Device and Method for the Ablation of Fibrin Sheath Formation on a Venous Catheter
An indwelling venous catheter and method capable of destroying undesirable cellular growth is provided. The catheter includes a shaft having at least one lumen and adapted to be placed inside a vein for long term use. A plurality of electrodes are positioned near a distal section of the shaft and are adapted to receive from a voltage generator a plurality of electrical pulses in an amount sufficient to cause destruction of cells in the undesirable cellular growth that have grown around the shaft. In one aspect of the invention, a probe is configured to be removably insertable into the at least one lumen and the electrodes are positioned near the distal section of the probe.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of priority under 35 U.S.C. Section 119(e) to U.S. Provisional Application Ser. No. 61/074,504, filed Jun. 20, 2008, entitled “Device And Method For The Ablation Of Fibrin Sheath Formation On A Venous Catheter Using Electroporation”, which is fully incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to a medical device and method for the destruction of undesirable cellular growth on a venous catheter, such as fibrin sheath formation and/or infectious cells, by delivering a plurality of electrical pulses.
BACKGROUND OF THE INVENTION
Catheters, and more particularly, venous access catheters have many very important medical applications. For example, if a patient requires long-term dialysis therapy, a venous assess catheter, such as a chronic dialysis catheter, will be implanted in a patient's body. Chronic dialysis catheters typically contain a polyester cuff that is tunneled beneath the skin approximately 3-8 cm and helps to anchor the dialysis catheter to the body. The chronic dialysis catheter is connected to a dialysis machine when the patient is treated. Hemodialysis is a method for removing waste products such as potassium and urea from the blood, such as in the case of renal failure. During hemodialysis, waste products that have accumulated in the blood because of kidney failure are transferred via mass transfer from the blood across a semi permeable dialysis membrane to a balanced salt solution.
In another example, a venous catheter can be used in combination with an implanted port. A port can be implanted in patients that require frequent access to the venous blood, such as chemotherapy patients. An implanted port includes attachment means for fluidly connecting a catheter. The port is implanted in a surgically created pocket within the patient's body and has a reservoir for delivering fluids through the catheter. One end of the catheter is connected to the port, and the other end terminates in a vein near the patient's heart.
Another example of a long-term venous access catheter is a peripherally inserted central catheter, also known as a PICC line. PICC lines are placed in patients requiring long-term access for the purpose of blood sampling and infusion of therapeutic agents including chemotherapeutic drugs.
Notwithstanding the importance of venous catheters, one problem that is associated with their use is the undesired formation of fibrin sheaths along the catheter wall. See, for example, Savader, et al., Treatment of Hemodialysis Catheter-associated Fibrin Sheaths by rt-PA Infusion: Critical Analysis of 124 Procedures, J. Vasc. Interv. Radiol. 2001; 12:711-715. Fibrin sheath formation is an insidious problem that can plague essentially all central venous catheters. It has been reported that fibrin sheath formation occurred as early as 24 hours after catheter placement and that this phenomenon was seen on 100% of central venous catheters in 55 patients at the time of autopsy.
The growth of a fibrin sheath along a catheter shaft can prevent high flow rates, adversely affect blood sampling and infusion of chemotherapeutic drugs, and provide an environment in which bacteria can grow, which may result in infections. Despite fibrin sheath build up, infused fluids may still enter the blood circulation, but when negative pressure is applied, the fibrin sheath can be drawn into the catheter, occluding its tip, thereby preventing aspiration. Complete encasement of the catheter tip in a fibrin sheath may cause persistent withdrawal occlusion. This can lead to extravasation of fluid where fluid enters the catheter to flow into the fibrin sheath, backtracks along the outside of the catheter, and exits out of the venous entry point and into the tissue. The presence of a fibrin sheath on the catheter shaft may also result in difficulty removing the venous catheter, particularly PICC lines, from the patient.
Often patients who need prolonged intravenous regimens have compromised peripheral venous access and thus venous catheters are often the only means available for the delivery of necessary treatment. Therefore, such venous catheters should be configured to remain in a patient so that drugs and other fluids can be effectively delivered to the patient's vasculature and to break up any fibrin sheath growth.
There are a number of different techniques that have been developed to address the fibrin sheath-impaired venous access catheter. These techniques include new catheter placement, catheter exchange ever a guide wire, percutaneous fibrin sheath stripping, and thrombolytic therapy. For example, fibrin sheaths may be removed by mechanical disruption or stripping with a guidewire or loop snare, or by replacing the catheter. Mechanical disruption can help prevent the need to replace the catheter, and thereby eliminate disruption to the patient. However, mechanical disruption may not be effective because the fibrin sheath may not be completely removed and often causes damage to the catheter shaft and vessel wall. Mechanical removal of fibrin build-up may also increase the risk of embolism due to free floating debris within the vessel.
Replacing the catheter is also an option, but this can cause increased trauma to the patient, increased procedure time and costs, increased risks of pulmonary emboli, and may require numerous attempts before removal is successful. Thus, both mechanical disruption and catheter replacement may adversely affect a patient's dialysis schedule, cause patient discomfort, and loss of the original access site. Drug therapies that address the fibrin sheaths can also result in complications and are unreliable.
Therefore, it is desirable to provide a device and method for the destruction of undesirable cellular growth on a venous catheter in a safe, easy, and reliable manner without having to remove the catheter from the patient and without damaging the vein or catheter itself.
SUMMARY OF THE DISCLOSURE
Throughout the present teachings, any and all of the one, two, or more features and/or components disclosed or suggested herein, explicitly or implicitly, may be practiced and/or implemented in any combinations of two, three, or more thereof, whenever and wherever appropriate as understood by one of ordinary skill in the art. The various features and/or components disclosed herein are all illustrative for the underlying concepts, and thus are non-limiting to their actual descriptions. Any means for achieving substantially the same functions are considered as foreseeable alternatives and equivalents, and are thus fully described in writing and fully enabled. The various examples, illustrations, and embodiments described herein are by no means, in any degree or extent, limiting the broadest scopes of the claimed inventions presented herein or in any future applications claiming priority to the instant application.
Disclosed herein are devices for delivering electrical pulses for destruction and/or removal of undesirable cellular growth formations on a venous catheter and methods of using such. In particular, according to the principles of the present invention, an indwelling venous catheter capable of destroying undesirable cellular growth is provided. The catheter includes a shaft having at least one lumen and adapted to be placed inside a vein for long term use. A plurality of electrodes are positioned near the shaft and are adapted to receive from a voltage generator a plurality of electrical pulses in an amount sufficient to cause destruction of cells in the undesirable cellular growth that have grown around the shaft. In one aspect of the invention, a probe is configured to be removably insertable into the at least one lumen and the electrodes are positioned near the distal section of the probe.
BRIEF DESCRIPTION OF DRAWINGS
DETAILED DESCRIPTION OF THE DRAWINGS
Electroporation is defined as a phenomenon that makes cell membranes permeable by exposing them to certain electric pulses. As a function of the electrical parameters, electroporation pulses can have two different effects on the permeability of the cell membrane. The permeabilization of the cell membrane can be reversible or irreversible as a function of the electrical parameters used. Reversible electroporation is the process by which the cellular membranes are made temporarily permeable. The cell membrane will reseat a certain time after the pulses cease, and the cell will survive. Reversible electroporation is most commonly used for the introduction of therapeutic or genetic material into the cell, irreversible electroporation, also creates pores in the cell membrane but these pores do not reseal, resulting in cell death.
Irreversible electroporation has recently been discovered as a viable alternative for the ablation of undesired tissue. See, in particular, PCT Application No. PCT/US04/43477, filed Dec. 21, 2004. An important advantage of irreversible electroporation, as described in the above reference application, is that the undesired tissue is destroyed without creating a thermal effect. When tissue is ablated with thermal effects, not only are the cells destroyed, but the connective structure (tissue scaffold) and the structure of blood vessels are also destroyed, and the proteins are denatured. This thermal mode of damage detrimentally affects the tissue, that is, it destroys the vasculature structure and bile ducts, and produces collateral damage.
Irreversible and reversible electroporation without thermal effect to ablate tissue offers many advantages. One advantage is that it does not result in thermal damage to target tissue or other tissue surrounding the target tissue. Another advantage is that it only ablates cells and does not damage blood vessels or other non-cellular or non-living materials such implanted medical devices (venous catheters for example).
Fibrin sheaths that form on venous catheters are primarily made up of smooth muscle cells with membranes. Therefore, destruction of the fibrin sheath by irreversible electroporation without causing any thermal effects is a viable method of treating fibrin growth. It is also possible to destroy the cellular structure of fibrin sheath formations using reversible electroporation combined with a drug. This process is known as electroporation-mediated chemotherapy and has been used to introduce chemotherapy drugs into a tumor at an intracellular level. What has not been previously described is the use of electroporation-mediated chemotherapy for the introduction of therapeutic agents, such as cytotoxic agents, into healthy but undesirable tissue such as the smooth muscle cells of a fibrin sheath formation. Cytotoxic agents are transported into the interior of the cell through the transient pore formations, ultimately causing cell death. In this manner, the underlying cellular structure of a fibrin sheath formation can be destroyed by the introduction of cytotoxic agents into the smooth muscles cells comprising the sheath.
Although the following example discusses using the present invention and method to destroy fibrin sheath growth, persons of ordinary skill in the art will appreciate that the present device and method can treat any undesirable cellular growth, including infectious cells.
Catheter 10 includes an electrical connector 500 extending proximally from hub 49 and in the illustrated embodiment positioned between the extension tubes 30 and 32. Catheter 10 also includes a plurality of electrodes 150 attached to the outer surface of the catheter shaft 25. The location of the electrodes on the catheter may be anywhere along the shaft, but the electrodes may generally be located near the distal section of the shaft where the fibrin sheath formation most severely compromises the fluid flow of the device. Furthermore, the size and shape of the electrodes can vary. For example, the electrodes can be ring-shaped, spiral-shaped, or can exist as segmented portions. The electrodes may also be a series of strips placed longitudinally along the catheter shaft surface. The electrodes may be comprised of any suitable electrically conductive material including but not limited to stainless steel, gold, silver and other metals.
A plurality of electrically conducting elements (e.g., electrical wires) 160, shown in
The electrodes 150 are adapted to administer electrical pulses as necessary in order to reversibly or irreversibly electroporate the cell membranes of the smooth muscle cells comprising the fibrin sheath 200 located along the outer surface of catheter shaft 25 or inside of the catheter shaft 25 within a treatment zone. By varying parameters of voltage, number of electrical pulse and pulse duration, the electrical field will either produce irreversible or reversible electroporation of the cells within the fibrin sheath 200. The pulse generator of the present invention can be designed to deliver a range of different voltages, currents and duration of pulses as well as number of pulses. Typical ranges include but are not limited to a voltage level of between 100-3000 volts, a pulse duration of between 20-200 microseconds (more preferably 50-100 microseconds), and multiple sets of pulses, (e.g. 2-5 sets) of about 2-25 pulses per set and between 10 and-500 total pulses. The pulse generator can administer a current in a range of from about 2,000 V/cm to about 6,000 V/cm. The pulse generator can provide pulses which are at a specific known duration and with a specific amount of current. For example, the pulse generator can be designed upon activation to provide 10 pulses for 100 microseconds each providing a current of 3,800 V/cm +/−50% +/−25%, +/−10%, +/−5%. The electroporation treatment zone is defined by mapping the electrical field that is created by the electrical pulses between two electrodes.
When electrical pulses are administered within the irreversible parameter ranges, permanent pore formation occurs in the cellular membrane, resulting in cell death of the smooth muscle ceils of the fibrin sheath, in another aspect, by proactively administering the electrical pulses according to a predetermined schedule, fibrin sheath growth 200 on the catheter can be prevented altogether. Alternatively, electrical pulses may be administered within a reversible electroporation range. Cytotoxic drugs, such as a chemotherapy agent, may be administered through either catheter lumen into the volume of fibrin sheath during the electroporation treatment. Temporary pores will form in the cellular membranes of the smooth muscle cells comprising the fibrin sheath, allowing the transport of the drug into the intracellular structure, resulting in cell death.
Other methods known in the art for electrically coupling the electrodes 150 and electrically conducting elements 160 are within the scope of this invention. Examples of coupling methods include spot welding the electrode 150 to the conducting element 160, soldering and mechanical crimping, among other techniques. Other electrically conducting element configurations are also within the scope of this invention. For manufacturing efficiencies, for example, shaft 25 may be extruded with all electrically conducting elements 160 embedded in the shaft for substantially the entire length of the catheter shaft 25. Only the electrode 150 to which the conducting element 160 is coupled will be activated when the electrical circuit is energized. Those segments of the electrically coupling elements 160 distal of the electrode 150 connection will not generate an electrical field of sufficient intensity to induce a clinical effect when activated since they are not connected to any other electrodes.
The strongest (defined as volts/cm) electrical field is nearest to the electrodes 150 and is depicted by gradient line 210 in
Because the voltage pulse generation pattern from the generator does not generate damaging thermal effect, and because the voltage pulses only ablate living cells, the treatment does not damage blood, blood vessels or other non-cellular or non-living materials such as the venous catheter itself.
By utilizing separate electrically conducting elements 160 for each electrode 150, different fibrin sheath growth 200 segments may be treated independently. For example, a computer (not shown) within the generator can control the firing of each electrode pair independently and according to a predetermined pattern. Alternatively, the creation of a series of electrical fields may be accomplished by sequentially firing pairs of electrodes within one treatment session to ensure that the entire length of the fibrin sheath is treated. Sequentially polarizing and applying electrical energy to a subset of the total number of electrodes as described herein may be used to target fibrin growth on a specific segment of the catheter shaft. As an example,
In another aspect of the invention, the device and method can be used to cause the destruction of infectious cells, such as catheter-related bacteremia, that have grown around the indwelling catheter. These infectious cells can be located anywhere along the indwelling shaft. Research has also shown that infectious cells can form in combination with fibrin sheath growths, because fibrin sheath can enhance catheter-related bacteremia by providing an interface for adherence and colonization. These pathogens may then produce a “biofilm” which is impenetrable to systemic antibiotics leading to a cause of catheter dysfunction, subsequent removal, and the attendant increase in morbidity and mortality. Referring again to
In another aspect of the invention, by periodically administering the electrical pulses according to a predetermined schedule, fibrin sheath growth on the catheter shaft 20 can be prevented altogether. As an example, the formation of a fibrin sheath may occur as early as 24 hours after catheter implantation. Smooth muscle cells develop within seven days. Application of electrical pulses applied to fibrin sheath at regular intervals post-implantation may be effective in preventing fibrin sheath growth during the catheter implantation period.
Referring now to
The embodiment illustrated in
Button 713 on hub 712 is used to deploy and retract the electrically conducting elements 709 and 704 relative to the outer sheath 701. The undeployed position of electroporation probe 700 is illustrated in
Electrically conductive elements 704 and 709 may be formed of any suitable electrically conductive material including but not limited stainless steel, gold, silver and other metals including shape-memory materials such as nitinol. Nitinol is an alloy with super-elastic characteristics which enables it to return to a pre-determined expanded shape upon release from a constrained position. The outer sheath 701 constrains the distal segments of the undeployed electrically conductive elements 704 and 709 in a substantially straight distal configuration. Once the electrodes are deployed from the distal end of the outer sheath 701 as previously described, the distal sections of electrically conductive elements 704 and 709 form the “J-hook” curved profile shown in
If fibrin sheath has formed around end hole 26, electrode probe 700 may be inserted into lumen 16 (shown in
The deploying electrode probe 700 illustrated in
Referring now to
In one embodiment, the electroporation pulses can be synchronously matched to specifically repeatable phases of the cardiac cycle to protect cardiac cellular functioning. See, for example, U.S. Patent Application No. 61/181,727, filed May 28, 2009, entitled “Algorithm For Synchronizing Energy Delivery To The Cardiac Rhythm”, which is fully incorporated by reference herein. This feature is especially useful when the electroporation pulses are delivered in a location that is near the heart.
The present invention affords several advantages. Fibrin sheath growths are destroyed without having to remove the catheter from the patient. The treatment is minimally-invasive and highly efficacious. Because irreversible electroporation does not create thermal activity, the catheter is not damaged by the treatment. Fibrin sheath growths are treated quickly, and the catheters can be maintained according to a predetermined schedule to insure that the distal openings remain clear.
Although the irreversible electroporation device and method has been described herein for use with dual-lumen catheters, it should be understood that the irreversible electroporation device can be used with single lumen catheters or multiple-lumen catheters. Another type of venous catheter which is prone to fibrin sheath formation is a venous catheter that is connected to an implanted port. An example of a venous catheter attached to an implanted port is disclosed in U.S. Pat. Application Publication No. 2007/0078391, which is incorporated herein by reference. Electrode probe devices described in
While the embodiments shown use pulses that cause IRE, persons of ordinary skill in the art will appreciate that other types of pulses can be used for the destruction of the fibrin sheath growths. In particular, ultrashort sub-microsecond pulses (pulses of less than 1 microsecond in duration) can be used to induce apoptosis that cause damage to the intracellular structures such as a cell nucleus.
The above disclosure is intended to be illustrative and not exhaustive. This description will suggest many modifications, variations, and alternatives may be made by ordinary skill in this art without departing from the scope of the invention. Those familiar with the art may recognize other equivalents to the specific embodiments described herein. Accordingly, the scope of the invention is not limited to the foregoing specification.
1. An indwelling venous catheter capable of destroying undesirable cellular growth comprising:
- a shaft having at least one lumen and adapted to be placed inside a vein for long term use; and
- a plurality of electrodes positioned near the shaft and adapted to receive from a voltage generator a plurality of electrical pulses in an amount sufficient to cause destruction of cells in the undesirable cellular growth around the shaft.
2. The catheter of claim 1. wherein the shaft has two lumens and the electrodes are attached at a distal section of the shaft.
3. The catheter of claim 1, wherein the catheter is a dialysis catheter and the shaft has an arterial lumen and a venous lumen.
4. The catheter of claim 1, further comprising a probe adapted to be removably inserted into the shaft lumen, wherein the probe includes at least one of the electrodes.
5. The catheter of claim 1, further comprising:
- a probe having a lumen and adapted to be removably inserted into the shaft lumen; and
- at least two electrically conducting elements positioned within the probe lumen and adapted to be movable from a retracted position to a deployed position, wherein a distal section of the electrically conducting elements extend past the distal end of the shaft to define the plurality of electrodes.
6. The catheter of claim 5, wherein the distal section of the electrically conducting elements has a pre-curved profile that, in the deployed position, curves radially outwardly and then extends proximally along the shaft.
7. The catheter of claim 1, wherein at least one of the electrodes is ring-shaped and is coaxially arranged with the lumen.
8. The catheter of claim 1, further comprising:
- a plurality of electrically conducting wires connected to the electrodes and running along the shaft.
9. The catheter of claim 1, wherein the electrically conducting wires are positioned within a wall of the shaft so as to electrically insulate the electrically conducting wires.
10. The catheter of claim 1, further comprising the voltage generator wherein the voltage generator is adapted to generate a set of between two and twenty-five electrical pulses with each pulse having a duration of from 50 to 200 microseconds and a voltage in a range of from 2,000 V/cm to 6,000 V/cm.
11. The catheter of claim 1, further comprising the voltage generator adapted to generate the electrical pulses in an amount sufficient to cause destruction of fibrin sheath that have grown around the shaft.
12. The catheter of claim 1, further comprising the voltage generator adapted to generate the electrical pulses in an amount sufficient to cause destruction of the infectious cells that have grown around the shaft.
13. The catheter of claim 1, further comprising a synchronization device adapted to receive electrocardiogram (ECG) signals and controls generation of the electrical pulses of the voltage generator based on the ECG signals.
14. The catheter of claim 1, further comprising the voltage generator adapted to generate the electrical pulses with each pulse having a duration of less than 1 microsecond.
15. An indwelling venous catheter device capable of destroying undesirable cellular growth comprising:
- a shaft having at least one lumen terminating at a distal end opening, the shaft configured to be positioned inside a vein for long-term use;
- a probe configured to be removably insertable into the at least one lumen;
- a plurality of electrodes positioned near the probe, the electrodes being configured to receive from a voltage generator a plurality of electrical pulses in an amount sufficient to cause destruction of cells in the undesirable cellular growth around the shaft.
16. The catheter device of claim 15, wherein the probe has a tapered distal tip so as to provide a leading edge capable of advancing through the undesirable cellular growth.
17. The catheter device of claim 15, wherein, the probe has a lumen, further comprising:
- at least two electrically conducting elements positioned within the probe lumen and adapted to be movable from a retracted position to a deployed position, wherein a distal section of the electrically conducting elements extend past the distal end opening of the shaft to define the plurality of electrodes.
18. The catheter device of claim 17, wherein the distal section of the electrically conducting elements has a pre-curved profile that, in the deployed position, curves radially outwardly and then extends proximally along the shaft.
19. The catheter device of claim 15, further comprising the voltage generator wherein the voltage generator is adapted to generate a set of between two and twenty-five electrical pulses with each pulse having a duration of from 50 to 200 microseconds and a voltage in a range of from 2,000 V/cm to 6,000 V/cm.
20. The catheter device of claim 15, further comprising the voltage generator adapted to generate the electrical pulses whose voltage is in a range of from 2,000 V/cm to 6,000 V/cm.