PORTAL CIRCULATORY ASSIST DEVICE AND USES THEREOF

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to the field of liver pathophysiology and treatment for portal hypertension. More specifically, the present invention discloses a portal circulatory assist device that can be used for the treatment of portal hypertension (PH).

Description of the Related Art

Blood is contained in blood vessels with clearly defined boundaries and walls in most of the organs. However, the liver that has a dual blood supply and also has a sponge-like structure (sinusoids) that permits direct contact of the blood plasma with the liver cells (Fig. 1). Like most organs, it receives arterial oxygenated blood via branches from the aorta, which constitutes only about 25% of the 1.5 L/min total hepatic blood flow. The remainder (75%) comes from the portal vein, which drains blood from the small and large intestines, stomach, spleen, pancreas and gall bladder.

Sinusoids receive blood from both the hepatic artery and the portal vein before it is drained into branches of the hepatic vein and enters the inferior vena cava to return to the heart. The purpose of this elaborate system is to allow the liver to modulate the content of nutrients (e.g. glucose, amino acids) and maintain stable blood concentrations as well as "detoxify" the blood of substances such

as ammonia produced by bacteria in the large intestine.

The portal vein is formed behind the neck of the pancreas by the union of the superior mesenteric vein and the splenic vein (Fig. 2). Portal hypertension (PH) represents an increase of the hydrostatic pressure within the portal vein or its tributaries and is defined as an increase in the pressure gradient between the portal vein and hepatic veins or inferior vena cava (IVC). Thus, portal hypertension may be defined as a portal pressure gradient of 12 mm Hg or greater and is often associated with varices and ascites. Although many conditions are associated with portal hypertension, cirrhosis is the most common cause of portal hypertension. The frequency of portal hypertension is therefore generally related to the frequency of cirrhosis. In the United States, for example, alcohol is the most common cause of cirrhosis and is found in 2 to 10% of autopsies.

The two most important pathophysiological factors contributing to portal hypertension can be predicted from an extrapolation of Ohm's law to fluid flow: P=F x R, where P is the pressure gradient through the portal venous system, F is the volume of the blood flowing through the system and R is the resistance to flow. Changes in either F or R can thus, affect pressure, leading to portal hypertension. Initially, there is an increase in vascular resistance due to reduction in sinusoidal radius (in case of cirrhosis, but it can also occur presinusoidally, or postsinusoidally in portal hypertension due to other causes). This reduction has both a fixed component due to scarring and fibrosis as well as a dynamic component, due to increases in blood flow that further contributes to portal hypertension. When deprived of portal venous blood and hormones such as insulin and glucagon, the liver may atrophy, resulting in increased hepatic dysfunction.

Thus, the mortality and morbidity of portal hypertension is related to: (1) the underlying cause of portal hypertension, e.g., cirrhosis, portal vein thrombosis and/or splenic vein thrombosis and veno-occlusive disease; (2) complications of portal hypertension. Hemorrhage due to esophageal varices or rectal varices, is a major complication of portal hypertension (Fig. 3).

Mortality rates in adults with cirrhosis vary and are 30-60% for each esophageal varices bleeding episode. Another complication is excess fluid in the peritoneal cavity, ascites, which can become very large and produce discomfort and respiratory distress, or become infected (spontaneous bacterial peritonitis) (Fig. 4).

Current treatment options for portal hypertension are mainly palliative and aimed at complications. This includes endoscopic treatment of varices (e.g. banding) or treatment of ascites (diuretics or fluid drainage). Ideally, therapy for portal hypertension should decrease portal pressures and therefore, beta blockers are commonly used in such therapy. However, adequate reduction of portal pressures is generally difficult to achieve and adequately maintain. Another way to lower portal pressure is to shunt the blood away directly into hepatic veins, bypassing the liver sinusoids. This is most commonly done by interventional radiologists using a procedure called transjugular intrahepatic porto-systemic shunt (Fig. 5). Like most shunts, this is associated with loss of liver detoxification and consequently, encephalopathy. Further, transjugular intrahepatic porto-systemic shunt stents are prone to occlusion. Hence, shunting is generally reserved for complications of portal hypertension that are either refractory (e.g. tense ascites) or not amenable (e.g. gastric varices) to medicinal or endoscopic therapy.

However, the current therapies for portal hypertension have several limitations. First, most therapies are essentially palliative and directed towards complications. Second, pharmacological therapy is generally inadequate to achieve robust reductions in portal pressure. Third, shunting worsens encephalopathy. Fourth, no method corrects the reduction in portal blood flow to the liver parenchyma, and therefore, will not reverse hepatic atrophy and loss of regenerative capacity.

Thus, prior art is deficient in a therapy for portal hypertension that will reduce portal pressure and increase portal blood flow to the sinusoids. The present invention fulfills this long-standing need and desire in the art.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, there is provided a portal circulatory assist device. Such a device comprises a means for developing a partial pressure vacuum on the inlet side to reduce portal pressures and increase portal blood flow to the sinusoids.

In another related embodiment of the present invention, there is provided a method of preventing or treating complications of portal hypertension in an individual in need of such treatment. Such a method comprises the step of implanting the device described supra in the individual.

In yet another related embodiment of the present invention, there is provided a method of reducing portal pressure and improving portal blood flow through the liver of an individual. Such a method comprises implanting the device described supra in the individual, where the device provides forward flow of the blood to the liver and decreases backward pressure in the portal circulation, thereby reducing portal pressure and improving portal blood flow through the liver of the individual.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a section of a liver lobule with the hepatic veins, hepatic cells, liver sinusoids and branches of the portal vein and hepatic artery (From: Porth's Pathophysiology: Concepts of Altered States, Seventh Edition, Lippincott Williams and Wilkins).

Figure 2 shows a schematic representation of the portal circulation. Blood from the gastrointestinal tract, spleen and pancreas travels to the liver by way of the portal vein before moving into the vena cava for return to the heart. (From: Porth's Pathophysiology: Concepts of Altered States, Seventh Edition, Lippincott Williams and Wilkins).

Figure 3 shows relative obstruction to blood flow in the portal vein that causes opening up of collateral veins and development of varices. (From: Porth's Pathophysiology: Concepts of Altered States, Seventh Edition, Lippincott Williams and Wilkins). Figure 4 shows development of ascites in portal hypertension.

(From: The John Hopkins Division of Gastroenterology Website).

Figure 5 is an illustration of the transjugular intrahepatic portosystemic shunt procedure. Figure 5A shows creation of conduit between systemic (hepatic vein) and portal circulations within the liver under fluoroscopy. Figure 5B shows placement of stent and creation of portosystemic shunt. (From: The John Hopkins Division of Gastroenterology Website).

Figure 6 is a schematic representation of the portal circulation and the effects of the portal circulatory assist pump. The left hand side of the figure is a schematic of the portal circulation in untreated portal hypertension showing high pressure throughout the vein. The right hand side of the figure illustrates the effects of a pump in the pre-sinusoidal portal vein. The high pressure is now confined to a small area. The parts of the portal system inferior to the pump are now low-pressure again, allowing decompression of varices and prevention of other complications.

Figure 7 shows one embodiment of a "para-axial" pump for portal circulation assist. The pump itself is implanted inside the body but has external leads for power and control.

Figure 8 shows another embodiment of a pump for portal circulation assist that uses an "intra-axial" device. External leads for power and control are also shown.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a portal circulatory assist device for portal hypertension that develops a partial pressure vacuum on the inlet side to reduce portal pressure and increase portal blood flow to the sinusoids.

As discussed supra, the factors contributing to portal hypertension are change in either the volume of blood flowing through the portal venous system and/or change in resistance to the flow. Traditionally the problem with portal hypertension has been approached as one in the portal vein proper and has led to attempts to reduce either portal flow or resistance resulting in an overall reduction of pressure. However, the real problem is one of reduced flow in the sinusoids. Therefore, the logical approach would be to increase the forward flow in the portal vein. In the absence of any intrinsic mechanism to generate such flow, this can be achieved with a fluid pump system. The portal system is particularly amenable to this since it has no valves.

As described herein the invention provides a number of therapeutic advantages and uses, however, such advantages and uses are not limited by such description. Embodiments of the present invention are better illustrated with reference to the figures however, such reference is not meant to limit the present invention in any fashion. The embodiments and variations described herein in detail are to be interpreted by the appended claims and equivalents thereof.

The Device - General Features

The portal circulatory assist device disclosed herein is a pump. This pump can provide several advantages. First, as the pump rotates, it develops a partial vacuum on the inlet ("suction") side, permitting blood to flow into the pump inlet as well as decreasing pressure in the pre-pump venous system (i.e. all of the splanchnic vascular bed). Second, as the pump ejects this blood, it does not necessarily create pressure in front of it. It merely moves it, causing the flow. The actual pressure is created by the load on the blood as determined by the sinusoidal resistance. Thus, the only region of increased pressure in the portal vein is now between the pump and liver. Therefore, this pump will not only reduce pressure in the pre-pump portal vein but also increase flow through the sinusoids (Fig. 6).

The use of such a pump has the following benefits. First, the

portal system is decompressed and complications such as varices and ascites are avoided. Second, nutritious portal flow is restored to the liver parenchyma reversing atrophy. Third, the ability of the liver to detoxify portal blood is restored, avoiding encephalopathy. Several different types of blood pumps are currently in use for cardiac patients, both for short-term care (as a bridge to transplantation), as well as providing a long-term option for patients with refractory heart failure. The various devices include extracorporeal and intracorporeal, pulsatile and nonpulsatile designs. Any one or more of these designs can be incorporated into an ideal portal circulatory assist device. Figures 7 and 8 illustrate two such specific embodiments although many more can be envisioned.

Figure 7 shows an implantable para-axial pump 10 for portal circulation that has external leads for power and control. This pump 10 has a diameter in the range of 1-10cm (range) is placed in subcutaneous or peritoneal space. The pump 10 is connected to an electrical source 15 via a driveline 14. Placed within this driveline is skin portal 13. Additionally, there is a cannula 11 comprising of 11 A and 11 B attached to the pump 10 for outflow and a cannula 12 comprising 12A and 12B attached to pump 10 for inflow.

Figure 8 shows an intra-axial pump 16 placed via the transjugular route like the stent in a transjugular intrahepatic porto-systemic shunt procedure. The intra-axial pump is at least 15F (5mm) and not more than 48F (16mm) in diameter. Since the portal vein is usually greater than 10-12.5mm in diameter, pump sizes of 30-36F can be easily placed in the vein. The intra- axial pump 16 is also connected via drive 14 to an electrical source 15. Placed within the drive 14 is a skin portal 13.

In general, the device disclosed herein may be defined as any device that facilitates the flow of portal blood towards the liver. Such a device may include any kind of pump based on any mechanism and material. For instance, the pumps designed to be useful as portal circulatory assist device are not limited to but may include trans-axial or intra-axial, pulsatile or nonpulsatile, continuous or intermittent flow, peristaltic pump or centrifugal or impeller-based pumps. Additionally, the device or the pump may also comprise

a feedback option to monitor the intravascular pressure and prevent fluctuations (either too much or too little pressure) and collapse of the vascular walls behind the pump. Furthermore, the pump may be regulated to maintain a flow in the desired range that is optimal for liver perfusion (typically in the range of 40-90ml/min/100ml as measured by MRI studies) (Annet et al., 2003). The pump may be implanted using the least invasive method that is available. For instant, the intra-axial pump may be placed via a transjugular route like the stent in a transjugular intrahepatic porto-systemic shunt procedure. Other methods of placement are not limited to but may include percutaneous, surgery (laproscopy or traditional) or endoscopy (transluminal) means.

The present invention is directed to a portal circulatory assist device, comprising: means for developing partial pressure vacuum on the inlet side to reduce portal pressure and to increase portal blood flow to the sinusoids. Generally, such means may comprise a rotating blood pump effective to develop the partial pressure vacuum to permit blood to flow into the pump inlet and to decrease pressure in the pre-pump venous system with a driveline. The pump ejects blood without creating pressure and permits an increased blood flow to the sinusoids. Additionally, the pump may be present by itself or may be attached to two separate cannulae. When attached to cannulae, one of the cannulae may allow flow of the blood into the pump and the other cannula may allow the blood to flow from the pump into the vein. Additionally, the pump may comprise a means to monitor the intravascular pressure, where the monitoring may prevent fluctuations in pressure and may prevent collapse of vascular walls behind the pump. The flow within the pump may be in the range of 40-90 ml/min/100ml.

Furthermore, the pump may be implanted in the body or placed in the portal vein or its branches. The means by which the pump may be implanted are not limited to but may include percutaneous, surgical, radiological or endoscopic means. Examples of such a pump may include but are not limited to a trans-axial pump, an intra-axial pump, a pulsatile pump, a non-pulsatile pump, a continuous flow pump, an intermittent flow pump, a peristaltic pump, a centrifugal pump or a impeller-based pump. The pump

described herein may be 5mm-16mm in diameter. The driveline in the device described herein may be attached to the pump at one end and to an electrical source at the other end. This driveline may also comprise a skin portal.

The present invention is further directed to a method of preventing or treating complications of portal hypertension in an individual, comprising the step of implanting the device described herein in the individual. Such a device may provide forward flow of the blood to the liver and decrease backward pressure in the portal circulation, thereby reducing portal pressure and improving portal blood flow through the liver. Additionally, the complications of portal hypertension are not limited to but may include hemorrhage due to esophageal varices or rectal varices, ascites or a combination thereof. Examples of the individual benefiting from such a device may include but is not limited to the individual suffering from cirrhosis, portal vein thrombosis, splenic vein thrombosis, veno-occlusive disease, or a combination thereof. The present is still further directed to a method of reducing portal pressure and improving flow through the liver of an individual, comprising implanting the device described herein, where the device provides forward flow of the blood to the liver and decreases backward pressure in the portal circulation, thereby reducing portal pressure and improving portal blood flow through the liver of the individual. The examples of the individual who may benefit from such a method are the same as those described supra.

As used herein, the term, "a" or "an" may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words "a" or "an" may mean one or more than one. As used herein "another" or "other" may mean at least a second or more of the same or different claim element or components thereof.

As used herein, the term "cannula" may mean a flexible tube that is inserted into the portal vein and allows the blood to flow into the pump (inflow) at one end and allows the blood to flow back (outflow) at the other end. As used herein, the term "driveline" may refer to components of device that transmit power from electrical source to pump.

One skilled in the art will appreciate readily that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends and advantages inherent herein. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.

The following references were cited herein:

1. Porth's Pathophysiology: Concepts of Altered States, Seventh Edition, Lippincott Williams and Wilkins.

2. The John Hopkins Division of Gastroenterology website: http://hopkins-ai.nts.jhu.edu 3. Annet et al. Radiology 2003 Nov, 229(2): 409-414.

Any patents or publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. Further, these patents and publications are incorporated by reference herein to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.