Apparatus and method for vascular hyperperfusion of the extravascular space - Patents.com

Abstract

A method for delivering therapeutic agents to a region of the body through vascular isolation and manipulation of fluid flux into and out of the region of the body is provided. The method includes the steps of restricting vascular inflow to a region of the body, increasing an outward oncotic pressure gradient from said region of the body to flush oncotically active plasma proteins from said region of the body, inducing ischemia in said region of the body, controlling pressure and fluid flow in major blood vessels entering and leaving said region of the body, and providing said therapeutic substance to said region of the body when said fluid flow to said region of the body is controlled.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to improved devices and methods for improved vascular isolation of organs and segments thereof, in particular for vascular isolation of human extravascular spaces in organs and segments thereof to enhance the delivery and activity of therapeutic agents, such as chemotherapeutic agents and stem cells, to these extravascular spaces.The present invention further relates to devices for engagement of vascular spaces and segments thereof. [Background technology]

[0002] 2. Background of the Invention Many different medical and therapeutic situations require engagement and long term access to an artery or vein. This usually involves cannulation of the artery or vein. The interface between the vein or artery and the cannula requires pressure to deliver material or receive blood and to minimize the possibility of blood stasis around the interface causing thrombosis.

[0003] If blood is not collected or a substance is not delivered into the vein or artery, it is necessary to block the lumen between the cannula and the vein or artery to stop blood leaking out. Typically, the ends of the cannula and / or plug include edges or protrusions or recesses that extend into the vein or artery or that result in areas of dead space within the cannula. Protrusions and recesses represent areas where blood can pool and stagnate, creating a condition where thrombosis can occur. Dead spaces also create areas where blood can pool and stagnate, presenting a condition where thrombosis can occur. The dead spaces may also present areas where gas can collect creating a risk of gas embolism.

[0004] The access devices used in such procedures or treatments typically include a cannula connected to the patient's circulatory system on one end and an adapter port connected to a blood flow pump or other injection device on the other end. When not in use, the isolation system relied on a plunger slidable within a cavity in the cannula to close access to the cavity and prevent fluid communication between the circulatory system and any of the ports on the access device. Such access devices are sometimes referred to as single lumen access devices.

[0005] US Patent Nos. 5,993,333 and 5,993,663 describe access devices for remote access quarantine systems. Related access devices and systems are described in US Patent No. 5,993,333. Each of these three patents is incorporated herein by reference in its entirety by the present inventor.

[0006] When a venous or arterial access, such as a cannula, is connected to a patient's blood vessel at a perpendicular angle, the tip of the plunger can slide through the cavity or lumen of the cannula until it reaches the location where the proximal end of the cannula is connected to the vessel wall. Thus, after use of the cannula, the plunger can completely prevent the patient's blood from filling the lumen of the cannula, thereby avoiding fluid stasis that could otherwise lead to thrombosis. However, when the cannula is connected to a patient's blood vessel at a non-perpendicular angle, the conventional cylindrical shape of the plunger tip cannot prevent a small amount of blood from filling the lower part of the cannula lumen (referred to as the "dead space") unless the tip slides further through the lumen of the cannula and the leading part of the tip protrudes into the lumen of the vessel. Such dead space below the cannula lumen, or if dead space is at the plunger tip, such protrusion of the leading part of the tip into the lumen of the blood vessel, can cause hemodynamic disturbances, including fluid stasis in the patient's circulatory system, which can lead to thrombosis.

[0007] When a single lumen access device of the type described in these patents, such as a cannula, is connected at a perpendicular angle to a patient's blood vessel, the tip of the plunger can slide through the cavity or lumen of the cannula until it reaches the location where the proximal end of the cannula is connected to the wall of the vessel. Thus, after use of the cannula, the plunger can completely prevent the patient's blood from filling the lumen of the cannula, thereby avoiding fluid stasis that could otherwise lead to thrombosis. However, when a cannula with a properly beveled proximal end is connected at a non-perpendicular angle to a patient's blood vessel, the conventional cylindrical shape of the tip of the plunger cannot prevent a small amount of blood from filling the lower part of the cannula lumen (referred to as the "dead space") unless the tip slides further through the lumen of the cannula and the leading part of the tip protrudes into the lumen of the vessel. Such dead space within the lower portion of the cannula lumen, or protrusion of the leading portion of such tip into the lumen of the blood vessel if the dead space is occupied by the plunger tip, can cause hemodynamic disturbances, including fluid stasis within the patient's circulatory system, which can lead to thrombosis.

[0008] Furthermore, as shown in FIG. 51 of the present inventor's patent document 3, an access device with a multi-access treatment cap is known. However, these access devices with a multi-access treatment cap have access ports such that only a single catheter can be received through the lumen of the access device after passing through a selected access port. Thus, each such device can only promote either outflow from the circulatory system to the blood flow pump or inflow from the blood flow pump in the circulatory system, but not both. That is, these access devices with a multi-access treatment cap cannot advance two or more inflow and outflow catheters at the same time because the lumen of these devices cannot receive two or more catheters. Furthermore, these multi-access treatment caps cannot direct a catheter to a specific position using the multi-access treatment cap.

[0009] Intra-arterial or intravenous infusion of drugs or other therapeutic agents is the standard method for chemotherapy, gene therapy, and stem cell therapy in the treatment of neoplasia. The effect on the target tissue is reduced as a result of dilution of the therapeutic agent by the normal blood flow and / or detoxification of the therapeutic agent by the blood. To counter these effects, techniques have been developed to "stop the flow," usually by impeding inflow and outflow from the target tissue.

[0010] For example, there is a standard technique for the chemotherapeutic treatment of neoplasia in the pelvis, where the aorta and inferior vena cava are occluded, a tourniquet is applied to the leg, and then the isolated segment is infused with chemotherapy for a short period during the ischemic period of the pelvis. Another approach is to remove the blood containing the chemotherapy agent and to use various extracorporeal filters to neutralize the agent before systemic recirculation. The goal in this situation is to minimize the toxic side effects if blood containing the chemotherapy agent is released into the systemic circulation. This type of approach can be operatively performed in the liver by cannulating the portal vein and the hepatic artery of the liver, using a pump to recirculate the agent, and using an extracorporeal filter to minimize systemic effects. This is called "isolated hepatic infusion".

[0011] A remote access isolation system for localized hyperperfusion to enhance blood flow to an intravascular space is described (see US Pat. No. 5,399,633). Generally, hyperperfusion occurs when a greater than normal amount of fluid or cells passes through a space. The isolation system requires an inlet, an outlet, an isolation balloon, and a pump to control blood flow to the target organ. The pressure generated is up to four times the normal arterial mean pressure and can be increased up to eight times the normal flow rate. The purpose of hyperperfusion in US Pat. No. 5,399,633 is to relieve ischemic limb symptoms in the short term to prevent amputation, and to increase shear stress in the long term to encourage new blood vessel growth.

[0012] A corollary effect of hyperperfusion of a therapeutic agent locally in the desired intravascular space is that the agent may then migrate into the interstitial space, from where it may enter not only the target area but also the draining lymphatics and lymph nodes. This approach has important implications in the treatment of tumors, since many malignant cells infiltrate lymphatic vessels, migrate to lymph nodes, proliferate, and embolize via the thoracic duct before they migrate to the vasculature, from where they spread systemically. The involved lymph nodes are known to be difficult to treat due to their small size. Tumor recurrence often results from residual tumor within lymph nodes and lymphoid tissues. Other problems associated with the treatment of neoplasia may result from the presence of malignant cells in small numbers in relatively ischemic tissues, resulting in a reduced efficacy of systemic treatment. Some tumors are also known to induce higher interstitial pressures due to the surrounding pseudo-capsule associated with compression of normal structures and / or secondary inflammatory effects. There are also non-proliferating malignant cells, and therefore the therapeutic agent, which mainly affects cell division, will have little or no effect on such cells.

[0013] The access devices used in such remote access isolation systems for localized hyperperfusion to a target area and for therapeutic procedures or procedures requiring long-term arterial or venous engagement include cannulae, catheters (and particularly balloon catheter systems), balloons, plungers, adapter ports, and other devices necessary for those therapeutic procedures or procedures.

[0014] Previous remote access isolation systems have been able to provide intermittent or acute access to a patient's circulatory system for the purpose of hyperperfusion of an ischemic limb. The access device used in such systems typically includes a cannula connected to the patient's circulatory system on one end and an adapter port connected to a blood flow pump on the other end. When not in use, the isolation system relied on a plunger slidable within a cavity in the cannula to close access to the cavity and prevent fluid communication between the circulatory system and any of the ports of the access device. Such access devices are sometimes referred to as single lumen access devices.

[0015] Nos. 5,233,993 and 5,399,426 describe such access devices for remote access quarantine systems. Related access devices and systems are described in U.S. Patent No. 5,399,426. Each of these three patents by the present inventor is incorporated herein by reference in its entirety.

[0016] When a single lumen access device of the type described in these patents, such as a cannula, is connected at a perpendicular angle to a patient's blood vessel, the tip of the plunger can slide through the cavity or lumen of the cannula until it reaches the location where the proximal end of the cannula is connected to the wall of the vessel. Thus, after use of the cannula, the plunger can completely prevent the patient's blood from filling the lumen of the cannula, thereby avoiding fluid stasis that could otherwise lead to thrombosis. However, when a cannula with a suitably beveled proximal end is connected at a non-perpendicular angle to a patient's blood vessel, the conventional cylindrical shape of the plunger tip cannot prevent a small amount of blood from filling the lower part of the cannula lumen (referred to as the "dead space") unless the tip slides further through the lumen and the leading portion of the tip protrudes into the lumen of the vessel. Such dead space within the lower portion of the cannula lumen, or such protrusion of the leading portion of the tip into the lumen of the blood vessel if the dead space is occupied by the plunger tip, can cause hemodynamic disturbances, including fluid stasis within the patient's circulatory system, which can lead to thrombosis.

[0017] Furthermore, as shown in FIG. 51 of the present inventor's patent document 3, access devices with multi-access procedure caps are known. However, these access devices with multi-access procedure caps have access ports such that only a single catheter can be received through a selected access port and then through the lumen of the access device. Thus, each such device can only facilitate either outflow from the circulatory system to the blood flow pump or inflow from the blood flow pump in the circulatory system, but not both. That is, these access devices with multi-access procedure caps cannot facilitate two or more inflow and outflow catheters at the same time because the lumen of these devices cannot receive two or more catheters. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] U.S. Patent No. 7,766,853 [Patent Document 2] U.S. Patent No. 8,419,672 [Patent Document 3] U.S. Patent No. 9,078,982 Summary of the Invention [Problem to be solved by the invention]

[0019] The present inventors have discovered that there are several ways in which vascular isolation can enhance the delivery of therapeutic agents to human organs and segments thereof (eg, tumors), and thereby enhance therapeutic activity.

[0020] First, an enhanced mass effect can be created by delivery of a drug to a specific isolated target area, increasing the concentration of the drug in a limited tissue mass within that area. This effect is based on the relative tumor mass and is termed "mass targeting." The degree of enhancement depends on the mass of the target tissue compared to the total body mass. For example, pancreatic head cancer typically weighs 35 g at clinical presentation. In a 70 kg man, the therapeutic benefit of mass targeting is close to 2000 times that of systemic intravenous delivery.

[0021] The second enhancing effect of vascular isolation is called "prolonged exposure time" and involves avoidance of washout or dilution of the drug that controls influx and efflux, especially during periods of ischemic time in the relevant organ. This is a time effect multiplied by the mass effect described above. In pharmacokinetic terms, this is known as the "area under the curve" and is obtained from a graph in which drug concentration is plotted against time.

[0022] A third enhancing effect of vascular sequestration is the ability to neutralize the drug, such as by administering an antidote before sequestration is reversed. This is called "neutralization of residual active chemotherapy." To avoid any systemic effects, the flow through the isolated organ or part thereof can be reversed to extract the residual material and discard it before it leaves the organ. This is called the residual concentration of the drug, which can be measured by assessing the concentration of the drug in the discarded volume.

[0023] A fourth enhancing effect of vascular isolation is by controlling the osmotic gradient to the isolated target area, and thus the oncotic pressure. Although the access device allows for the control of arterial inflow and venous outflow, the replacement of intravascular plasma proteins with a hypotonic solution containing a therapeutic agent may provide a more targeted treatment. The hypotonic solution may create an osmotic gradient that controls the movement of the therapeutic agent from the intravascular space to the extravascular space, and in particular to the interstitial space surrounding the tumor cells. The interstitial space contains the metabolic substrates required by the tumor cells and is drained by the lymphatic system. Thus, not only can tumor cells be specifically targeted in this way, but also the lymphatic vessels and lymph nodes draining the tumor cells.

[0024] Control of the osmotic gradient can include control of oncotic pressure, which can result in the removal or partial removal of intravascular proteins.

[0025] A further way in which vascular isolation can enhance therapeutic activity is by selectively controlling the venous outflow of an organ while simultaneously controlling the arterial inflow.

[0026] Also in accordance with the present invention, yet another way in which vascular isolation can enhance therapeutic activity is by increasing the hydraulic force for injection as much as possible up to and including the vascular outflow pressure, typically by elevating the venous outflow pressure above the Mean Arterial Pressure (MAP) and Mean Capillary Pressure (MCP), thereby directing this hydraulic force laterally, which can be measured with an instrument attached to the infusion system.

[0027] Previously, there were various external fistulas, usually for hemodialysis treatment. The original shunts were described by Quentin Scribner, Allen Brown and Thomas Shunts. There could be a direct anastomosis to the donor input artery and the recipient vein (Thomas and Allen Brown). In some cases, an intraluminal connection was used with ligation of the distal vessels without anastomosis (Quentin Scribner). To access the systemic circulation, the arterial and venous sides were temporarily fixed and the interconnecting device was removed. This device is generally a simple intraluminal connecting tube that can easily become dislodged. There are obvious safety concerns. The system was connected to a therapeutic or diagnostic system. A prime example is renal hemodialysis.

[0028] High flow rates are common when external fistulas are used. High flow rates can contribute to congestive heart failure due to high flow rates, which manifest as peripheral edema, lethargy, shortness of breath, and chest pain. It can also induce peripheral "steal" syndrome, where high flow rates cause ischemia in areas distal to the fistula. High flow can also result in venous hypertension. [Means for solving the problem]

[0029] Summary of the Invention In a first embodiment, the present invention aims to provide a method for delivering a therapeutic agent to a region of the body through vascular isolation and manipulation of fluid flux into and out of the region of the body, the method comprising: restricting vascular inflow to said area of ​​the body; flushing oncotically active plasma proteins from said region of the body into the systemic circulation of the body by increasing an oncotic pressure gradient outward from said region of the body; inducing ischemia in said region of the body; controlling pressure and fluid flow in major blood vessels leading to and from said region of the body; hyperperfusing the therapeutic substance into the region of the body when the fluid flow to the region of the body is controlled; Includes.

[0030] In controlling the pressure and fluid flow of the main blood vessel to flush out proteins and allow therapeutic treatment, the present invention aims to dispense with drugs that can release albumens and allow therapeutic substances to cross the extravascular space barrier.

[0031] Preferably, said region of the body is an organ.

[0032] Preferably, the pressure via the vascular inflow is controlled to be below 20 mmHg.

[0033] Preferably, pressure via the vascular inflow is controlled to induce critical capillary closure.

[0034] Preferably, the oncotically active plasma proteins are washed out between 28mmHg and 35mmHg.

[0035] Preferably, the exit of the therapeutic substance from the region of the body is occluded using positive end expiratory pressure (PEEP).

[0036] Use of PEEP eliminates the need for mechanical occlusion of the outflow port to limit leakage of therapeutic substances via the outflow.

[0037] Preferably, the outflow of said therapeutic substance from said region of the body is controlled using relative movement of the body limbs.

[0038] Hyperperfusion does not require the use of drugs to aid in the transfer of substances into the extravascular space.

[0039] Preferably, the hyperperfusion is provided at or below 35 mmHg.

[0040] Preferably, occlusion of vascular flow is accomplished by insertion of a multi-balloon catheter line into at least one of the blood vessels surrounding the target area.

[0041] Preferably, said therapeutic treatment comprises at least one of chemotherapy, nanoparticle delivery, stem cells, immunotherapy and / or gene therapy.

[0042] Preferably, said manipulation of fluid flux comprises at least one of flow occlusion, partial flow occlusion, isoperfusion or hyperperfusion of major vessels to said target area.

[0043] Preferably, said manipulation of fluid flux is accomplished using at least one of an intravascular device or an extravascular device.

[0044] Preferably, the method includes assessing and adjusting the fluid pressure of an intravascular fluid by infusion.

[0045] Preferably, the method comprises the steps of: delivering the therapeutic treatment to the interstitial spaces where tumor cells reside, or to the necrotic center of the tumor along the oncotic gradient that follows the oncotic gradient and penetrates the pseudocapsule; providing a fluid that traverses the lymphatic vessels and delivers the treatment to the lymph nodes; Repeating the delivery of the therapeutic treatment over time, which may target cells that are not dividing in one particular treatment cycle; Includes.

[0046] Using the oncotic gradient to target tumor cells, cells can be better targeted without collateral damage.

[0047] In a second embodiment, the present invention provides an assembly for delivering therapeutic treatment to a region of the body through vascular isolation and manipulation of fluid flux into and out of the region of the body, comprising: a first occlusion device adapted to restrict vascular inflow to said region of the body; a second occlusion arrangement for restricting vascular outflow from said region of the body; and wherein the first occlusive device is adapted to increase an outward oncotic pressure gradient from the region of the body to flush osmotically active plasma proteins from the region of the body to render the region of the body ischemic. an injection device configured to provide a therapeutic substance for said therapeutic treatment when said area is in an ischemic state; a removal device configured to remove the therapeutic substance from the region of the body; The present invention relates to an assembly including:

[0048] Preferably, said region of the body is an organ.

[0049] Preferably, the first occlusion device is configured to control pressure via the vascular inflow at or below 20 mmHg.

[0050] Preferably, pressure via the vascular inflow is controlled to induce critical capillary closure.

[0051] Preferably, the osmotically active plasma proteins are washed out between 28mmHg and 35mmHg.

[0052] Preferably, the exit of said therapeutic substance from said region of the body is occluded using positive end-expiratory pressure.

[0053] Preferably, the outflow of the therapeutic substance from the region of the body is controlled using relative movement of the limbs of the body.

[0054] Preferably, the therapeutic substance is adapted to be hyperperfused into the region of the body via a catheter.

[0055] Preferably, said hyperperfusion is provided at a pressure less than the venous outflow pressure from said region of the body.

[0056] Preferably, the hyperperfusion is provided at or below 35 mmHg.

[0057] In a third embodiment, the present invention provides a vascular access device for chronic use, comprising: a beveled cannula including a beveled cannula end configured to engage the blood vessel at an angle; a removable plunger configured to occlude and seal the lumen of the cannula; wherein the removable plunger includes a chamfered end configured to eliminate dead space within the cannula when the plunger is fully inserted into the cannula to occlude an inner lumen of the cannula. A vascular access device is provided.

[0058] Eliminating said dead space minimizes the risk of thrombosis.

[0059] Preferably, the bevelled end of the removable plunger is arranged such that when the plunger is fully inserted into the cannula it does not protrude into the blood vessel to block the cannula.

[0060] Preferably, the chamfer angles of the chamfered cannula end and the chamfered end of the plunger are the same.

[0061] Preferably, the cannula includes an inner wall profiled to matingly correspond to an outer stem wall of the plunger.

[0062] Preferably, the inner wall of the cannula is profiled for mating correspondence with the outer stem wall of the plunger to prevent rotation of the plunger, and a protrusion on the outer stem wall of the plunger is positioned to be received within a recess in the inner wall of the cannula.

[0063] Preferably, mating counterparts of the inner cannula wall and the outer plunger wall are arranged so that the chamfered cannula end is parallel to and aligned with the chamfered end when the plunger is fully inserted into the cannula.

[0064] Preferably, the cannula includes a vessel and a graft end disposed to engage a body part, wherein the graft end is configured to connect with the body part.

[0065] Preferably, the cannula includes a connection assembly distal to the graft end that is adapted to connect to a medical supply device.

[0066] Preferably, the connection assembly is arranged to connect with the body part.

[0067] In a fourth embodiment, the present invention provides a multiport adaptor for a cannula system, comprising: A multi-port adapter is provided having a plurality of tubes feeding into a central lumen, the central lumen being configured to connect to a primary cannula line configured to connect to a vasculature.

[0068] Preferably, the multiple tubes can be used to provide multiple cannulas within the vasculature via a central lumen.

[0069] Preferably, the multiple cannulas are used to create anastomoses within the vasculature.

[0070] Preferably, each of the plurality of tubes is configured to receive and route a guidewire within the central lumen.

[0071] Preferably, the plurality of tubes are flexible and configured such that the lumens in each of the tubes do not intersect.

[0072] Preferably, the guidewires are configured to be delivered individually or together into the vasculature.

[0073] Preferably, the guidewire is configured to include a balloon.

[0074] Preferably, the guidewire is configured to direct the inflow and outflow vasculature of a particular region so that the particular region can be isolated with a medical device associated with the guidewire.

[0075] Preferably, each of the plurality of tubes is configured for connecting an external medical device.

[0076] Preferably, the plurality of tubes are configured to connect to the external medical device using a Luer lock.

[0077] Preferably, the multiple tubes are configured to simultaneously provide multiple intravascular devices within the vasculature.

[0078] In a fifth embodiment, the present invention provides an external arteriovenous fistula connection configured to connect between an arterial cannula and a venous cannula, comprising: an arterial connection means configured to sealingly connect to said arterial cannula; a venous connection means configured to sealingly connect to said venous cannula to form a sealed passageway; at least one reusable access portal; wherein the access portal provides an external arteriovenous fistula connection configured to receive a catheter for insertion into a vein connected to the venous cannula or an artery connected to the arterial cannula.

[0079] Preferably, the external arteriovenous fistula connection comprises: a reusable arterial access portal configured to receive a catheter for insertion into the arterial cannula; and a venous access portal configured to receive a catheter for insertion into the venous cannula. In a sixth embodiment, the present invention aims to provide a system for increasing hepatic artery flow using a multiple transarterial balloon system to reduce total intestinal flow and therefore reduce portal vein flow and activate hepatic artery buffer response. [Brief description of the drawings]

[0080] BRIEF DESCRIPTION OF THE DRAWINGS While other embodiments may fall within the scope of the present invention, one embodiment of the present invention will now be described, by way of example only, with reference to the accompanying drawings. [Figure 1] FIG. 1 is a schematic diagram of an arterial occlusion balloon positioning arrangement for controlling arterial flow in the pelvic region according to one embodiment of the present invention. [Diagram 2] FIG. 2 is a schematic diagram of a vascular occlusion balloon positioning device for controlling vascular flow in accordance with one embodiment of the present invention. [Diagram 3] FIG. 3 is a schematic diagram of a vascular occlusion balloon positioning device of a single balloon catheter system providing collateral flow control for use in right breast vascular isolation, in accordance with one embodiment of the present invention. [Figure 4] FIG. 4 is a schematic diagram of an arterial occlusion balloon positioning device of a multi-balloon catheter system providing control of collateral arterial flow for use in right breast vascular isolation according to one embodiment of the present invention with super selection of arterial inflow. [Diagram 5]FIG. 5 is a schematic diagram of an arterial occlusion balloon positioning device of a balloon catheter system for controlling vascular flow to the liver, in accordance with one embodiment of the present invention. [Figure 6] FIG. 6 is a schematic diagram of an arterial occlusion balloon positioning device of a balloon catheter system that provides control of collateral arterial flow for use in hepatic hyperperfusion, in accordance with one embodiment of the present invention. [Figure 7] FIG. 7 is a schematic diagram of a vascular occlusion balloon positioning device according to one embodiment of the present invention for treatment of the cranial region. [Figure 8] FIG. 8 is a schematic diagram of an arterial occlusion balloon positioning device for controlling vascular flow to the lower extremities in accordance with an embodiment of the present invention. [Figure 9] FIG. 9 is a schematic diagram of an arterial occlusion balloon positioning device for controlling vascular flow to the lower extremities in accordance with an embodiment of the present invention. [Figure 10] FIG. 10 is a schematic diagram of an arterial occlusion balloon positioning device of three separate balloons in a catheter system providing vascular flow control to the pancreas, according to one embodiment of the present invention. [Figure 11] FIG. 11 is a schematic diagram of a pressure-controlled intraluminal balloon for use in the duodenum for vascular isolation of a tumor in the pancreas according to another embodiment of the present invention, and the connected distal end of a multi-channel catheter shaft system according to another embodiment of the present invention. [Figure 11A] FIG. 11A is a side view of the compression balloon of FIG. [Figure 12] FIG. 12 is a schematic diagram of an arterial occlusion balloon positioning device for three separate balloon catheter systems providing control of collateral arterial flow for use in hepatic hyperperfusion. [Figure 13] FIG. 13 is a schematic diagram of vascular isolation of the upper lobe of the lung. [Figure 14] FIG. 14 is a side cross-sectional view of a prior art single lumen access device. [Figure 15] FIG. 15 is a side cross-sectional view of the cannula of another prior art single lumen access device, showing the tip of the device's plunger stem protruding from the cannula into the lumen of the patient's blood vessel. [Figure 16] FIG. 16 is a side cross-sectional view similar to FIG. 15, except showing the tip of the plunger stem of the device no longer protruding into the vessel lumen but retracted within the lumen of the cannula to create a dead space within the lumen of the cannula. [Figure 17] FIG. 17 is a side view of a cannula of a single lumen access device according to one embodiment of the present invention. [Figure 18] FIG. 18 is a cross-sectional end view through BB of the cannula of FIG. [Figure 19] FIG. 19 is a side view of a plunger stem with a chamfered tip for use with the cannula shown in FIGS. 17 and 18 of the single lumen access device. [Figure 20] 20 is a cross-sectional end view through AA of the plunger stem of FIG. 19. FIG. [Figure 21] FIG. 21 is a side view of a single lumen access device formed from the cannula of FIGS. 17 and 18 and the plunger stem of FIGS. 19 and 20, said single lumen access device being connected to a patient's blood vessel and showing no resulting protrusions or dead spaces. [Figure 21A] FIG. 21A is a side view of an alternative cannula to that of FIG. [Figure 22] 22 is a side cross-sectional view (longitudinal) of the cannula of FIG. [Diagram 23] FIG. 23 is an enlarged view of cross-sectional portion B of the cannula shown in FIG. [Figure 24] FIG. 24 is an enlarged view of cross-sectional portion C of the cannula shown in FIG. [Diagram 25] FIG. 25 is a perspective view of a multi-port adapter according to one embodiment of the present invention connected for use with a cannula of a single lumen access device. [Figure 25A] FIG. 25A is a perspective view of a multi-port adapter according to one embodiment of the present invention. [Figure 26] FIG. 26 is an exploded view of the multiport adapter shown in FIG. 25 along with the cannula. [Figure 27] FIG. 27 is a side view of the interconnected multiport adapter and cannula of FIG. 25 showing the occlusion balloon positioning devices of three separate balloon catheter systems that are connected to a patient's circulatory system and all enter the circulatory system through the lumen of the cannula to control vascular flow to or from an organ. [Figure 28] FIG. 28 is a perspective view of a multi-port adapter according to another embodiment of the second invention connected, in use, to an implantable cannula of a single lumen access device. [Figure 29] FIG. 29 is an exploded view of the multi-port adapter shown in FIG. 28 along with the distal end of the implantable cannula. [Diagram 30] FIG. 30 is a side view of the interconnected multiport adapter and cannula of FIG. 28 showing the occlusion balloon positioning devices of three separate balloon catheter systems connected to a patient's circulatory system and providing vascular isolation of an organ, all passing through the lumen of the cannula and into the circulatory system. [Diagram 31] FIG. 31 is a side view of an external ostomy device according to one embodiment of the present invention. [Diagram 32] FIG. 32 is a side view of an external ostomy device according to one embodiment of the present invention. [Diagram 33] 33 is a side view of a port used in the external ostomy device of FIG. [Diagram 34] FIG. 34 is a side view of an external stoma connector device according to one embodiment of the present invention. [Diagram 35] 35 is a side view of the cannulated external fistula connector device of FIG. 34. FIG. [Diagram 36] FIG. 36 is a side view of a multi-port catheter connection and plunger according to one embodiment of the present invention. [Figure 37] FIG. 37 is a side view of an external ostomy device according to the present invention. [Figure 38] FIG. 38 is a side view of an external ostomy device according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0081] Detailed Description of the Invention Generally, referring to Figures 1-13, one embodiment of the present invention relates to a system and device for improving the delivery of therapeutic substances for therapeutic treatment to extra vascular or interstitial spaces where target cells or lesions are located, and in particular to hyperperfuse ischemic interstitial spaces. Hyperperfusion is defined as passing more than the normal amount of fluid (or cells) through the space. An inevitable effect of hyperperfusion of therapeutic agents to the interstitial space is to hyperperfuse the target as well as the draining lymphatic vessels and lymph nodes. This concept has important implications for the treatment of neoplasia, since many malignant cells infiltrate lymphatic vessels, migrate to lymph nodes, proliferate, and then embolize to the venous system via the thoracic duct and therefore spread throughout the body. Lymph node involvement is known to be difficult to treat for lymph nodes that are small in size. Tumor recurrence is often associated with residual tumor in lymph nodes and lymphocytes. Other problems associated with the treatment of neoplasia relate to the presence of malignant cells in small numbers in relatively ischemic tissues, which are assisted by systemic treatment, since their penetration ability is significantly reduced. Some tumors are also known to induce higher interstitial pressures, due in part to the surrounding pseudocapsule associated with compression of normal structures and / or secondary inflammatory effects. There are also non-proliferating malignant cells, and many therapeutic agents have a primary effect on cell division. The physiological laws governing fluid flux across capillary membranes are described in the Starlings equation:

[0082] The Stirlings equation is:

number

number

[0083] The reflection coefficient is a correction factor that reflects the variability of the oncotic pressure gradient. Usually, the reflection coefficient is less than 1.

[0084] Below are approximate values ​​of the variables in the equations for both arterioles and venules in the body. [Table 1]

[0085] Assuming that the net driving force decreases linearly, there is an average net driving force outward from the capillaries overall, which also results in more fluid flowing out of the capillaries than re-entering them. The lymphatic system drains this excess.

[0086] Changes in variables due to hyperperfusion of the interstitial space The following embodiments of the device and method reduce the capillary pressure below the "critical closing pressure." When infusion begins, the capillaries reopen and receive the infused substrate. When infusion stops, they close again to minimize dilution by red blood cells and plasma. Typically, the critical closing pressure is 20 mmHg.

[0087] Embodiments of the present invention that improve pressure-driven washout and hyperperfusion of the interstitial space affect the following variables: (a) Decreasing Pc when the pressure gradient from arteriole to venule is usually high and the venous volume is several times the arteriolar volume. A reduction in perfusion pressure is essential to avoid rapid washout of therapeutic substances. (b) increasing the oncotic gradient to flush red blood cells, plasma, and proteins from the interstitial space; (c) Increase in therapeutic perfusion pressure (Pp) via an infusion catheter. Often, Pp is greater than the original Pc, and optimally, Pp is greater than Pc, so that maximum therapeutic drug crosses the basement membrane and enters the interstitial space. (d) The reduction of πc as intravascular albumen dilutes with saline is important for the oncotic osmotic gradient, which drives a net outward flux from the intravascular to the extravascular space. This is enhanced by many low molecular weight therapeutics that passively cross from the intravascular to the extravascular space and therefore function therapeutically. Many active therapeutics lose their efficiency when albumen binds. For example, 70% of oxalyplatin is rapidly and irreversibly bound to albumen. The described device can improve interstitial hyperperfusion by diluting albumen as oncotic pressure decreases. (e) The device can also increase the filtration coefficient (Kf) by inducing ischemia. Decreased intravascular red blood cells decrease oxygen delivery to the capillary endothelium, resulting in increased capillary permeability and increased net outward flux. Local ischemia induces vasodilation, which increases the local cross-sectional area and total outward flux, promoting extra vascular flow.

[0088] An embodiment of the apparatus of the present invention comprises, at least in part: 1. Reducing, equalizing, or reversing the gradient of Pc and potential vorticity Pv; 2. Increasing the outward oncotic gradient by diluting or removing intravascular albumen and plasma proteins; 3. Optimizing therapeutic activity by minimizing covalent binding; 4. Creating ischemia that increases outward flux across the endothelial membrane; 5. Increasing cross-sectional area by ischemia-induced vasodilation; 6. Inducing critical closure of capillaries; 7. Increasing venous outflow pressure as much as possible; and 8. Inject no more than the maximum critical volume v to prevent the therapeutic agent from entering the systemic circulation; The purpose is to:

[0089] On the venous side, the devices allow for varying degrees of occlusion and, depending on the treatment site, can be extravascular in an intravascular balloon to occlude outflow, positive end-expiratory pressure (PEEP), or an occlusion device that can be inflated or deflated percutaneously to control outward flow.

[0090] The effect of controlling extravascular flux from intravascular flux: (a) delivering therapeutic agents to the interstitial spaces where tumor cells are scarce or along the oncotic gradient to the necrotic core of the tumor; (b) increased ability to penetrate the pseudocapsule following a colloid osmotic gradient; (c) the fluid traverses the lymphatic vessels and delivers the treatment to the lymph nodes; (d) Repeated delivery of drugs over time may target cells that are not dividing in a given treatment cycle.

[0091] The critical closing pressure is usually 20 mmHg and can be used as a valve. The critical closing pressure can be relied upon for operation as a valve, since the inflow port to the extravascular space is occluded. After the washout of excess vascular space has been performed and the delivery of the therapeutic agent is completed, the capillary system remains closed, and then minimal dilution of the area by normal blood can be expected. Hyperperfusion and the pressure difference between the intravascular and extravascular spaces are extreme. Intravascular hyperperfusion requires pressures higher than those normally generated by the heart. Increased shear stress and reduced venous flow are associated with the dilation of distal blood vessels. Gas flux from red blood cells to and from cells is immediate, i.e. diffusion times are extremely short, and is independent of osmolarity and plasma.

[0092] In many tumors, vascular inflow is tortuous, irregular in diameter, and can end up blind. The flow, pressure, and resistance are reduced, resulting in reduced chemotherapy doses. Capillary inflow pressure can drop to 5mmHg. In these situations, hyperperfusion results in greater net inflow pressure and increases to MAP and MCP, thereby creating greater net inflow pressure and greater therapeutic delivery. Hyperperfusion also applies to the lymphatic system, where there is greater lymph flow associated with higher interstitial pressure. The increased flow containing the therapeutic is delivered to both lymphatic vessels and lymph nodes.

[0093] Possible treatments involving vascular isolation of organs or anatomical regions of the human body include, but are not limited to, the liver, pancreas, pelvic organs, lower extremities, cranial regions, etc. In various embodiments of the present invention, multiple cannulation systems utilizing balloons 24 and catheters 22 are inserted into the patient's vascular system using cannulation techniques and subsequently placed into the arteries and / or veins supplying blood to the target region. The balloons of these balloon catheter systems are then inflated to block or occlude arterial or venous inflow to the target region and establish an isolated zone of significantly reduced blood inflow. This isolated zone allows for the infusion of therapeutic agents into the target region while minimizing systemic exposure. Vascular isolation can be further enhanced by using another access device to place additional balloon catheter systems within the veins to occlude venous outflow from the target region or lesion, or by using positive end-expiratory pressure (PEEP).

[0094] With an isolation zone established, it is within the scope of the present invention to provide injection into the target area with or against the blood flow within the vessel.

[0095] Generally, the present invention provides a vascular occlusion balloon positioning assembly 20 for isolating an area within a body. The vascular occlusion balloon positioning assembly includes an access device 41 arranged to engage, pierce and provide access within a blood vessel, a plurality of catheter lines 22, and a catheter balloon 24 disposed about the catheter lines 22 arranged to expand within the blood vessel to control blood flow. The catheter lines 22 and balloon 24 are disposed about the area within the body to isolate it from the blood flow.

[0096] An embodiment of the present invention contemplates measuring pressure within a blood vessel 23 and controlling flow and pressure within a section of said blood vessel 23 .

[0097] FIG. 1 shows a vascular occlusion balloon positioning device 20 according to an embodiment of the present invention used in the pelvic region from the aorta 81. This includes, but is not limited to, targeting of the bladder, rectosigmoid colon, prostate, anal canal, vagina, cervix, uterus, ovary, lymphoma, carcinoma, and sacral tumors. Typically, this region includes a large number of blood vessels 23. In the device of FIG. 1, the balloon positioning device 20 includes an access device 41 for piercing and accessing the blood vessels 23, a number of catheter lines 22, and a catheter balloon 24 around the catheter lines 22 arranged to expand within the blood vessels to control blood flow to the target site. In the embodiment of FIG. 1, the target site is a tumor 11. The catheter lines 22 and balloon 24 are inserted into the blood vessel via the access device 41 and positioned within the blood vessel 23 around the tumor 11 to isolate it from the blood flow.

[0098] Typically, target organs / areas in the pelvic region have a bilateral blood supply that requires control of blood flow through both supplying vessels. This may require a co-rail system with two catheter lines 22 with separate balloons 24, with balloons 24 placed in both blood supplying vessels by the two catheter lines 22. For example, if the tumor 11 is a prostate cancer, a balloon at the origin of the internal iliac system encompassing both anterior and posterior divisions with a super selective catheter entering the inferior vesical artery, which is the optimal artery desired for injection, is used.

[0099] 2 illustrates the use of the balloon positioning device 20 according to one embodiment of the present invention in a blood vessel 23 from the inferior vena cava 46. The vascular occlusion balloon positioning device 20 includes an access device 41 for penetrating and providing access to the blood vessel 23, a number of catheter lines, and a catheter balloon 24 around the catheter lines 22 configured to be inflated within the vein to control blood flow to a target site. In the embodiment of FIG. 2, the target site is a tumor 11. The catheter lines 22 and balloon 24 are positioned within the blood vessel 23 around the tumor 11 in the body to isolate it from the blood flow.

[0100] 1 and 2, if bilateral injection is required, access device 41 can be used individually from the contralateral or ipsilateral side.

[0101] FIG. 3 shows an example of a flow control balloon 24 for minimizing collateral venous flow and optimizing chemotherapy infusion in the right breast.

[0102] FIG. 4 shows an example of multiple blood flow balloons 24 used to minimize collateral arterial flow and further optimize chemotherapy infusion into the right breast.

[0103] The balloon 24 cooperates to allow selective arterial infusion of chemotherapeutic or other therapeutic agents to the target area via an infusion channel 116 through the catheter 22 and balloon 24 in the external thoracic artery 118. The collateral flow control balloon 114 minimizes arterial collateral flow to the target area by occlusion of the distal vessels of the innominate artery 120, the internal thoracic artery 124, the superior thoracic artery 126, and the thyrocarotid artery 128. The common carotid artery 122 feeds into the innominate artery 120.

[0104] In one embodiment of the irradiated particles of the present invention, the irradiated particles can be injected during or after arterial injection into an isolated region of the body that may have some blood flow to it at the time the irradiated particles are injected.

[0105] With particular reference to Figure 3, the collateral flow control balloon 24 minimizes venous collateral flow from the target area by occlusion of the proximal vessels of the innominate vein 130, the internal thoracic vein 134, the pectoral vein 136, and the external thoracic vein 138. In this manner, there is occlusion of the axillary and subclavian arterial systems to the right breast (as shown in Figure 4), and there is occlusion of the axillary and subclavian venous systems from the right breast (as shown in Figure 3). The internal jugular vein 132 joins the right subclavian vein 141. Occlusion of the main venous outflow from the right breast increases the venous pressure in the target area, thereby optimizing the effect of the chemotherapy agent on the lesion.

[0106] FIG. 3 also shows a shaft 140 containing a separate guidewire and inflation channel (not shown) that leads to the balloon 24 via the basilic vein and then the right subclavian vein 141, and an end 142 of said shaft 140.

[0107] 4 also shows shaft 143 containing a separate guidewire and inflation channel (not shown) that leads to balloon 24 via the brachial artery or alternative access point and then to the axillary artery, as would be understood by one of ordinary skill in the art. Also shown is shaft 145, also containing a separate guidewire and inflation channel that leads to balloon 24 via the brachial artery, artery and then to the axillary artery 144, and end 146 of said shaft 145.

[0108] With reference to FIG. 4, it is within the scope of the present invention that other arteries, such as the internal mammary artery, may be infused.

[0109] 5 shows an arterial occlusion balloon positioning device 20 of a balloon catheter system for isolating the blood vessels of the liver 21. Three catheter balloons 24 on catheter lines 22 are inserted into the blood vessels 23 supplying blood to and from the liver 21. The balloons 24 are positioned in multiple superior mesenteric arteries 25, gastroduodenal arteries 43, common or proper hepatic arteries 23, and splenic arteries 42. 46 is the inferior vena cava and 44 is the celiac axis.

[0110] FIG. 6 shows an example of vascular isolation of the liver 21 to treat a tumor 11 by positioning an inflated occlusion balloon 24 in the hepatic artery 23 and by a microcatheter 3 placed through the central guidewire channel of the occlusion balloon 24 and extending to the inner opening of the hepatic artery 23. The microcatheter 3 is shaped to be wedged inside the blood vessel supplying the tumor 11 and to impede flow through the arterial collateral circulation by pressing the walls of the microcatheter 3 against the walls of the blood vessel supplying the tumor. The umbra or flow shadow is dense due to the double occlusion minimizing flow to the tumor 11. The portal vein collaterals are also occluded by either intravascular or extravascular balloons 24 surrounding the celiac trunk 44, superior mesenteric artery 25, and inferior mesenteric vessels, respectively. As a result, arterial flow in the intestine 35 is low and secondary flow through the portal vein 69 is low, further reducing flow to the tumor 11. In one embodiment, this flow can be further reduced by inflating an implantable cuff 26 around the portal vein. This vascular isolation method also enhances the ischemic effect, thereby inducing central necrosis in the tumor 11 with growing edges 5. Interstitial fluid flow from the tumor 11 into the lymphatic vessels 4 is enhanced by controlling positive end-expiratory pressure (PEEP) to increase pressure in the hepatic veins 73 and inferior vena cava (IVC) 46. Outward flow from the tumor 11 can be controlled by varying PEEP. Alternatively, three separate balloon 24 catheters 22 can be positioned to occlude each of the three hepatic veins 73. Ballooning in the celiac, gastric, superior and inferior mesenteric arteries (combination of one or more during occlusion) results in a decrease in portal vein flow. There is a physiological response defined as the hepatic artery buffer response (HABR). This substantially increases hepatic artery flow mediated by nitric oxide adrenergic and other local humeral substances. Delivery of therapeutic substances, stem cells, nanoparticles, chemotherapy or radioactive particles may be effective in activating the HABR.

[0111] Tourniquets or other forms of restriction other than an inflatable cuff to restrict flow are also within the scope of the present invention.

[0112] Figure 7 shows an embodiment of the invention applied to the isolation of blood vessels and arteries in the cranial region 39. This may include tumors 37 of the brain or carcinomas of the tongue, larynx, pharynx, facial skin and submandibular glands.

[0113] In one embodiment, the origin site of treatment may be the access device 41 at the origin of the external carotid artery 74, or from either the groin or arm, or both. The access device may be implanted unilaterally or bilaterally. The access device 41 is implanted bilaterally for blood-fed structures close to the midline. For inflow, the main axis is superselected to the target area and controlled with an intravascular or extravascular balloon 24 occlusion system on the catheter 22 as described above. In some situations, the occlusion system is associated with excellent collateral flow of the proximal balloon 24 system and the distal balloon 24 system (the collateral system is necessary to reduce the pressure corresponding to the critical closure pressure, which is 20 mmHg at the precapillary level).

[0114] For concomitant control, depending on the radiological appearance and the pressure obtained after occluding the main shaft, it may be necessary to cannulate other branches of the external carotid artery 74. Other adjacent branches of the external carotid artery may need to be controlled, including branches of the subclavian vessels such as the costocervical and thyrocervical canals.

[0115] Outflow control is achieved by postural manoeuvres (e.g., movement into Trendelenburg position), positive and expiratory pressure, and occlusion catheters in the internal jugular vein 75, common face or anterior jugular veins (which may include intravascular or external vascular occlusion systems).

[0116] Internal occlusion of the internal jugular vein is accomplished using balloon 24 and catheter 22 as described above. External occlusion is accomplished using an extravascular occlusion device 78 that applies pressure to the outside of the vein via inflation line 79.

[0117] The external occlusion using an extravascular occlusion device 78 is applied to the same side of the same vessel as the access device is applied. The fact that the occlusion device 78 is shown on the contralateral side in Figure 7 indicates its bilateral use.

[0118] Venous pressure is continuously monitored. Once vascular control is involved, plasma proteins and blood are washed out of the target segment and replaced with saline containing the therapeutic agent. Once blood flow is re-established, collateral circulation and main arterial inflow are constricted first and venous outflow control is continued for 5-20 minutes to minimize systemic recirculation. Once the plasma proteins are washed out, the effect of the patient's antibodies is greatly reduced or eliminated. Once the effect of the patient's antibodies in the target segment is eliminated or reduced, the chance of an immune response in the target segment is greatly reduced or eliminated.

[0119] There are several constraints in the procedure of delivery of therapeutics into the brain parenchyma. The blood-brain barrier (BBB) ​​prevents more than 95% of therapeutic substances from passing through the endothelium. Molecules smaller than 500 daltons can usually pass. The problem is that the tight junctions between endothelial cells do not allow free movement across this barrier. The next problem is related to the tumor itself, since tumors tend to be diffuse rather than concentrated in a specific mass. With regard to fluid flux, this is associated with an increase in intracranial pressure, which can induce symptoms associated with the syndrome of intracranial hypertension. The next problem is relative cerebral ischemia, especially with local injections. Isolation treatments are best performed under local anesthesia to regulate the injection time. The last problem is the good collateral flow in some parts of the brain, which makes it difficult to create an oncotic osmotic gradient, due to the difficulty in washing out the oncotic osmotically active crystal proteins in the injected segment. The last problem concerns the difficulty in increasing the outflow pressure so that there is a net movement from the intravascular to the extravascular space.

[0120] For segmental cerebral isolation, the establishment of inflow control is via arterial access via the inguinal external carotid artery 74 or the brachial artery. Collateral flow is minimized by the use of collateral vessels, so that one balloon is proximal in a larger vessel and the other balloon is usually adjacent to the lesion in the same vessel, and the infusion proceeds along a central or guidewire channel, i.e., the Corelle system. Outflow cerebral hypertension can be improved by specific occlusion to the Trendelenburg or internal jugular vein, either with an occlusive balloon system intravascularly, or with an extravascular occlusion system implanted around the internal jugular vein in the neck. This system can be activated and deactivated percutaneously.

[0121] Plasma proteins and blood are washed out of the segment and replaced by active therapy. This can be assisted by increasing the endothelial pore size by using hypertonic carrier solutions to shrink the endothelial cells. Another possibility is to use other carrier substances, especially if lipophilic drugs pass the blood-brain barrier more easily.

[0122] Figures 8 and 9 show the vascular isolation method and device of the present invention applied to the lower extremity 82. Figure 8 shows arterial isolation and Figure 9 shows venous isolation. The site of origin of the intraluminal catheter may be on the contralateral extremity in the common femoral or accessory or brachial vessels, or via an arteriovenous fistula. If the lymphatic system has the opportunity to receive treatment, the control system may be located near the lymph nodes, i.e., the iliac system. In some circumstances, an implantable extravascular occlusion system may be used.

[0123] Those skilled in the art will readily appreciate that the vascular isolation methods and devices shown in Figures 8 and 9 are readily adapted for use in the upper extremity.

[0124] Those skilled in the art will appreciate that the origin site of treatment can be the access device 41 at the origin of the common femoral artery 81, or from either the groin or arm, or both.

[0125] By using the balloon 24 on the catheter line 22 as described above, the isolation of the tumor 11 is achieved by controlling the deep vessels or the internal iliac artery or the correl system individually. In the embodiment of FIG. 8, the balloon 24 is placed in the superficial femoral artery 83. In one embodiment, this is monitored by suitable pressure transducers. In the embodiment of FIG. 9, the balloon 24 is placed in the superficial femoral vein. Outflow control can be assisted by reverse Trendelenberg positioning. In some cases, an intravascular balloon, either ipsilateral or contralateral, or a tourniquet 42, can be appropriate, and positive and expiratory pressures can be applied. Outflow can be controlled using any or all of the above mechanisms. Removal of the plasma and blood of the gelatin active substances and their replacement with therapeutic substances in a biocompatible solution, and the resumption of normal circulation can be delayed by removing the outflow occlusion after several minutes of the inflow control system. Control of the deep vessels is achieved ipsilaterally or contralaterally.

[0126] 10 shows an arterial occlusion balloon positioning device in three separate balloon 24 positions of balloon positioning device 20 for vascular isolation of pancreas 53 via anterior superior pancreaticoduodenal artery 193, anterior inferior pancreaticoduodenal artery 191, and posterior superior pancreaticoduodenal artery 95. Also shown are posterior inferior pancreaticoduodenal artery 97, superior mesenteric artery 194, gastroduodenal artery 192, proper hepatic artery 94, and celiac axis 44.

[0127] 11 shows an example of an inflated mucosal compression balloon 230 positioned in the duodenum 231 for use with one embodiment of the balloon positioning device 20 of the present invention. Also shown is the superior pancreaticoduodenal artery 232, its posterior branch 234, and its anterior branch 236. Also shown is the gastroduodenal artery 238 and the pancreatic branch 240 from the anterior branch 236 of the superior pancreaticoduodenal artery 232.

[0128] Both the posterior bifurcation 234 and the anterior bifurcation 236 normally communicate with the posterior and inferior pancreaticoduodenal bifurcations 242, which arise from the superior mesenteric vessels 244. The balloons 24 are positioned at the origin of the spleen 252, the superior pancreaticoduodenal artery 232, and the superior mesenteric vessels 244, respectively. A pancreatic tumor 254 is shown at the head of the pancreas 256. The inflated mucosal compression balloon 230 traverses all four portions of the duodenum 231.

[0129] Chemotherapy agents to treat the target area (or tumor) can be injected as the pancreas 256 is isolated.

[0130] The outer infusion balloon of the mucosal balloon 230 may be filled with ice water, which has the effect of compressing the duodenal blood vessels, with the secondary effect of minimizing the effects of hypoxia and thereby lengthening the ischemic time, i.e., the "cold ischemic time" is longer than the "warm ischemic time". The low temperature also causes vasoconstriction of the small blood vessels of the duodenum, which protects them from the infusion of cytotoxic drugs. However, blood vessels within the tumor 254 have little or no vasomotor tone due to the absence of smooth muscle and nerves within the vessel walls. As there is a continuous heating effect from the surrounding structures (albeit minimized by the reduced blood supply) to maintain the required low temperature by the balloon 230, continuous infusion of temperature control fluid is necessary to maintain a constant ambient duodenal temperature. Varying the PEEP may increase venous pressure in the liver and portal system by minimizing leakage of chemotherapy into the systemic circulation. Similarly, direct balloon occlusion of the hepatic veins may increase venous pressure.

[0131] Because tumor vasculature does not respond to cold like other tissues, ice water can be used to target tumors while avoiding delivery of therapeutic agents to the duodenum due to the reaction of mucosal tissue to ice water.

[0132] FIG. 11A shows the mucosal balloon 230 in more detail. The multi-channel catheter 192 is passed through the mucosal balloon 230. The mucosal balloon 230 includes an inner inflation balloon 194 that is pressurized and an outer infusion balloon 196 that contains or delivers a vasoconstrictor or cold fluid to the surrounding tissue via an elution port 198. A temperature controlled fluid is injected into the inner balloon 194 via an opening 214 in a channel of the catheter 192, and an inflation fluid (such as air) is injected into the inner balloon 194 through an opening 216 in a second channel of the catheter 192 to inflate and maintain pressure within the inner balloon 194. A therapeutic substance is injected into the space between the inner inflation balloon 194 and the outer infusion balloon 196 through an opening 224 in a third channel of the multi-channel catheter 192. The therapeutic substance is delivered to the surrounding tissue via an elution port 198, and the cold temperature aids in targeting tissue such as tumor tissue.

[0133] FIG. 12 shows three alternative balloon catheter systems 75, 76, 77 arterial occlusion balloon positioning devices that minimize collateral flow and optimize hyperperfusion in the liver. The balloon 78 of system 75 is a flexible, malleable balloon with a lumen 79. The balloon 78 extends longitudinally into the aorta 81 beyond the celiac axis 80 and into the orifices of many small vessels as well as other collateral vessels of the common hepatic artery 84, such as the left gastric artery 82, the splenic artery 83, and the right gastric artery 85 and the right gastroepiploic artery 86. The balloon 87 of system 76 is positioned in the left hepatic artery 88, and the balloon 89 of system 77 is positioned in the right hepatic artery 90. Two separate catheters 91, 92 for each balloon 87, 89 can pass through the inner diameter of the lumen 79 provided by the wider catheter 93 for the balloon 78.

[0134] The balloon positioning device shown in FIG. 12 allows optimal delivery of therapeutic agents by controlling the inflow from the common hepatic artery 84 and from the collateral vessels. The balloon 78 is at least 5 cm long when inflated, but can be up to 40 cm long to occlude as many collateral vessels as possible. It is malleable to fit the original vessel (i.e., the common hepatic artery 84) and protrude partially into the opening of the collateral vessels. The lumen 79, which also defines the central guidewire channel, is larger in diameter than the guidewire channels of the prior art. As a result, the lumen 79 can act like a stabilizing sheath. This allows the balloon 78 and other similar balloons to be used to isolate and occlude vessels that branch off very sharply from the main vessel.

[0135] A common method for inserting a balloon catheter system into an acute vessel involves first inserting a guidewire into the vessel and then inserting the balloon catheter system over the guidewire to the desired location. However, when the guidewire is removed to allow for inflation of the balloon and subsequent injection of a therapeutic agent, the uninflated balloon may slip out of the vessel. This problem can be avoided with a long collateral balloon 78 shown in FIG. 12, whose lumen 79 acts like a stabilizing sheath even when the balloon is uninflated. The guidewire can then be removed and an additional collateral balloon system can then be inserted through the lumen of the long collateral balloon. Alternatively, the guidewire may be removed after the long collateral balloon is inflated. In that case, because the balloon 78 is very compliant and partially protrudes into the opening of the collateral vessel, it creates a larger frictional resistance force and the inflated balloon does not slip out of the vessel even when the guidewire is removed.

[0136] The lumen or central guidewire channel of most prior art balloon catheter systems has a diameter of 0.035 inches or 0.038 inches. However, balloon catheter system 75 using balloon 78 allows for the passage of two separate balloon infusion catheter systems through its lumen, each with a minimum diameter of 0.039 inches.

[0137] The balloon positioning device shown in Figure 13 illustrates the mechanism of isolation and injection of the right upper lobe of a lung 100. Shown are the main bronchus 101 and pulmonary veins 102. Those skilled in the art will readily recognize that any portion or the entirety of any lung may be isolated in a similar manner.

[0138] Non-ventilation of a lung or segment results in atelectasis or collapse of that lung or segment. Pulmonary artery vasoconstriction continues physiologically to shunt blood to the aerated segments. Tumor blood flow is less responsive to vasoconstriction related to their primitive nature and thus the degree of vascular cell activity compared to normal tissue for selective injection purposes. Some of the blood supply is from the brachial artery which is less affected. Associated with atelectasis is increased pulmonary venous pressure which can be assisted by PEEP.

[0139] As a result, treatment of a primary or secondary pulmonary neoplasia in the right upper lung 100 according to the present invention is as follows. (a) Induction of atelectasis by non-ventilation with balloon occlusion of the bronchi; (b) Occlusion of the pulmonary artery 103 at its end 104 and introduction of a superselection catheter 624 having anterior compartment 106 from peripheral venous access by balloon 24; (c) washout of osmotically active substances from the supplying vessels to the isolated lung lobe or segment; (d) application of PEEP; and (e) Infuse aggressive therapy to predicted pulmonary venous pressure.

[0140] The lungs weigh approximately 450 g (right) and 400 g (left) with three lobes on the right side. Predicted mass ratio advantage in a 75 kg patient of approximately 600 times the lobes. Disintegration of the entire tumor can be achieved by injecting only the affected segmental parts, as required by the anatomical distribution of the tumor.

[0141] The balloon positioning device of the present invention can be used for the above applications and the following applications.

[0142] Head and neck lesions This includes tumors of the nose, pharynx and larynx, tongue, floor of the mouth, paranasal sinuses, submandibular glands, and malignant areas of the skin and mucous membranes. The usual location of the origin of treatment is a multi-access port at the origin of the external carotid artery, or it may be from either the groin or the arm, or both. Access devices are implanted bilaterally for structures with blood supply close to the midline. Upon inflow, the main axis is superselected to the target area and controlled with an intravascular or extravascular balloon occlusion system, associated in some circumstances with excellent collateral flow of the proximal and distal balloon systems (the Corelle system is necessary to reduce the pressure corresponding to the critical closure pressure, which is 20 mmHg at the precapillary level).

[0143] Depending on the radiological appearance and the pressure obtained after occluding the main shaft, other branches of the external carotid artery may need to be cannulated. Other adjacent branches of the external carotid artery may need to be controlled, including branches of the subclavian vessels such as the costocervical and thyrocervical canals.

[0144] Spill Control This is accomplished by positional maneuvers such as Trendelenberg, positive and expiratory pressure, and occlusion catheters in the internal jugular, common facial, or anterior jugular veins (which may include intravascular or external vascular occlusion systems). Venous pressure is continuously monitored. Once vascular control is accommodated, plasma proteins and blood are washed out of the target segment and replaced with saline containing the therapeutic agent. Once blood flow is reestablished, collateral and main arterial flow are initially constricted, and venous outflow control is continued for 5-20 minutes to minimize systemic recirculation.

[0145] Vascular isolation and onconic manipulation of pelvic lesions This includes the bladder, rectum, intravaginal lesions, anal canal, prostate, uterus, cervix, lymphatics and other primary or secondary lesions. The catheter origin is a vascular access system located in one or both groins, including the common femoral, superficial femoral system, and venous access systems located in the common femoral, superficial femoral, external and iliac veins. Occasionally, management of the great saphenous vein is required. The actual inflow is controlled at two levels by superselection of the target organ, e.g., the inferior vesical artery for prostatic lesions, and another balloon controlling the origin of the internal iliac system. As these organs receive blood flow from side to side, synchronous control of the contralateral main axis is achieved by superselection, introducing a catheter placed retrogradely across the aortic bifurcation. The pressures monitored are the superselected final pressures converted separately and together on both sides, as well as the concomitant pressures measured unilaterally and then bilaterally. From these measurements, the need for simultaneous contralateral flow control was determined. In some cases, embolization of important collateral vessels may be necessary to adequately reduce inflow pressure.

[0146] Spill Control Outflow control is achieved by simultaneous occlusion of internal, external or selected pelvic veins, iliac veins, or venous outflow. Increased venous outflow pressure is achieved both by postural maneuvers (head up) and application of positive and expiratory pressure (PEEP).

[0147] Oncotic pressure manipulation Blood is removed from the isolated organ being treated and replaced with the appropriate chemotherapy or other form of treatment in a hypo-oncotic solution. To maximize retention, venous pressure remains elevated for 5-20 minutes after resumption of normal arterial flow.

[0148] Isolation and control of fluid flux to the pancreas The main axis arterial inflow is controlled by a common intrahepatic catheter and balloon with superselection of the stomach or superior pancreaticoduodenal artery. In other lesions of the pancreas, the splenic vessels or pancreatic magna may need to be the main axis control system, and occasionally inferior pancreaticoduodenal superselection is required. Collateral control is achieved via a balloon system controlling the stomach, gastroepiploic, hepatic vessels, and splenic artery, depending on the location of the target tumor.

[0149] Venous obstruction This is achieved by positive expiratory pressure (PEEP) and extravascular occlusion devices surrounding the portal vein or possibly the splenic vein. The hepatic vein may also require control via a balloon. This degree of occlusion was controlled percutaneously and radiologically. After vessel isolation, plasma proteins and blood are flushed from the isolated segment and replaced with saline solution containing the chemotherapy agent. Monitoring of collateral circulation as well as axial pressure and radiologically appropriate catheter placement are mandatory. Offline measurement of chemotherapy activity and levels also aids in management, and in some cases cryoinfusion into the stomach and duodenum and the first part of the duodenum can be used to induce reactive vasoconstriction and minimal blood flow, eliminating the need to occlude the surrounding mucosa.

[0150] Vascular isolation and manipulation of lesion flux in the breast Inflow Control The access system is implanted in the arm, either in the brachial vessels or in the groin. In medial lesions, the medial mammary vessels are superselected and occluded, ready for injection. In lateral lesions, the lateral thoracic vessels are superselected. Very rarely, the medial and lateral thoracic fossae may be separated with two balloons, proximal and distal to their origin. Collateral vessels, other vessels not superselected, i.e., internal mammary, medial and lateral thoracic, thyrocervical, temporal cervical trunk, and external thoracic vessels, are occluded if necessary depending on the lesion site. One single or two balloons are sufficient to occlude all collateral flows with adequate decompression.

[0151] spill The outflow cannula occludes all of the subclavian and axillary tributaries from the upper arm. Thus, the external thoracic vein, the internal and external thoracic veins, the veins from the thyro-cervical and jugular trunks, and the internal mammary vein are all occluded simultaneously. Venous and arterial pressures are monitored, both axial and collateral. The arterial system is then occluded, plasma proteins are then flushed out, the outflow balloon is then inflated, and the closed segment is replaced with saline containing the therapeutic agent.

[0152] Reconstruction Release of the collateral balloon is first the primary axial balloon, followed by a venous outflow occlusion system that contracts 5-20 minutes after arterial reconstitution to minimize therapy entering the systemic circulation.

[0153] upper limb The site of origin of the catheter / balloon access system depends on the site of the original lesion and associated lymphatic drainage, and may originate from the groin in some cases. Proximally, an inflow control system is placed on the proximal, i.e. cardiac side of the lesion. This may use double containment of the main shaft or a fistula to control inflow to the lesion.

[0154] Collateral circulation control This may involve proximal and distal balloons in the radial ulnar interstitial or axial selective occlusion of the circumflex humeral vessels depending on the site of the lesion and the results of the pressure transducer recordings.

[0155] Control of positive and expiratory pressure, positioning, and balloon placement on the cardiac side of the lesion, and appropriate tributaries form tributaries of the main venous return shaft. These vessels may be accessory brachial vessels or subclavian vessels. Blood exchange with a biocompatible solution containing the appropriate therapeutic agent. Upon resumption of circulation, the venous outflow can be deflated after a few minutes of inflow control system to minimize recirculation of active therapeutic agent to unwanted areas. The cannulas, catheters and balloons of the above embodiments can be inserted into the body through a single access point into the inflow and outflow vessels, if desired, reducing the number of access points required, making the embodiments easier to perform within the body and reducing injection points. By isolating the extravascular space in this manner and directing the therapeutic substance to the target space while minimizing escape of the therapeutic substance from the target space, the above embodiments may increase the frequency of therapeutic treatments.

[0156] Generally, with reference to Figures 17-24, one embodiment of the present invention relates to a vascular access device with beveled ends to eliminate the formation of dead spaces when a cannula is inserted into a blood vessel.

[0157] 14, 15 and 16 show a single lumen access device of the prior art. The access device 410 shown in FIG. 14 includes a cannula 411 with an adapter port 412, which is connected to a patient's blood vessel 413 at a vertical angle (90°). In this manner, the tip 414 of the stem of the plunger 415 in the cannula 411 can be slid far enough toward the proximal end of the cannula to reach a point where the proximal end of the cannula is level with the wall. This prevents the patient's blood from filling the cavity or lumen 416 of the cannula. As a result, when the cannula 411 is connected to the patient's blood vessel at a vertical angle, there is no dead space between the plunger tip 414 and the vessel 413.

[0158] However, as shown in Figures 15 and 16, when a cannula 417 is connected to a patient's blood vessel at a non-perpendicular angle (e.g., 30°), the regular cylindrical shape of the plunger tip 414 may create a protrusion 418 in the lumen of the vessel (see Figure 15). Alternatively, when the tip 414 is retracted into the cannula to eliminate the protrusion, a dead space 419 is created in which a small amount of blood fills the lumen of the cannula (see Figure 16). Both the protrusion 418 and the dead space 419 may cause or contribute to hemodynamic disturbances or turbulence in the patient's circulatory system that may result in a thrombotic event. The amount of dead space or protrusion, if any, will vary depending on the location of the remote access, e.g., axillary, femoral, iliac, or jugular vein.

[0159] The plunger 420 shown in Figures 19 and 20 for use with the cannula 421 of the present invention shown in Figures 17 and 18 to form a single lumen access device avoids this problem by configuring a chamfered tip 422 or proximal end, so that the angle between the chamfered surface of the tip 422 and the longitudinal axis of the plunger 420 is the same as the angle between the longitudinal axis of the cannula 421 through which the plunger stem passes and the wall of the patient's blood vessel connected by the cannula 421. The plunger 420 stops blood flowing upward through the cannula 421, which could cause thrombosis.

[0160] In one embodiment, the plunger 420 can include an internal lumen (not shown) that extends its entire length. The internal lumen can be blocked by a second plunger. The second plunger can be removed to allow material to be dispensed through the internal lumen.

[0161] 17 and 21, the cannula 421 has a proximal graft end 423 with the same chamfer angle as the plunger tip 422, and a body portion 432 within which the plunger stem 424 seats. When the plunger stem 424 slides down the body portion 432 of the cannula 421, the chamfered surface of the plunger tip 422 is parallel to the patient's vessel wall 428, preventing dead spaces and thereby reducing the possibility of thrombosis. In one embodiment, the cannula 421 includes a Dacron cuff along its length positioned to secure the cannula 421 within the body.

[0162] 18 and 20, the inner wall 425 of the body portion 432 of the cannula 421 is contoured to matingly correspond to the contour of the outer wall 426 of the plunger stem 420. The plunger stem 424 is guided during passage through the cannula 421 so that the chamfered surfaces of the plunger stem and the proximal end or tip 122, 123 of the cannula are properly aligned. If the cannula 421 is connected to the patient's vessel at a non-perpendicular angle and the plunger stem 424 slides down the cavity 427 of the cannula 421, the alignment provided by said corresponding contoured walls 425, 426 ensures that the chamfered surface of the plunger tip 422 is parallel and aligned with the vessel wall 428 to prevent dead space within the lumen 427 of the cannula 421 or protrusion into the vessel lumen. Hemodynamic compromise which may result in thrombosis is prevented by this feature, thereby allowing the access device to be used for longer implantation periods without compromising its safety.

[0163] Figure 22 shows a longitudinal cross-sectional view of cannula 421. Figure 23 shows in cross-sectional detail how connection assembly 429 interconnects proximal graft end 430 of cannula 421 to adjacent end 431 of body 432 of cannula 421. Figure 24 shows in cross-sectional detail how connection assembly 433 connects to distal end portion 434 of body 432 of cannula 421. Connection assembly 433 allows connection to medical delivery devices such as multi-port adapters, pumps, drug sources, radiation sources, etc.

[0164] 21A, an alternative to the use of a cannula 421 with a plunger stem 424 is shown. Instead, a second plunger stem 420A is used to stop blood flow over the lumen of the cannula 421. The second plunger stem 420A includes a passageway 422A along its length. The passageway 422A includes a one-way valve 423A that allows material to be injected into the cannula 421 while preventing the flow of fluids and particulates from the cannula 421 into the passageway 422A.

[0165] The beveled end vascular access device of Figures 14-24 provides an access device for catheters 22 and balloons 24 for isolation and therapeutic treatment of the body or organ regions described above.

[0166] Generally, with reference to Figures 25-30, one embodiment of the present invention relates to a multi-port adapter device for facilitating the insertion of multiple catheters into a single cannula lumen.

[0167] The multi-port adapter 235 shown in Figures 25-27 has a single end port 236 which connects to the connection assembly 233 at the distal end portion 234 of the cannula 421 of Figures 17-24. The adapter 235 has a branch 237 which branches into three tubes, each of which has releasably connected to it an item of external tube 238, 239, 240 having an external port 241, 242, 243 each designed to fit other medical equipment with a male luer lock medical fitting of the type described in U.S. Patent No. 5,047,021. Those skilled in the art will appreciate that alternative connection means can be used to connect the external ports 241, 242, 243 to other medical equipment. Such medical devices may be hemostasis valves (see U.S. Pat. No. 5,195,980; European Patent No. 0875262; U.S. Pat. No. 6,22,1057), medical three-way stopcocks (see U.S. Pat. No. 7,914,495), and syringes (see U.S. Pat. No. 8,652,109). The adapter 235 can also receive the catheter 44 and balloon 45 of a three balloon catheter system, all of which pass through the lumen of the cannula 421 and are used in vascular isolation systems and to improve and enhance communication with the patient's circulatory system.

[0168] As shown in the embodiment of FIG. 25A, the multi-port adapter 225 is shown. The multi-port adapter 225 is flexible and contains four tubes 541, 542, 543, 544 that serve as guides for placement of catheters placed through the different tubes. The flexible tubes 541, 542, 543, 544 allow independent steering for placement of catheters through the feeder connection port 545, where moving one flexible tube only acts on one catheter without affecting the other catheters. The tubes 541, 542, 543, 544 are connected at their distal ends to outer ports 546, 547, 548, 549.

[0169] In another embodiment, the multiport adapter includes more than three tubes. In yet another alternative embodiment, the multiple tubes of the multiport adapter are disposed within a single body to fix the positions of the tubes relative to one another.

[0170] Those skilled in the art will appreciate that alternative connection mechanisms to a male luer lock may be used and still fall within the scope of the present invention.

[0171] The vascular isolation system introduced into the patient's circulatory system is then used to control or occlude blood flow to and / or from an organ or segment thereon through blood vessel 246. Adapter 235 serves as the extracorporeal component of the access device. If multiple small cannulas 44 are fed into cannula 221 via multi-port adapter 235, each of the small cannulas 44 can be directed to a different location to occlude or control blood flow.

[0172] Figures 28-30 show the implantable cannula 421 of Figures 17-24 connected at its distal end to the single end port 236 of a multi-port adapter 247, similar in structure and function to Figures 25-27. Figure 30 shows the cannula 421 connected directly to the wall 228 of a patient's artery or vein. The multi-port adapter 247 also branches to form multiple outer ports with ISO standard fluid / seal connections suitable for vascular applications. All three catheters 244 and balloon 245 pass through the lumen of the implantable cannula 421 via the outer ports of the multi-port adapter 247, and the balloon 245 occludes blood flow through the blood vessel 246.

[0173] Due to the function of the multi-port adapters 235, 247 in facilitating the insertion of additional devices through the lumen of the implantable cannula 421, multiple intravascular devices, such as catheters and balloons (hereinafter "balloon catheters"), may be simultaneously introduced into the patient's vascular system through the implantable cannula. These intravascular devices may then be used simultaneously to administer treatment in a variety of ways.

[0174] Examples of possible treatments include vascular isolation of organs or anatomical regions of the human body, including but not limited to the liver, pancreas, or pelvic organs. In this example, multiple cannulation systems using balloons and catheters are inserted into the patient's vascular system using an implantable cannula 421 and a multiport adapter 235, 247, and then placed in the artery supplying blood to the target area or lesion. The balloons of these balloon catheter systems are then inflated to block or occlude the arterial inflow to the target area and establish an isolated zone of significantly reduced blood inflow. This isolated zone allows the infusion of therapeutic agents to the target area while minimizing systemic exposure. Vascular isolation can be further enhanced using a separate access device to place additional balloon catheter systems in the vein to occlude the venous outflow from the target area or lesion, or using positive end-expiratory pressure (PEEP).

[0175] 31-35, external vascular fistula devices 300, 315, 320 according to one embodiment of the present invention are shown. These fistula devices 300, 315, 320 allow repeated sterile access to the arterial and venous sides of the circulation without impeding blood flow through the fistula devices 300, 315, 320. Furthermore, the connectors can be removed and replaced after arterial and venous control. The device allows blood to be taken without a separate venipuncture. This feature improves the quality of life of cancer patients, especially those undergoing chemotherapy where many tests are required to investigate the hematological effects of chemotherapy. The device allows catheters to be inserted for continuous remote intra-arterial or intravenous infusion for delivery of chemotherapy, stem cells or nanoparticles or antibiotics. The system may also have a catheter loop, for example for real-time recognition of cell types. When a catheter is inserted into the arterial side of the fistula device 300, 315, 320, it immediately recognizes the cell types in real time and traverses the device to return blood to the venous system without impeding the fistula flow. A similar system is the removal of the fistula device 300, 315, 320 via the venous portion and reinsertion into the arterial system via a pump. This is known as remote closed loop recirculation. This is appropriate for certain chemotherapy, especially when detoxification is required. The device is also suitable for repeat diagnostic angiograms, with catheters inserted into the arterial and venous sides as needed. The device construction addresses safety concerns by substantially minimizing the possibility of spontaneous dislocation and tampering.

[0176] In the past, in fistulas, the venous system may have experienced intimal hyperplasia with gradual reduction in blood flow and eventual inclusion, which may or may not be treatable with appropriate angioplasty or surgery. Under such circumstances, the fistula device 300, 315, 320 allows continued access by plugging the tube with a plunger, i.e., the access device can be removed and replaced, if necessary, by the plunger of one or both of the access tubes.

[0177] Alternatively, a previous single intra-arterial device can be converted into a fistula device 300, 315, 320 if access to the opposite side of the circulation is required.

[0178] Referring to FIG. 31, an external fistula device 300 is shown. The external fistula device 301 includes a bridging device 307 designed to connect to an arterial cannula 303 and a venous cannula 305. The bridging device 307 provides a passageway 310 between the arterial cannula 303 and the venous cannula 305 to allow blood to flow. The bridging device 307 includes an engagement means 309 for securing the bridging device 307 to the arterial and venous cannula 303, 305. The engagement means 309 may be threads, clips, snap fits, or other forms that will be understood by those skilled in the art. The passageway 210 of the bridging device 307 sealingly engages the passageway of the arterial and venous cannula 303, 305 at an engagement point 311. The engagement point 311 includes a seal that prevents leakage of blood into or out of the bridging device.

[0179] An access portal 301 is placed on the bridging device 307 to provide access to the arterial and venous cannulas 303, 305. The access portal 301 may be fed directly into the passageway 210 to feed a catheter into either or both of the arterial or venous sides of the fistula connection. This device allows repeated insertion of a catheter through the access portal without compromising the connection between the arterial and venous cannulas.

[0180] Referring to Figure 32, an alternative external fistula device 315 is shown connected to an arterial cannula 303 and a venous cannula 305. Similar to the embodiment of Figure 31, a bridging device 313 with a passageway 310 is used to connect the arterial cannula 303 and the venous cannula 305 together. A connecting device 319 sealingly secures the bridging device 313 to the arterial and venous cannulae 303, 305. The bridging device includes both an arterial access portal 317 and a venous access portal 318. The arterial access portal 317 is used to insert a catheter into an artery through the arterial cannula 303. The venous access portal 318 is used to insert a catheter into a vein through the venous cannula 305. Seals at the tops of the arterial access portal 317 and the venous access portal 318 allow repeated insertion of a catheter through the bridging device without puncturing the artery or vein.

[0181] Figure 33 shows the arterial access portal 317 of Figure 32. A catheter is inserted through passageway 321, through seal 323 and into arterial cannula 303.

[0182] FIG. 34 illustrates an alternative external fistula device 320. As in the previous embodiment, a connection means 327 secures the external fistula device 320 to the arterial and venous cannulas 303, 305. The arterial access portal 322 includes a seal and is configured to receive a catheter for insertion into an artery. The venous access portal 324 includes a seal and is configured to receive a catheter for insertion into a vein. The connection means may be in the form of a threaded screw means, a clip, a clamp, or other methods as will be understood by those skilled in the art. The arterial and venous access portals 322, 324 are arranged for repeated use to allow easy insertion and removal of the catheter. In one embodiment, the T arterial and venous access portals 322, 324 include a pierceable membrane.

[0183] In one embodiment, the external ostomy device is flexible.

[0184] Referring to FIG. 35, an alternative external fistula device 320 of FIG. 34 is shown with arteries and veins catheterized via arterial and venous access portals 322, 324.

[0185] 36 illustrates a scenario in which the alternative external fistula device 320 has been removed from the connection between the arterial cannula 303 and the venous cannula 305 and is connected to the artery 333 and vein 335. A plunger 337 is placed into the venous cannula 305 via the connection means 327 to occlude the venous blood. A multi-port adapter 35 is connected to the arterial cannula 303 to allow insertion of a catheter 44 and a balloon 45. This allows the arterial occlusion and organ isolation for therapeutic treatment using the methods described above.

[0186] 37 and 38, there is shown an external ostomy device 350. The external ostomy device includes an inner tube 351.

[0187] In the embodiment of FIG. 37, a first constriction device 353 engages the outer housing 354 of the external ostomy device 350. A constriction control element 355 passes through the external ostomy device and engages the inner tube 351. The constriction device applies a force to the inner tube, narrowing a smaller diameter portion 356 of the inner tube 351. The constriction device 353 can apply a constriction to the left and right of the inner tube 351. Alternatively, the constriction device 353 can apply a circumferential constriction to the inner tube. The constriction device 353 can be applied by threads, hydraulics, pneumatic means, or other methods as would be understood by one of skill in the art.

[0188] In the embodiment of Figure 38, like elements present in Figure 38 are described with the same numbers. A second constriction device 357 is disposed about the outer housing 354 of the external ostomy device 350. The second constriction device 357 constricts both the outer housing 354 and the inner tube 351 at a constricted region 359 of the external ostomy device 350. The constriction can be either side-to-side or circumferential and is controlled with a control element 361, which may be a screw, hydraulic, pneumatic means, or as would be understood by one of ordinary skill in the art.

[0189] In the embodiment of Figures 38 and 39, a narrowed inner tube 351 controls the rate of fluid flow through the stoma.

[0190] Modifications and variations of the embodiment Various additions, modifications and substitutions of design and construction can be made without departing from the spirit and scope of the present invention.

[0191] Modifications and variations as would be apparent to one skilled in the art are deemed to be within the scope of the present invention. The present invention should not be limited in scope by any of the specific embodiments described herein. These embodiments are for illustrative purposes only. Functionally equivalent products, formulations and methods are clearly within the scope of the invention described herein.

[0192] References to descriptions of positions such as lower and upper should be interpreted in the context of the embodiments shown in the drawings and should not be interpreted as limiting the invention to a literal interpretation of the terms, but rather as understood by one of ordinary skill in the art.

[0193] Throughout this specification, unless the context requires otherwise, the use of "comprise" or "comprises" or variations such as "comprising" will be understood to mean the inclusion of a stated integer or group of integers but not the exclusion of other integers or groups of integers.

Claims

1. 1. A vascular access device for providing long term vascular access for infusion of therapeutic agents and / or insertion of one or more intravascular devices into a blood vessel, comprising: a beveled cannula having an interior wall defining a lumen, the beveled cannula end being configured to directly connect to a wall of the blood vessel at an angle such that the lumen of the cannula opens in fluid communication with blood flow within the blood vessel; and a removable plunger positioned for insertion into the lumen of the cannula and to occlude and seal the lumen of the cannula, wherein the removable plunger includes an outer wall that occludes a lumen of the beveled cannula when the removable plunger is inserted into the lumen of the beveled cannula, and a beveled end, the beveled end interfaces with blood flow within a blood vessel when the removable plunger is fully inserted into the beveled cannula to occlude and seal the lumen of the beveled cannula; the beveled end of the removable plunger is positioned parallel to and aligned with a wall of the blood vessel; the beveled end of the removable plunger is positioned so as not to protrude into blood flow within a blood vessel to occlude the beveled cannula when the removable plunger is fully inserted into the lumen of the beveled cannula; and an inner wall of the chamfered cannula defining the lumen configured to interact with an outer wall of the removable plunger such that the removable plunger cannot rotate within the chamfered cannula when the removable plunger is fully inserted into the lumen of the chamfered cannula; Vascular access devices.

2. 10. The vascular access device of claim 1, wherein the beveled end of the removable plunger is positioned so that when the plunger is fully inserted into the beveled cannula to plug and seal the beveled cannula, the beveled end of the removable plunger does not protrude into a blood vessel.

3. The vascular access device of claim 1 , wherein the chamfer angle of the chamfered cannula end and the chamfered end of the removable plunger are the same.

4. 2. The vascular access device of claim 1, wherein an inner wall of the chamfered cannula defining the lumen is cross-sectionally shaped to matingly correspond to an outer wall of the removable plunger such that mating correspondence with the inner wall of the chamfered cannula prevents the removable plunger from rotating.

5. The vascular access device of claim 4 , wherein one or more protrusions on an outer wall of the removable plunger are positioned to be received within corresponding recesses in an inner wall of the beveled cannula.

6. 5. The vascular access device of claim 4, wherein a mating counterpart of an inner wall of the cannula and an outer wall of the removable plunger are positioned such that when the removable plunger is fully inserted into the cannula, the beveled cannula end is parallel and aligned with the beveled end of the plunger.

7. The vascular access device of claim 1 , wherein the beveled cannula end is configured as a graft end configured and arranged to engage and connect with a blood vessel via a vascular graft.

8. The vascular access device of claim 1 , wherein an end of the beveled cannula opposite the beveled end includes a connection assembly arranged to connect to a medical delivery device.

9. The vascular access device of claim 8 , wherein a connection assembly is positioned to connect the beveled cannula body portion and a medical delivery device.

10. The vascular access device of claim 9 , wherein a connection assembly is positioned to connect with an external hub or connection element of the removable plunger to seal the beveled cannula from an external environment.

11. 10. The vascular access device of claim 9, wherein the medical delivery device includes a multi-port adapter, a pump, a drug source, and a radiation source.

12. 10. The vascular access device of claim 9, wherein the medical delivery device is configured for infusion of medication, introduction of one or more intravascular devices, and / or extraction of bodily fluids.

13. 10. The vascular access device of claim 1 adapted for chronic use to extract and / or return bodily fluids from and / or to a blood vessel.

14. The vascular access device of claim 1 , wherein the removable plunger comprises an internal lumen adapted to be occluded by a second plunger.

15. The vascular access device of claim 1 , wherein when the beveled cannula is plugged and sealed to the removable plunger, the beveled surfaces of the beveled cannula and the removable plunger are parallel to the wall of the blood vessel.

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