
therapeutic levels in the entire body may cost substantially more
than that required to treat a specific site within the heart. The
system described by Arzbaecher has one primary advantage over
electrical atrial defibrillation: the delivery of therapy to
terminate an arrhythmia does not cause patient pain, and some
recent abstracts have appeared in the literature which suggest that
this technique is viable. See Arzbaecher, et al., Development Of An
Automatic Implanted Drug Infusion System For The Management Of
Cardiac Arrhythmias, 76 IEEE Proc. 1204 (1991); Bloem, et al., Use
Of Microprocessor Based Pacemaker To Control An Implantable Drug
Delivery System, Computers in Cardiology 1 (1993); Bloem, et al.,
Microprocessor Based Automatic Drug Infusion System For Treatment
Of Paroxysmal Atrial Fibrillation, 26S J. Electrocardiogr. 60
(1993); and Wood, et al., Feedback control of antiarrhythmic
agents, in Molecular Interventions and Local Drug Delivery, (WB
Saunders 1995).
[0008] Drug delivery directly into the heart has been proposed for
other conditions. In my own prior patent, Altman, Implantable
Device for the Effective Elimination of Cardiac Arrythmogenic
Sites, U.S. Pat. No. 5,551,427 (Sep. 3, 1996) I describe an
implantable substrate for local drug delivery at a depth within the
heart. The patent shows an implantable helically coiled injection
needle which can be screwed into the heart wall in the ventricles
and connected to an implanted drug reservoir outside the heart.
This system allows injection of drugs directly into the wall of the
heart by merely injection of drugs through the skin into the
reservoir. The patent also shows a helical coil coated with coating
which releases drug into the myocardium. This drug delivery may be
performed by a number of techniques, among them infusion through a
fluid pathway, and delivery from controlled release matrices at a
depth within the heart. Pending application Ser. No. 08/881685 by
Altman and Altman, describes some additional techniques for
delivering local pharmacological agents to the heart.
[0009] Other implanted drug delivery systems have been proposed.
Levy, System for controlled release of antiarrhythmic agents, U.S.
Pat. No. 5,387,419 (Feb. 7, 1995), describes the placement of
controlled release matrices on the surface of the epicardium (on
the outside of the heart) for delivery of antiarrhythmic agents,
but all dosage forms described are for steady state drug delivery
and do not address the advantages of transient drug delivery from
an implantable epicardial structure. In addition, the device
described by Levy does not address the critical issue of surgical
access to the epicardial surface.
[0010] Controlled release matrices are drug polymer composites in
which a pharmacological agent is dispersed throughout a
pharmacologically inert polymer substrate. Sustained drug release
takes place via particle dissolution and slowed diffusion through
the pores of the base polymer. Prior work has shown that
antiarrhythmic therapy administered by epicardial application of
controlled release polymer matrices is effective in treating and
preventing ventricular arrhythmias in canine ventricular
tachycardia model systems [Siden, et al., Epicardial Controlled
Release Verapimil Prevents Ventricular Tachycardia Episodes Induced
by Acute Ischemia in a Canine Model, 19 J. Cardiovascular
Pharmacology 798 (1992).] This work shows the viability of
controlled release therapy delivered locally for the treatment of
arrhythmias. This work is identical to that described by Levy above
in that drug delivery structures are placed on the outside surface
of the heart during open heart surgery. No delivery at a depth
within the heart is described, there is no discussion of how one
would implant the structure non-invasively, and there is no
discussion of how one would deliver drugs upon demand to the
heart.
[0011] Cardiac Pacing
[0012] In the past, devices implanted into the heart have been
treated with anti-inflammatory drugs to limit the inflammation of
the heart caused by the wound incurred while implanting the device
itself. For example, pacing leads have incorporated steroid drug
delivery to limit tissue response to the implanted lead, and to
maintain the viability of the cells in the region immediately
surrounding the implanted device. Berthelson, Medical Electrical
Lead Employing Improved Penetrating Electrode, U.S. Pat. No.
5,002,067 (Mar. 26, 1991) describes a helical fixation device for a
cardiac pacing lead with a groove to provide a path to introduce
anti-inflammatory drug to a depth within the tissue. The groove
does not provide a patent fluid pathway to a depth within the
heart, no tube end to end is described, and the device is designed
for pacing the heart. No descriptions of using antiarrhythmic
agents or other approaches are described.
[0013] Moaddeb, Myocardial steroid releasing lead, U.S. Pat. No.
5,324,325 (Jan. 24, 1994) describes a myocardial steroid releasing
lead whose tip of the rigid helix has an axial bore which is filled
with a therapeutic medication such as a steroid or steroid based
drug. There is no fluid pathway from the proximal end of the
catheter, the drug delivery structure is limited in its size, the
device is designed for cardiac pacing. Moaddeb describes a
reservoir that is small in that it fills only the core region of
the distal portion of a helix historically formed of 0.010 inch
diameter to 0.012" diameter wire.
[0014] Vachon, Implantable Stimulation Lead Having an Advanceable
Therapeutic Drug Delivery System, U.S. Pat. No. 5,447,533 (Sep. 5,
1995) and U.S. Pat. No. 5,531,780 (Jul. 2, 1996) describe pacing
leads having a stylet introduced anti inflammatory drug delivery
dart and needle which is advanceable from the distal tip of the
electrode. No end to end tube is provided, and no means for
transient delivery of agents in an implantable setting is
provided.
[0015] Cardiac Ablation
[0016] The infusion of different fluids to a depth within the
myocardium has been described in the patent literature as being
useful for ablation. Lesh, Cardiac imaging and ablation catheter,
U.S. Pat. No. 5,385,148 (Jan. 31, 1995) describes a cardiac imaging
and ablation catheter in which a helical needle may be used to
deliver fluid ablative agents, such as ethanol, at a depth within
the tissue to achieve ablation. Lesh proposes permanently killing
the tissue with a one time application of ethanol such that the
heart is permanently damaged, not controlled. In one embodiment he
does describe the potential of temporarily deadening the tissue
with either Lidocaine or iced saline solution, but this is merely
in preparation of killing the tissue. The entire patent here
teaches away from implantable materials and applications as the
fundamental device use is for acute ablation procedures. No means
for transient delivery of agents in an implantable setting is
provided.
[0017] Mulier, Method and apparatus for ablation, U.S. Pat. No.
5,405,376 (Apr. 11, 1995), Method and apparatus for R-F ablation,
U.S. Pat. No. 5,431,649 (Jul. 11, 1995); and Method for R-F
Ablation, U.S. Pat. No. 5,609,151 (Mar. 11, 1997) each describe a
hollow helical delivery needle to infuse the heart tissue with a
conductive fluid prior to ablation to control the lesion size
produced. In addition delivery of an agent to affect cardiac
conduction to evaluate an ablation site, and delivery of RF energy
to the helical needle are disclosed. In all embodiments the device
is described as an acute use ablation catheter using different
techniques. No means for transient delivery of agents in an
implantable setting is provided.
[0018] Cardiovascular Restenosis
[0019] Igo, Apparatus And Method For Transpericardial Delivery Of
Fluid, U.S. Pat. No. 5,634,895 (Jun. 3, 1997) shows a technique for
delivering drugs locally to different regions of the surface of the
heart and within the pericardial sac via a subxiphoid surgical
route, for treating vascular thrombosis and restenosis. The
subxiphoid surgical route requires open chest surgery, and
penetration of the pericardial sac. Such invasive procedures can be
complicated by pericarditis and pericardial tamponade. No
techniques for less invasive delivery of bioactive agents to the
surface of the heart or into the pericardial space are described.
No systems for transient delivery, or transient delivery upon
demand are described. No techniques for delivering antiarrhythmic
agents or terminating atrial arrhythmias are addressed.
[0020] Antiarrhythmic Drugs
[0021] There are a number of viable pharmacologic therapies that
are also available. Drugs that predominantly affect slow pathway
conduction include digitalis, calcium channel blockers, and beta
blockers. Drugs that predominantly prolong refractoriness, or time
before a heart cell can be activated, produce conduction block in
either the fast pathway or in accessory AV connections including
the class IA antiarrhythmic agents (quinidine, procainimide, and
disopyrimide) or class IC drugs (flecainide and propafenone). The
class III antiarrhythmic agents (sotolol or amiodorone) prolong
refractoriness and delay or block conduction over fast or slow
pathways as well as in accessory AV connections. Temporary blockade
of slow pathway conduction usually can be achieved by intravenous
administration of adenosine or verapamil. [Scheinman,
Supraventricular Tachycardia: Drug Therapy Versus Catheter
Ablation, 17 Clinical Cardiology II-11 (1994)]. Other agents such
as encainide, diltiazem, and nickel chloride are also
available.
[0022] Drugs currently used for antiarrhythmia control can actually
kill people. The Cardiac Arrhythmia Suppression Trial showed that
specific agents delivered systemically resulted in substantially
higher mortality rates than those individuals receiving no drugs at
all. [The Cardiac Arrhythmia Suppression Trial (CAST)
Investigators, The effect of encainide and flecainide on mortality
in a randomized trial of arrhythmia suppression after myocardial
infarction, 321 N. Engl. J. Med. 406 (1989). Echt, et al.,
Mortality and morbidity in patients receiving encainide,
flecainide, or placebo--the Cardiac Arrhythmia Suppression Trial,
324 N. Engl. J. Med. 781 (1991).] This is likely due to the
problematic pro-arrhythmia effects of systemic drug delivery.
Minimization of dose by local transient drug delivery has potential
to eliminate the side effects of these antiarrhythmic agents. There
is a need to improve pharmacological therapy for the treatment of
arrhythmias by providing for local delivery of these and other
agents to regions within the heart tissue.
[0023] There are embodiments of this invention which incorporate
noninvasive surgical techniques for delivering drugs to the
pericardial space and overcoming the difficulties of the invasive
sub-xiphoid procedure described by Igo. In order to develop these
techniques it is important to touch on the prior art regarding
pericardial access and delivery.
[0024] Pericardial Access and Delivery
[0025] There are a number of approaches for placing devices
epicardially. Crosby, Apparatus for cardiac surgery and treatment
of cardiovascular disease, U.S. Pat. No. 4,181,123 (Jan. 1, 1980)
and Method And Apparatus For Permanent Epicardial Pacing Or
Drainage Of Pericardial Fluid And Pericardial Biopsy, U.S. Pat. No.
4,319,562 (Mar. 16, 1982) and Chin, et al., Method And Apparatus
For Providing Intrapericardial Access And Inserting
Intrapericardial Electrodes, U.S. Pat. No. 5,033,477 (Jul. 23,
1991) to disclose methods for placing electrodes in contact with
the heart muscles from within the pericardial space without the
need for a thoracotomy. Access to the pericardial space is gained
via a sub xiphoid approach. This involves penetrating the chest
wall below the xiphoid process.
[0026] The sub xiphoid route has several disadvantages. First,
because the pericardial sac which surrounds the heart is a tight
fitting fibrous membrane, the pericardial space is so small that it
is difficult to penetrate the sac without also puncturing, and
thereby damaging the heart itself. Second, accessing the heart via
a subxiphoid route entails a high risk of infection. These are
likely to account for the failure of these methods to be adopted in
common clinical practice.
[0027] Several patents, including Elliott, et al., Method For
Transvenous Implantation Of Objects Into The Pericardial Space Of
Patients, U.S. Pat. No. 4,884,567 (Dec. 5, 1989) and Elliott,
Defibrillator System With Cardiac Leads And Method For Transvenous
Implantation, U.S. Pat. No. 4,946,457 (Aug. 7, 1990) and Cohen, et
al., Travenously Placed Defibrillation Leads, U.S. Pat. No.
4,998,975 (Mar. 12, 1991) have proposed methods for transvenous
implantation of electrodes into the pericardial space. A catheter
is introduced through a vein to the right atrium where the lateral
wall is penetrated in order to introduce electrodes into the
pericardial space. A major problem encountered by these methods is
how to penetrate the lateral atrial wall without puncturing the
tight fitting pericardium.
[0028] The methods of these patents attempt to solve this problem
through several elaborate schemes. One scheme involves using
complex catheters to attach to the lateral wall and to pull it back
away from the pericardium prior to penetrating the atrial wall in
order to avoid puncturing the pericardium. Another approach
involves injecting a fluid into the pericardial space to distend
the pericardium away from the lateral atrial wall prior to
penetrating the wall.
[0029] Cohen, Method and System for Implanting Self Anchoring
Epicardial Defibrillation Electrodes, U.S. Pat. No. 4,991,578 (Feb.
12, 1991) discloses a method for implanting epicardial
defibrillation electrodes into the pericardial space via the
subxiphoid route. As discussed above, it is difficult to penetrate
the pericardial sac via the sub xiphoid route without also
puncturing and thereby damaging the heart itself. Like the method
discussed directly above, the '578 patent discloses injecting a
fluid into the pericardial space or attaching and pulling on a
catheter to distend the pericardial sac away from the heart.
[0030] Cohen, Transvenously Placed Defibrillation Leads Via An
Inferior Vena Cava Access Site And Method Of Use, U.S. Pat. No.
4,991,603 (Feb. 12, 1991) discloses a method for implanting
defibrillation electrodes in contact with epicardial or pericardial
tissue from an inferior vena cava access site. A hole is made in
the inferior vena cava and a catheter is transvenously inserted
into the inferior vena cava and out through a hole into the chest
cavity adjacent to the heart. The catheter then pierces the
pericardial sac to access the pericardial space. The risk of
damaging the heart muscle remains high with this method.
[0031] The pericardial sac has been used for containment of
pharmacological agents for a number of years in experimental
settings, but delivery has required open chest surgery to access
the pericardial space. Ellinwood, Apparatus And Method For
Implanted Self-Powered Medication Dispensing, U.S. Pat. No.
4,003,379 (Jan. 18, 1977) and Ellinwood, Self-Powered Implanted
Programmable Medication System And Method, U.S. Pat. No. 4,146,029
(Mar. 27, 1979) disclose an implantable medication dispensing
apparatus which is adapted to dispense drugs to the pericardial sac
over a long period of time, for example to prevent arrhythmias. The
Ellinwood patents do not teach a method for routing drugs to the
pericardial sac. Epicardial delivery of pharmacological agents to
the heart is similar to that described in Igo, Apparatus And Method
For Transpericardial Delivery Of Fluid, U.S. Pat. No. 5,634,895
(Jun. 3, 1997) which describes a balloon catheter for sub xiphoid
access. Levy, System for controlled release of antiarrhythmic
agents, U.S. Pat. No. 5,387,419 (Feb. 7, 1995) describes
implantable control release matrices. Verrier, Method For
Transvenously Accessing The Pericardial Space Via The Right Auricle
For Medical Procedures, U.S. Pat. No. 5,269,326 (Dec. 14, 1993)
describes a technique for accessing the pericardium through the
right atrial appendage and describes the possibility of infusing
the pericardium with antiarrhythmic agents.
[0032] No systems or techniques for local drug delivery to the
epicardial surface of the heart upon demand have been described. In
addition, no means of creating a viable atriotomy closure after
transatrial implantation of devices has been described. Further, no
means has been provided for hybrid local drug delivery therapies
involving electrical therapy and ablative therapy for the treatment
of arrhythmias.
SUMMARY OF THE INVENTION
[0033] Several inventions described below permit local transient
therapy for arrhythmias. Drugs or other anti-arrhythmia agents may
be delivered into one or more regions of the atrial or ventricular
wall to control arrhythmia of the atrium or ventricle with devices
implanted into the chest, including a drug delivery catheter with a
tip for implantation into the heart wall and a drug reservoir
implanted in the chest. The devices can deliver drugs into the wall
of the heart, into the left atrium through a catheter which is
implanted in the right atrium, and into the left ventricle which is
implanted in the right ventricle. The devices may be combined with
other therapies such as implantable defibrillators and cardiac
pacemakers. The devices may also be used to transiently created a
long linear lesion within the atrium or used to augment the effects
of a region of permanent ablation transiently. Different
embodiments of the systems described may be used together.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1 is an overview of an implantable cardiac drug
delivery system.
[0035] FIGS. 1a through 1d are detail views of the system of FIG.
1.
[0036] FIGS. 1Ea and 1Eb illustrate a new use of the system of FIG.
1.
[0037] FIG. 2a is an overview of an implantable epicardial drug
delivery system.
[0038] FIGS. 2b through 2d are detail views of the system of FIG.
2.
[0039] FIGS. 2e through 2i illustrate catheters for transatrial
access to the epicardial space.
[0040] FIG. 2J illustrates a helical catheter for transatrial
access to the epicardial space.
[0041] FIG. 2K illustrates an epicardial patch drug delivery system
deployed from inside the right atrium.
[0042] FIGS. 2L through 20 illustrate deployable epicardial patch
drug delivery systems.
[0043] FIGS. 2P through 2Qa are detail views of the system of FIG.
2k.
[0044] FIG. 2R illustrates an epicardial patch drug delivery system
deployed from inside the right atrium.
[0045] FIG. 2S is a detail view of the system of FIG. 2R.
[0046] FIG. 3A is a view of an endocardial catheter installed in
the right ventricle for trans-septal injection of drugs into the
left ventricle.
[0047] FIG. 3B illustrates the expected concentration of drugs in
the heart when delivered according to the method illustrated in
FIG. 3A.
[0048] FIG. 4 illustrates a method of creating long lesion in the
right atrium with a catheter.
[0049] FIGS. 4A and 4B show details of the catheter of FIG. 4.
[0050] FIG. 5 illustrates the system of filling a drug reservoir to
be used with the various catheters.
[0051] FIGS. 6A and 6B illustrate transient drug delivery catheters
in combination with implantable defibrillators.
[0052] FIGS. 7A and 7B illustrate methods of transiently delivering
drugs in conjunction with creating long linear lesions in the right
atrium using an implanted drug delivery catheter.
DESCRIPTION OF INVENTION
[0053] The description of this invention will be broken down into
three parts which inter relate to one another: (I) the method and
devices for local delivery to the heart, (II) the methods and
devices for transient delivery of agents to the local drug delivery
systems described, and lastly (III) hybrid therapies of such
delivery systems and transient delivery techniques combined with
other therapies.
[0054] Method and Devices for Local Delivery to the Heart
[0055] Delivery from a Penetrating Structure
[0056] One embodiment for extremely local delivery of agents to the
myocardium involves a penetrating structure that has a fluid
pathway to a depth within the myocardium for local infusion of
pharmacological agents on demand. Such implantable infusion devices
are described by Altman in U.S. Pat. No. 5,551,427 as well as in a
pending patent application Ser. No. 08/8816850 filed by Altman and
Altman. Both of these should be incorporated here by reference.
[0057] For example, a single point source of pharmacological agents
delivered to a depth within the atrial tissue will enable a region
of atrium to be pharmacologically modified while the systemic doses
are extremely small. This will act as a region of slowed conduction
on which the wave fronts associated with atrial fibrillation will
be terminated. Unlike the transient effects of a paced site, a site
infused with drug will have slowed conduction for a substantial
period of time. The longer the drug is infused to the site, the
larger the region of inactive atrium will be. Very small doses can
be delivered to specific regions of tissue to terminate
arrhythmias. Systemic effects will be minimized. The quantity of
agents will be minimized, as will reservoir size and number of
physician follow-ups.
[0058] FIG. 1 shows a detailed drawing of a technique described
substantially in U.S. Pat. No. 5,551,427 Altman, as well as in a
pending patent application Ser. No. 08/8816850 filed by Altman and
Altman. Shown here is a subcutaneously implanted fluid pump 1
having a plurality of silicone septii 2 and 3 on its upward facing
surface to facilitate the filling of drug reservoirs within pump 1.
Also shown on the surface of pump 1 is a pressure switch 4 which
enables the patient to mechanically turn on the pumping mechanism
when judged appropriate. Pump 1 is connected to catheter 5 which
travels transvenously by way of the subclavian vein (not shown)
through the superior vena cava 7 and into the right atrium 6 which
is shown in a cut away view. These implantation techniques are well
known to those familiar with the placement of implantable cardiac
leads. The penetrating drug delivery structure, shown here as helix
15 on the end of catheter 5 is in fluid connection with pump 1 such
that drugs can be delivered directly to a depth within the atrial
wall tissue. The region within the atrium of implantation specified
may vary from patient to patient based on the characteristics of
the atrial arrhythmia being treated. Here it is shown placed in the
intra atrial septum which has been described as important for the
termination of atrial fibrillation.
[0059] FIG. 1A shows the distal end of catheter 5 shown in FIG. 1.
Catheter body 5 may enclose helical wire or cabled wire conductors
for monitoring the electrical activity of the heart or delivering
pacing energy which is coupled to hollow fixation structure 15
which delivers drugs to a depth within the heart tissue 10. The
progression of the drug transport 20 from the site of the drug
delivery helix 15 can be monitored during implantation in a number
of ways. Either pacing thresholds can be measured which will be
higher and correlate to a larger infused volume, or endocardial
electrophysiology mapping can be performed if desired.
[0060] An enlarged view of this drug delivery lead is shown in FIG.
1B. Here, hollow fixation structure 15 is shown to have a number of
apertures 25 along its length, and be connected on its proximal end
to both a tube 35 for drug delivery and a helical coil 40 for the
measurement of electrical signals from the heart and the delivery
of pacing energy. Structure 30 is made of an electrically
conductive material and stabilizes the hollow drug delivery
structure and allow for its connection to the conductive coil
40.
[0061] FIG. 1C shows another embodiment very similar to FIG. 1A
except here, the penetrating structure 45 is composed of two
elements. In the expanded view shown in FIG. 1D the two elements
are a fixation helix 50 and a centrally located needle 55 which is
porous over some region. It should be clear that it would be very
easy to design needle 55 so that it is not centrally located. This
hollow needle 55 is connected to the tube 35, and is also connected
electrically to the coil 40 and the helix 50. It would be
straightforward to make the needle or the helix the sole
penetrating conductive element connected to the coil 40.
[0062] FIG. 1Ea and FIG. 1Eb show another embodiment in partial
cross section that is similar to FIG. 1A. Here, a stylet wire 1 is
inserted into coil 40 and is used for steering the catheter
structure to a particular location as well as for deploying
penetrating helix 15 for infusing therapeutic fluid agents.
Adjacent to coil 40 is a drug delivery tube 2 which wraps helically
around coil 40 and is advanced in a region 7 over the hollow tube
or needle 8 which allows for fluid agents to be delivered either to
a depth within the tissue, or through the tissue. Stylet 1 is able
to transmit torque to distally located structure 11 by having the
stylet's distal cross section have one axis longer than the other,
such as an oval or rectangle and by having structure 11 be shaped
similarly such that stylet 1 fits within distal structure 11. Here
distal structure 11 is shown to be press fit onto the outside of
coil 40 and to the inside of fixation helix 15 shown here to have a
hollow cross section 9. Other means of joining these structures
such as crimping, swaging, welding, brazing, and bonding are also
possible. Further, the distal structure 11 may have different cross
sectional shapes along its length to provide for attachment, torque
transmission, and electrical continuity to fixation structure 15.
Upon transmission of torque to distal structure 11, the helix 15
advances through structure 12 and out the distal end of the
catheter to engage the tissue (not shown). The helical wrapping of
drug delivery tube 2 distends as shown by the difference in FIGS.
1Ea and 1Eb such that the fluid connections to the penetrating
structure and the proximal connections (not shown) are not
stressed. A distensible fluid pathway such as that shown could be
located at different regions along the catheter body, and not just
at the distal end as shown here. By placing it at the distal end, a
bi-lumen tubing could be used along the length of the catheter
until the region where the distensible drug delivery tubing is
located, and an appropriate transition (not shown) to a single
lumen tubing such as is shown could be implemented.
[0063] FIG. 1F shows a view similar to that shown in 1C, except now
the drug is delivered adjacent to a blood vessel 60 such that the
drug can percolate across the vessel wall and enter into the blood
pool that feeds this local tissue 10. For example, in the treatment
of supraventricular arrhythmias, a catheter placed in the right
atrium may be implanted in the free heart wall such that its drug
delivery structure may deliver to vessels such as the right
coronary artery (RCA), the sinus node branch of the RCA, the conus
branch of the RCA, the atrioventricular node branch of the RCA, and
the posterior descending interventricular branch of the RCA. The
flow from the catheter forces retrograde flow up regions of the
capillaries up the arterioles and into the larger coronary artery.
The drugs delivered in the coronary artery are then distributed to
portion of the myocardium that is supplied by the coronary
artery.
[0064] Delivery from an Epicardial Structure
[0065] FIG. 2A shows an intact heart 65 with ventricles 66, and
right atria 71 and left atria 72. Two epicardial drug delivery
patches 70 and 75 covering the right atria 71 and left atria 72,
respectively. These patches are shown to be connected to separate
but identical thin drug delivery catheters 80a and 80b which
connect the drug delivery patch structure to the implantable pump
76 which is located subcutaneously in the pectoral region. Drug
delivery patches are placed over the atria 71 and 72 to minimize
the drug delivery to the ventricles and to maximize the delivery to
the atria, although it is clear that the opposite scenario is also
possible. Drug delivery catheters 80a and 80b contain a fluid
pathway from drug delivery patches 70 and 75 for the infusion of
agents upon demand. Catheters 80a and 80b may also contain
electrical conductors which connect to the drug delivery patches to
either perform electrical measurements on the activation of the
heart, stimulate the heart, or facilitate delivery from the drug
delivery structure by opening some electromechanical valve in the
distal region.
[0066] FIG. 2B shows a side view of these same patch drug delivery
systems in which tube 80 allows the flow of fluid agents to the
thin space 95 which serves as a plenum, communicating with a fluid
resistant mesh 85. The fluid resistant mesh 85 serves as a
diffusing medium which allows the small volume of drug in space 95
to be uniformly distributed over the surface area of the patch as
it is delivered. In this way, a large surface of the heart is
treated simultaneously. Mesh 85 could also be a rate limiting
membrane. Rate limiting membrane could be made of ePTFE with small
pores such that the drug distributes more readily over the surface
of the rate limiting barrier inside the drug delivery patch than it
does through the rate limiting barrier. This will prevent all of
the fluidic agent being delivered at the point where it enters the
large surface of delivery patch. Such rate limiting membranes and
materials are well known in the field of transdermal drug delivery
systems, but have not been used in cardiac drug delivery systems.
Alternatively, the barrier could be a thin hydrogel or other
material through which the delivery would be required to diffuse
more slowly. There is a rim 90 around the drug delivery surface
defined by mesh 85 such that the patch may be sewn onto the surface
of the heart, or to the inside of the pericardial sac such that the
drug delivery surface is in contact within the myocardium.
[0067] FIG. 2C shows yet another embodiment of this patch drug
delivery system approach which includes an electrically conductive
surface. Here electrically conductive Titanium or Platinum mesh 100
is in contact with the heart such that electrical signals on the
surface of the heart or electrical energy can be delivered to the
heart. The mesh is installed on the patch over the rate limiting
membrane 85. Catheter body 11includes both a fluid pathway for drug
delivery and the electrical conductor which connects to mesh 100.
Rim 90 is provided to suture the patch to either the epicardium or
the inside of the pericardial sac.
[0068] FIG. 2D is a sectional view of the patch drug delivery
electrode shown in FIG. 2C that shows electrically conductive mesh
100 is connected at crimp 115 to conductor cable 120. In addition,
fluid agents may travel down tube 125 within catheter body 110 to
drug space 95 for uniform distribution through mesh 85.
[0069] Although shown as one large electrode used for delivering
uniform energy to a large surface of tissue, many smaller
electrodes could be incorporated in such a design for more precise
local measurements of the heart's electrical activity, and local
energy delivery. Such multi-electrode systems for epicardial
placement have been described in the fields of electrical
defibrillation and multi-site pacing.
[0070] The patch structures shown in FIGS. 2A, 2B, 2C, and 2D can
be placed by many of the techniques described in the prior art.
Many of the less invasive surgical techniques for heart access are
viable such as the sub xiphoid approach. The patches may be
delivered endovascularly through a transvenous approach in which
the patches are delivered to the pericardial space in a collapsed
form and deployed to their larger final form once within the
pericardial space. The specific descriptions of transvenous access
to the pericardial space here shall focus on a solution left
incompletely solved in Verrier, Method for Transvenously Accessing
the Pericardial Space via the Right Auricle For Medical Procedures,
U.S. Pat. No. 5,269,326 (Dec. 14, 1993). The scope of this
invention is not meant to be limited by this specificity, as all
techniques referenced for transvenous access to the pericardium may
be used. Although many techniques have been described in the prior
art for crossing the atria or the vena cava to access the
pericardial space, none of them solves the problem of the
trans-atrial placement of an implantable device with subsequent
wound closure. More importantly, none of the devices provide a
means for delivering antiarrhythmic agents to the pericardial space
and the surface of the heart transiently when an arrhythmia event
is present.
[0071] The patches shown placed over the atria in FIG. 2a are
placed with a relatively noninvasive trans-thoracic procedure in
which a small incision is made between the ribs and the pericardium
cut and entered with laparoscopic and microsurgical tools. The
patches are placed in their appropriate places using the techniques
similar to the placement of epicardial defibrillation patch leads,
and the rim 105 is sutured to hold it in place, such as to either
the visceral or parietal pericardium. The pericardial space is then
closed, and the proximal catheters 80a and 80b are tunneled through
the fascia to the region where the drug delivery pump is to be
placed, typically in the subcutaneous region over the pectoral
muscle. The catheters 80 are connected to the pump, and then the
pump is placed within the subcutaneous pocket and the wounds are
closed. Subsequent to placement, the pump reservoir can be refilled
by transcutaneous injection into silicone septum 77.
[0072] Installation of local atrial drug delivery systems can be
accomplished without open chest surgery, and only requires an
atriotomy in the right atrial appendage. FIG. 2E shows a simple
cylindrical transvenous catheter body 230 penetrating a region of
atrial myocardium 200 from the endocardial side 199 to the
pericardial side 201 of the myocardium. Flanges 205 and 210 are
mechanically attached to catheter body 230 and shown placed on
either side of the penetrated atrial wall 200. Flange 205 and 210
are connected to one another and the interspersed atrial tissue 200
by a ring of small staples, two of which are shown as 215a and
215b. The flange structures provide reinforcement to the thin
atrial tissue to provide stability for the closing staples.
Catheter 230 has a distal end 220 which lies in the pericardial
space and allows for infusion of the pericardium with
pharmacological agents through lumen ports 225.
[0073] FIG. 2F shows an isometric view of the same catheter system
shown in FIG. 2E without the presence of atrial tissue. Clearly the
larger cross sectional area of the flaps 205 and 210 for securing
the catheter to the atrial wall tissue make it desirable to have
these structures collapsible. Although two such flaps 205 and 210
are shown in this figure, it is clear that one or even no flaps may
be used in different embodiments.
[0074] FIG. 2G shows such a system with a non deployed collapsed
single flap 230. Flaps could be made out of materials such as
expanded polytetrafluoroethylene (ePTFE), silicone, dacron, and
combinations of these materials possible through lamination,
calendering, and other techniques. In this figure the flap 230 is
intended to be made out of ePTFE and be molded in its center to the
catheter body at its leading edge 236. The flap 230 is pulled back
and folded along fold lines 232 to its non deployed collapsed
position.
[0075] Delivery of the catheter system shown in FIG. 2G can be
performed with a variety of endoscopic techniques. One approach
uses a monorail tip lumen on the distal end 220 of the in-dwelling
catheter, such that the entire delivery catheter can be passed over
a smaller guide wire type structure that has been used to penetrate
the right atrial wall. In this embodiment, the catheter is
implanted with a short stylet which does not protrude from the end
of the catheter until the region where penetration of the atrium is
desired. A sharp and short penetrating region of the stylet is then
advanced from the distal end of the catheter structure, the
catheter advanced through the atrial wall, and the distally
protruding stylet removed. Here, the deployment of the flaps is
performed by catching trailing edge 234 lip on the atrial
myocardium. The catheter is inserted down through the atrial wall
into the pericardial space such that the entire flap 230 advances
into the pericardial space. Upon pulling back on the catheter the
flap deploys in the pericardial space. Alternatively, the
orientation of the flap is reversed such that the advancement of a
leading edge lip causes the catheter flap 230 to deploy in the
atrial endocardial space. One flap with each orientation
facilitates the location of a flap on either side of the atrial
myocardium. Radio opaque bands located on the catheter body at
different locations also help with visualization under
fluoroscopy.
[0076] A second approach for delivery of such a drug delivery
catheter system could be accomplished with a larger peel away
catheter. The large catheter is advanced to the region for crossing
the atrial wall, and a second centrally located catheter with a
sharpened tip is used to penetrate and cross the atrial wall. After
the large peel away catheter has been advanced across the atrial
wall, the centrally located catheter with a sharpened tip is
removed, and the drug delivery catheter is advanced to the
pericardial space. Here, the presence of the larger peel away
catheter can be used to control the deployment of the flaps on the
catheter body. In a similar technique to that described above, the
flaps could be deployed by pulling the proximally located flap lip
232 against the opening of the peel away catheter for deployment.
Flaps on both sides of the atrial wall are deployed in an identical
fashion, and the presence of radio opaque markers would add greatly
to the positioning techniques.
[0077] FIG. 2H shows a similar catheter system to that shown in
FIG. 2G, except there are two deployable catheter flaps 235 and
240, both with trailing edge lips 245 and 250. In another
embodiment, flap 240 would have a trailing edge lip 250 as shown,
and flap 235 has a leading edge lip. Further, the proximal flap 235
may be designed to slide on the catheter 230 to facilitate the
stapling process. The larger peel away guide catheter could be
useful for positioning deployed flaps for subsequent surgical
stapling.
[0078] FIG. 2I shows a cross section of a stapler catheter 260
advanced around the transatrial catheter 230 such that the stapler
comes into contact with an endocardial flap 205 and advances it
against the atrial wall 200. Such staplers would simultaneously
provide a number of staples or sutures around the periphery of the
catheter structure such that it repairs the atriotomy. Staples can
then be delivered around the periphery of catheter body 230 to
provide fixation of catheter 230 and a viable repair of the
penetrated atrial wall 200. In addition, contact sensors 270, 275,
280 and 285 could be used to know that the catheter is in contact
with at least the endocardial flap 205 and that flap 205 is fully
deployed. By having a ring of conductive material shown in section
as contact points 275 and 285 in the outside of flap 205, the
stapler could monitor electrical continuity between two or more
circumferentially placed electrodes 270 and 280. Continuity would
imply that the flaps are deployed and that the staples may be
effectively delivered.
[0079] FIG. 2J shows another embodiment of the transatrial
pericardial placement of a catheter for both delivery of drugs and
electrical stimulation of the myocardium. Here catheter 288 enters
the right atrium 305 via the superior vena cava 290 and exits the
right atrium 305 via the right atrial appendage. External catheter
flap 295 is shown with staples 300 securing the catheter and
effecting the repair of the penetrated atrium. Cylindrical catheter
288 is advanced such that a series of electrodes can surround the
heart along the catheters helical path. This view reveals a large
number of electrodes 385, 370, 355, 320, 330, and 335 placed around
the heart. In addition, drug delivery ports 380, 310, 315, 360,
325, and 350 are shown such that they also surround the heart.
There are many different therapies that can be achieved with such a
system. This example is meant to be instructive rather than
specific. For electrical stimulation, a number of electrodes could
be used with an endocardial return electrode for multi site pacing,
atrial defibrillation, and ventricular defibrillation. The
different electrodes could also be used for sensing activity in
different regions of the heart and combined with diagnostic
algorithms in implantable electrical devices (not shown). Such
multielectrode catheters have an extensive history in the field of
cardiac electrophysiology. The multiple drug delivery ports could
be connected to different lumens within the catheter body 288, or
could all be connected to a common lumen.
[0080] FIG. 2K shows another embodiment of the transatrial
pericardial placement of a device for both delivery of drugs and
electrical stimulation of the myocardium. Here, a deployable patch
system is shown placed over the ventricles. Here, larger surface
area electrodes 415 and 420 are shown within a large drug delivery
patch. As before, the catheter 401 enters the heart from the
superior vena cava 402 and penetrates the right atrium 305. The
proximal end of the catheter 401 is connected to a subcutaneously
placed implantable pump and electrical stimulation device 403.
Device 403 is shown with two silicone septii 404 and 405, used for
filling the internal reservoir with pharmacological agents.
[0081] FIG. 2L shows one embodiment of this deployable patch
structure in cross section where it is partially deployed. Arms 470
and 460 are wrapped around catheter body 450 and over one another
such that they generate shadow area coverage shown in FIG. 2M when
deployed. Deploying such a structure is readily done with simple
mechanical techniques.
[0082] For example, FIGS. 2N and 20 show a stylet mechanism for
deploying the patch shown in FIGS. 2K, 2L and 2M. Here, a simple
thin wire mechanism with five hinge joints 480, 490, 500, 510, and
520 is advanced down the lumen of the patch structure to deploy the
patch. FIG. 20 shows how concerted movement of stylet arms 525,
585, and 575 will result in the expansion of a planar wire
structure within the deployable epicardial patch forcing it to
expand. Other simple mechanisms and manipulations described in the
art may also be used.
[0083] As another example, FIGS. 2P, 2Qa, and 2Qb show a rolled
epicardial patch structure for distributed drug delivery to the
epicardial surface. In FIG. 2P, the rolled patch structure 600 is
attached to a catheter 610 that allows for the transport of drugs,
and potentially the presence of electrical conductors (not shown)
to connect to the rolled patch 600. The patch is advanced through
the opening in the atrium by a covering tubular structure 620 from
which it is advanced and deployed. This tubular delivery catheter
is essentially the same as the peel away catheter system which has
already been described. FIG. 2Qa shows a deployed patch 600
connected to catheter body 610 which is shown here to only have a
lumen for drug delivery 615. It is clear to those familiar with the
art that electrical conductors could be present as well. Patch 600
is shown to consist of a number of channels 640 connected by one or
more transverse channels 650. Although many geometries are viable
for the transverse channel, the angled pitch of the transverse
channel will result in a shape that may more readily be rolled to a
uniform diameter for delivery. Drug would pass down lumen 615 of
body 610 and into channels 640 and 650 to be spread uniformly
within the patch structure before being dispensed to the heart
surface. FIG. 2Qb shows the same patch structure in cross section
with channels 640, body 610, and molding 630. Here, a rate
controlling barrier 660, such as could be formed from a microporous
filter, membrane, mesh, or other structure will allow drug
molecules within the transport fluid to migrate to the surface of
the heart tissue. However, the resistance of the rate controlling
surface 660 is greater than that through the channels 640, and the
drug will be delivered relatively uniformly to the surface of the
tissue to be treated.
[0084] FIG. 2R shows two similar patches 670 and 680 over the left
and right atria 690 and 700. Here, these dual patches come from a
single transatrial catheter body 710. This single lead body
facilitates the closure and repair of the right atrial appendage or
other penetrated tissue after device implantation. Here also, the
implantable pump system 681 is shown implanted on the patient's
right side. For crossing the atrium, different surgeons may prefer
either a right or left access route. This will determine in which
side of the body the device is implanted.
[0085] FIG. 2S shows one potential delivery means in which the fork
720 takes place prior to the junction of the lead body 710 and the
proximal patch 670. Proximal patch 670 is wrapped around distal
catheter body 730 which is connected to distal patch 680.
[0086] Delivery Through a Septum of the Heart
[0087] Another embodiment for local cardiovascular drug delivery,
which has particular potential for the transient termination of
arrhythmias is shown in FIG. 3A. Here, a catheter system similar to
that shown in FIG. 1A without the pores 25 along the length of
hollow fixation structure 15, is implanted such that drug can be
directly infused into the left side of the heart from a device
which dwells in the right side of the heart.
[0088] FIG. 3A shows a drug delivered through the ventricular
septum. Catheter 145 is implanted in the right ventricle such that
penetrating fixation device 150 is advanced through the septal wall
185. Drug delivery here occurs through the septum and into the left
ventricle 190. In this way a bolus dose is delivered to the body
such that it is very concentrated in its first pass through the
heart.
[0089] This is shown reasonably well in FIG. 3B which shows a plot
of the drug concentration in the heart with respect to time. Here,
the drug is delivered into the left side of the heart at time t1
and enters the coronary arteries at a high concentration
immediately thereafter at time t2. The duration of the dosage is
very short such that by delivering a dose over a duration delta t
there is only a transient therapeutic concentration within the
heart. As the drug passes through the heart and begins to be
further diluted with the rest of the blood, the dosage will fall
below the therapeutic dose. The immediate dip after the dose is
delivered is due to the lack of drug in the blood that follows the
dose.
[0090] FIG. 3C shows a heart 140 with a drug delivery catheter 145
implanted in the right atrium 160, such that the penetrating
fixation device 150 is placed within the intra atrial septum 170
and the drug delivery occurs through the septum 170 and into the
left atrial blood pool 155. In this way a bolus dose is delivered
to the body such that it is very concentrated in its first pass
through the heart. The drug in the left atrium will be diluted
somewhat by the turbulent mixing as it passes in the left ventricle
and it will be delivered in that concentration to the heart without
dilution in the rest of the patient's effective blood volume.
[0091] The key advantage of these device methods is that they allow
a means to deliver drugs to the left blood pool of the heart
transiently without having a device implanted within the left side
of the heart. This advantage is significant. It is very difficult
to have a permanent implant in the left side of the heart because
of the potentially life threatening problem of thrombus formation
and stroke. In the left side of the heart small clots or thrombi
could be passed to the rest of the body and obstruct critical flow
to tissue such as the brain. If a device is implanted in the right
side of the heart, the lungs will act as a filter to remove
whatever clots and thrombi form and it is far less critical. By
having a very small structure slightly penetrate the septum, drug
delivery to the chambers of the left heart is achieved without the
issues of a left sided implant.
[0092] Delivery Adjacent to a Heart Wall
[0093] Another embodiment for local cardiovascular drug delivery,
which has particular potential for the transient termination of
arrhythmias is shown in FIG. 4. Here a simple catheter is
constructed so that it is extremely flexible but has a preferred
curved shape 803 that will push it against the atrial wall in a
preferred configuration after implantation. This can be achieved by
molding a portion of the curved portion of the catheter body 803
out of polyurethane or silicone. The catheter so formed is advanced
into place with a rigid stylet, such that it takes on the preferred
shape after the stylet is removed. Typically in this instance a
stylet is merely a long metal wire which may be shaped to provide
stiffness for implantation of such catheters. Stiffness of the
stylets can be varied by using different diameter wires, say from
0.01 inches to 0.020 inches and their shapes can be modified by
either the physician at the time of implant or during the
manufacturing process. Such stylets are well known in the field of
cardiac pacing. The drug delivery catheter 800 advances into the
heart from the superior vena cava 805 and is positioned by
advancing and retracting different stylets until it is
appropriately positioned. The proximal end of the catheter 800 is
connected to a subcutaneously placed implantable pumping mechanism
806 with drug filling septum 807. The drug lumen in catheter 800
may be separate from the lumen in which the stylet is used for
positioning purposes. The apertures along the distal portion of
catheter 800 cannot be seen in this view because they are oriented
so that they are adjacent to the heart wall.
[0094] FIG. 4A shows this more clearly. Along the outer portion of
the curved catheter there are a number of apertures 801 which allow
fluid to be delivered preferentially towards the atrial wall 802.
Such a delivery catheter would provide a means to alter a long
linear region of tissue within the atrium transiently. This has
great potential in treating supraventricular tachyarrhythmias.
[0095] FIG. 4B shows a cross section of the catheter shown in FIG.
4A along a region of the curve 803 which includes apertures 801.
Here the drug is shown in the catheter lumen 825 and passing into
the holes 810 which help define the apertures 801 in the main
catheter tubing body 815. It will be noted that here, catheter body
815 is covered with a thin porous structure 820 such as ePTFE which
may allow adhesion of the catheter to the heart wall in the region
of the apertures over time. This may be desirable as it may
facilitate the delivery of agents to specific regions of the atrium
to create transient linear regions of electrical slowed conduction
and possibly electrical block. Roughening the surface of the
catheter may be another means to promote adhesion of the catheter
to the endocardial atrial surface. In other embodiments the ePTFE
jacket would not be present, and the catheter would not be
roughened.
[0096] Part II: Methods and Devices for Transient Delivery of
Agents to the Local Drug Delivery Systems
[0097] Manually Triggered Drug Delivery Process
[0098] In one embodiment, a permanently implantable catheter will
enable the patient to deliver drugs to his or her atrium upon
experiencing symptoms. FIG. 5 shows such a system. The proximal end
of the catheter 850 systems described could be connected to a
subcutaneous injection port 855. Such injection ports are common in
the literature and often are made of a titanium body with a
silicone injection septum 860. With such a device in place, a
patient could self administer an injection through their skin,
through the silicone septum of the device, and into the tubing
which leads to the appropriate drug delivery structure embodiment.
In this way, a patient recognizing an arrhythmia is able to self
administer an agent to a specific location within his or her heart.
By prepackaging the syringes 865, the dosages can be
controlled.
[0099] An alternative approach is to provide the patient with a
subcutaneous self triggered pumping device that has a reservoir
filled by a physician. These are shown in FIG. 1, FIG. 2A, FIG. 2K,
FIG. 2R, and FIG. 3A. Multiple therapeutic doses could be stored in
such a device. Such pumping systems are already in the European
market, but have not been used for this application. The self
triggered pumping devices can be triggered by applying pressure to
the surface of the body over the pump and depressing a diaphragm in
one embodiment. In another, the pump could be an electronic device
that is activated by the placement of a magnet over the device such
as is known in the art of implantable electrical devices.
[0100] Instead of allowing the patient to self administer agents to
themselves upon experiencing an episode, another approach is to
incorporate algorithms for identifying particular arrhythmias and
delivering therapy with a microprocessor based approach as
described in the prior art and literature, which is hereby
incorporated by reference. A microprocessor based automated
pharmacological defibrillator would monitor cardiac electrical
signals and deliver agents locally to the heart tissue when the
electrical signals are determined by a programmed algorithm to
signify that the heart is experiencing an arrhythmia.
[0101] The small doses of defibrillating pharmacological agents
will be delivered to the heart tissue over a short period of time.
The diffusion from the delivery sites inactivates the tissue
electrically and terminates the arrhythmia. This system is
relatively inexpensive to manufacture.
[0102] Part III: Hybrid Therapy
[0103] Transient cardiovascular drug delivery will improve other
therapies such as implantable devices for electrical stimulation of
the heart and techniques for permanent cardiac ablation.
[0104] Transient Drug Delivery and Electrical Stimulation
Devices
[0105] In the first embodiment, the drug delivery systems shown in
FIG. 1 and described in detail in U.S. Pat. No. 5,551,427 Altman,
and in the pending application by Altman and Altman is coupled to
an implantable defibrillator. Such a system is shown schematically
in FIG. 6A and FIG. 6B. These systems provide the means to
incorporate an algorithm that will allow the implantable system to
identify a ventricular tachyarrhythmia and infuse antiarrhythmic
agents into the ventricular septum in order to terminate the
arrhythmia.
[0106] Typically, a tiered therapy automatic implantable
cardioverter defibrillator will sense a ventricular tachyarrhythmia
and identify an organized but excessive rate as ventricular
tachycardia, or VT. To terminate the VT, the devices typically
attempt to pace the heart at a faster rate than the
tachyarrhythmia, entrain the heart at this higher rate, and then
slow the paced rate below the tachyarrhythmia rate. This often does
not work, and the only alternative is to deliver a painful high
voltage shock to the patient to terminate the arrhythmia. Further,
antitachycardia pacing has potential to accelerate the patients
native arrhythmia and induce potentially life threatening
ventricular fibrillation. Both of these effects of the standard
therapies for VT are less than desirable. Since the reentrant
circuits that drive VT are often located within the ventricular
septum, it is possible with the systems shown in FIGS. 6a and 6b to
terminate these arrhythmias with local infusion of antiarrhythmic
agents to a depth within the myocardium.
[0107] FIG. 6a shows an implantable defibrillator 900 electrically
connected by lead 910 to electrically triggered pumping reservoir
920. Pumping reservoir 920 is connected to a drug delivery catheter
body 925 which delivers drug to a depth within the tissue by active
fixation penetrating drug delivery structure 930. Such drug
delivery structures have already been described here and in the
art. Defibrillator 900 is also electrically connected to
implantable electrical lead 970 which has one or more
defibrillation electrodes 960 along its length, and at least one
pacing electrode 940 at its distal end. Implantable electrical lead
also has a fixation mechanism to secure the distal end of the lead
at the implantation site, which in this figure is shown to be
passive tines 950. Upon detecting ventricular tachycardia, the
defibrillator 900 sends an electrical signal down the lead 910
which triggers the pumping reservoir 920 to infuse the ventricular
septum with antiarrhythmic agents.
[0108] It is important that the pacing/sensing electrodes 940 are
physically separate from the drug delivery structure 930 for such
automatic arrhythmia detection, because the infused drug will
affect the ability to measure the heart's electrical action at the
site of drug delivery.
[0109] FIG. 6b shows a very similar embodiment in which the
defibrillator and pump are combined in a defibrillator/pump 980
which delivers fluid and electrical energy down a single main lead
body 990 which splits at 1000 to allow for spatial separation of
drug delivery structure 930 and distal pacing/sensing electrodes
940.
[0110] This is just one embodiment of a means for coupling the
transient delivery of electrical and local pharmacological device
therapies. Drug delivery to a depth of the heart wall, to an outer
surface of the heart, to the left chambers of the heart, and to
long linear regions of the heart wall may be combined with
electrical stimulation and sensing algorithms to provide
substantially novel and unique results. Similar systems coula be
made combining: 1) local pharmacological atrial defibrillators with
state of the art DDD pacemakers or automatic implantable
cardioverter defibrillators, 2), devices to infuse drugs locally to
reduce pain prior to delivering high voltage electrical energy, and
3) devices to precondition the tissue pharmacological prior to
delivering electrical energy.
[0111] Transient Drug Delivery and Cardiac Ablation
[0112] In an attempt to cure atrial fibrillation, many researchers
are introducing long linear lesions to the heart wall with
different catheter techniques. The problem with such long lesions
that they prevent the propagation of signals through the heart even
when an arrhythmia is not present, and reduce functionality of the
heart. Using a drug delivery device has potential to provide
flexibility in the creation of these lesions which is not currently
available. An example of this is shown in FIG. 7A.
[0113] FIG. 7A shows a region of atrial tissue 1102 with three long
linear lesions 1100, 1105, 1110, and placed such that electrical
signals can propagate between them through the atria. In the center
of these three lesions is a single penetrating drug delivery
structure 1130 connected to catheter system 1140. Although the long
linear lesions 1105, 1110, 1100, and 1120 are insufficient to
completely eliminate the possibility of the tissue in question
sustaining an arrhythmia, they are also insufficient to
substantially decrease the viability of the atrial function. Upon
onset of an arrhythmia, antiarrhythmic drugs (amiodorone HCl,
procainimide, ibutilide, or other drugs) may be infused to a depth
within the tissue by drug delivery structure 1130, and now all of
the lesions 1100, 1105, and 1110 are effectively connected to one
another by a region of slowed conduction. In this way, a small
amount of drug delivery may be combined with lesions created by
ablative techniques to complete a region of block and terminate an
arrhythmia.
[0114] FIG. 7B shows a similar hybrid therapy approach in which the
catheter 1150 similar to those shown in FIGS. 4, 4A, and 4B
delivers agents to regions of the atrial wall. Here it intersects
radio-frequency ablated long linear lesions 1160 and 1170 in the
region where it delivers agents to the atrial wall. This connects
the two linear lesions to create an impassable line of slow
conducting tissue in the atrial wall. The atrium will not sustain
an arrhythmia with the conductive pathways blocked by this
connected and impassable line of slow conducting tissue. Clearly,
other variations are also possible.
[0115] The lesions shown here are intended to be instructive, but
not definitive. Many different lesion patterns are possible and
techniques and approaches for creating lesions of this type are
still under development.
Conclusions, Ramifications and Scope of Invention
[0116] Thus the reader will see that the different embodiments of
the invention provide a means to effectively deliver agents more
locally to the myocardium such that doses delivered are
minimized.
[0117] They enable transient drug delivery to the tissue for
treating cardiac arrhythmias, provide a means for sensing the
heart, and may be combined with cardiac ablation and electrical
cardiac sensing and stimulation devices.
[0118] While the above description contains many specifics, these
should not be construed as limitations on the scope of the
inventions, but rather as an exemplification the inventions. Many
other variations are possible. For example, the flow of liquid
agents may be driven by implantable infusion pumps with a variety
of energy sources, and the device could be made from as yet
unidentified biocompatible materials. Other examples include
distally located electrically activated piezoelectric crystals or
electrodes to act as energy sources for drug delivery for improving
the transport into cells, distally located ultrasound transducer
for implantation using ultrasound imaging. In addition, in the
embodiments where bipolar sensing through the drug delivery
structure is crucial, it is a simple task to add another electrode
to enable bipolar sensing.
[0119] In addition, the simple penetrating designs shown in FIGS.
1, 1a, 1b, 1c, 1d, 1Ea, and 1Eb could be modified slightly to
provide for a penetrating structure that protrudes through the
atrial wall and into the pericardial space. By eliminating
apertures along the penetrating structure such as is done in some
of the earlier embodiments for delivery at a depth, therapeutic
agents would only be delivered through the tissue to the
pericardial space. The devices would be placed in tissue regions
such as the Right atrial appendage where the tissue is thick enough
to support the penetration by a small structure, and the agents
would be infused through the penetrating structure to the surface
of the heart. The implantation of such a device would require
careful positioning such that the structure does not penetrate the
aorta, but this should not be difficult.
[0120] In such a design of a small structure, such as a hollow
active fixation helix, that penetrates the tissue, the successful
access of the pericardial space could be determined by monitoring
the pressure required to drive flow through the device. Another
potential approach would be to have an electrically isolated
electrode at the distal most point of the penetrating structure
which could be used to pace the tissue, and the pacing threshold
data used to determine whether the distal structure is in fact
within the tissue, or penetrating the tissue. Such an embodiment
could be useful for other embodiments all ready discussed.
[0121] Further, the delivery of the agents could be performed with
appropriately modified catheter shapes such that curves are located
to effect a certain position within and about the heart. Such
curves in a catheter could be molded into place, or held in place
by plastic deformation of the helical coil in the region it is
desired. Such curved structures may provide improved access to
certain regions such as the right atrium, left atrium, right
ventricle and left ventricle.
[0122] Further, the drug delivery catheters could be placed using
steerable guiding catheters. Acute non implantable steerable
catheters that can be secured to an implantable drug delivery
catheter and steered using pull wires to place and position the
different drug delivery catheters described. For acute use of the
drug delivery catheters described they could be modified so that
they are steerable having pull wires at the outer radii of the
catheter body and potentially ribbons at the catheter midline to
define the planes of bending. Many other designs are possible and
have been described in the relevant art. In applications where
stylets are to be used for the placement of a drug delivery
catheter, it may be desirable to have an independent lumen for the
delivery of fluid agents such that the stylet placement does not
introduce air into the system. This can be achieved readily by
having a tube which lies in parallel with the torque coil and moves
in tandem with it, within the outer catheter jacket. Other
potential designs include having multi lumen tubing up until the
distal end of the catheter and having a small flexible region of
drug delivery tubing connected to a deployable drug delivery
structure. Many other designs are possible.
[0123] For most applications, it may be appropriate to position the
components relative to their implantation such that the drug
delivery systems are filled with either the appropriate drug,
physiological saline, or heparinized drug solution or saline at the
time of implant. This would mean that the catheters would be
connected to the pumping systems and sensing devices prior to
implantation, and in the case of applications which require
tunneling of the devices such as shown in FIG. 1, the connection
would occur after a tunneling procedure which would occur before
implantation of either the device or the drug delivery system. For
such preconnected systems, an external steerable guiding catheter
for placement is attractive, as is an externally accessible stylet
lumen that is not involved in the connection of the device to the
drug delivery catheter.
[0124] Perhaps more broadening is the use for the drug delivery
systems described to deliver agents for the minimization of
coronary restenosis, initiation of therapeutic angiogenesis, or
performing gene therapy. Such techniques would involve a more
steady state approach for the delivery of therapeutic agents
independent of the electrical activity of the heart. However, the
systems shown here incorporate many details which are relevant for
the delivery of therapeutic and diagnostic agents in general. For
example, a slow steady infusion of amiodarone to a depth within the
heart, or delivery of such agents on a regular basis, may prove to
be advantageous and are enabled by the local drug delivery systems
described here.
[0125] More than one of these systems may be implanted so that they
can effect novel therapies. For example drug delivery to both the
atrial and ventricular walls with separate catheters coupled to
either the same or separate subcutaneously implanted drug delivery
pumps and reservoirs could be configured such that the drug
delivery is controlled such that delivery to each catheter is
controlled independently.
[0126] The drug delivery systems described here can be used acutely
during beating heart cardiac surgery to introduce a temporary stop
or marked slowing of the heart. Such induced bradycardia would
provide a quiescent heart for very short periods so that delicate
surgical procedures may be performed. Procedures as common and
important as suturing during bypass surgery are one example of
techniques that would be improved by such slowing of the heart. One
example of implementation of this approach would involve a infusion
of adenosine at a depth within the heart tissue adjacent to the AV
node or infranodal structures with acute versions of the catheters
shown in FIGS. 1A to 1F, followed after the quiescent period with
temporary ventricular pacing to control haemodynamics. Additional
agents could be given systemically to slow ventricular automaticity
and the delivery of agents to introduce AV nodal blockade or
infranodal blockade to result in a more marked slowing of the heart
that could be rapidly reversed with ventricular pacing. The use of
the catheter systems and local drug delivery schemes described in
this disclosure are relevant for transient delivery for such
slowing of the heart for improvement of surgical procedures.
[0127] Accordingly, the scope of the invention should be determined
not by the embodiments illustrated, but by the appended claims and
their legal equivalents.
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