WO2000043055A1

WO2000043055A1 - Low-prime cardiopulmonary bypass circuit

Info

Publication number: WO2000043055A1
Application number: PCT/US2000/001506
Authority: WO
Inventors: Clifford Ball; Bryan P. Byerman; Delos M. Cosgrove; Robert C. Foster; Patrick M. Grady; James R. Trickett; Jeffrey J. Valko; Rachael K. Weichel
Original assignee: Edwards Lifesciences Corporation; The Cleveland Clinic Foundation
Priority date: 1999-01-21
Filing date: 2000-01-21
Publication date: 2000-07-27
Also published as: AU3348000A; WO2000043055A9

Abstract

The present invention relates to apparatus and methods for passing a patient's blood from his body to a location outside the body and then returning it to the patient, in a manner that reduces inflammation and reduces the dysfunction of the immune and hemostatic systems associated with extracorporeal circulation. In particular, the invention relates to the use of a low-prime cardiopulmonary bypass circuit to effect inhibition of injury to a patient's circulatory system, in order to accomplish such therapeutic prophylaxis.

Description

LOW-PRIME CARDIOPULMONARY BYPASS CIRCUIT

FIELD OF THE INVENTION

The present invention relates to devices (or apparatus) and methods for passing a patient's blood from his/her body to a location outside the body and then returning it to the patient, in a manner that reduces inflammation and reduces the dysfunction of the immune and hemostatic systems associated with extracorporeal circulation. In particular, the invention relates to the use of a low- prime cardiopulmonary bypass circuit to effect inhibition of injury to a patient's circulatory system, in order to accomplish such therapeutic prophylaxis. BACKGROUND OF THE INVENTION

Numerous techniques have been developed for circulating the blood of a patient outside the body in an "extracorporeal" circuit and then returning it to the patient during a surgical procedure. For example, in dialysis for patients with kidney failure, blood is circulated extracorporeally and contacted with a large membrane surface separating the blood from a dialysate solution, and urea and other blood chemicals are migrated across the membrane to cleanse the blood, which is then returned to the patient. In ex vivo organ perfusion, such as liver perfusion for patients with liver failure, blood is circulated extracorporeally and perfused through a donor organ, typically a pig liver in the case of liver perfusion, before returning it to the patient. In cases of thermal treatment, blood is circulated out of the body and through a heat exchanger and returned to the body. In heart surgery, either or both ventricles of the heart may be isolated and surgically repaired while making use of the patient's lungs during the surgery. In left monoventricular surgery, the left ventricle is isolated for surgery by cannulating the left atrium into an extracorporeal circuit which pumps the blood into a cannulated femoral artery or other arterial source to the arterial bed. In biventricular surgery, the right ventricle is isolated for surgery by cannulating the right atrium and feeding the blood extracorporeally to the pulmonary artery, and the left ventricle is isolated by cannulating the left atrium and feeding the oxygenated blood extracorporeally to a femoral or other artery for perfusion of the arterial bed.

Another example of extracorporeal circulation is cardiopulmonary bypass ("CPB"), the procedure of mechanically bypassing both the heart and lungs to allow the whole heart to be isolated for surgical repair. A CPB machine, consisting of a number of independent and discrete components linked together by plastic tubing, assumes the function of the heart and lungs by oxygenating the blood of the patient, returning the oxygenated blood to the body, and pumping it through patient's circulatory system.

For example, in CPB, the patient's inferior and superior vena cava are cannulated and the blood is ducted from the patient to a venous reservoir in the CPB circuit. From the venous reservoir, this circuit then connects to a pump which circulates the blood. The next CPB element is the heat exchanger where the temperature of the blood can be altered and controlled. This device is often coupled in parallel to the oxygenator. The blood is then oxygenated by being pumped through a gas exchange reservoir ("oxygenator") where oxygen is added and carbon dioxide is removed from the system. The last element of the extracorporeal circuit is typically a filter used to eliminate particulate matter accumulated in the extracorporeal system. The oxygenated blood then enters the body of the patient through another cannula in the arterial system. Other elements which are part of the CPB system but operated in parallel to the circuit include systems used to retain suctioned blood in the operative field to return to the patient (vent and sucker) and systems to filter and concentrate the cells also to be given to the patient through the CPB circuit (hemoconcentrators).

Cardiopulmonary bypass (CPB) surgery requires a perfusion system, or heart-lung machine, to maintain an adequate supply of oxygen in the patient's blood during the surgery. Examples of such perfusion systems are shown in Figures 1-4. For example, looking at Fig. 1, a venous return cannula is inserted in one of the veins leading directly to the heart and receives the "used" blood for rejuvenation through the perfusion system. The blood flows along a conduit (typically a transparent flexible tube) to a venous reservoir which may be combined with a cardiotomy reservoir. Commonly, a suction apparatus extracts excess fluid from the chest cavity during the operation and diverts the fluid, which may contain bone chips or particulates, into the top of the cardiotomy reservoir. The cardiotomy suction device pulls pooled blood from the chest cavity using a vacuum which may be generated by a roller pump, for example. In addition, a vent cannula may be positioned in the heart for suctioning other fluids during the operation, those fluids also being directed to the cardiotomy reservoir through a roller pump. The fluid entering the cardiotomy reservoir is first filtered before being combined with the venous blood.

A venous reservoir and a cardiotomy reservoir are typically included in a cardiopulmonary bypass circuit. The venous reservoir accommodates and regulates variations in blood volume. The venous reservoir commonly consists of either a flexible bag or hard shell vessel having a blood inlet for receiving an inflow of blood, and a blood outlet for subsequent outflow of blood into the attendant portions of the bypass system (e.g. into the pump and/or membrane oxygenator). In surgical applications wherein the above-described cardiotomy reservoir component is employed, the blood inlet of the venous reservoir receives a mixture of (a) venous return blood obtained directly from the right atrium or vena cava of the patient, and (b) filtered cardiotomy blood which has been suctioned from the operative site and preprocessed (e.g. filtered and defoamed) in the separate cardiotomy reservoir/filter. (As noted previously, some CPB systems employ combined venous/cardiotomy reservoirs, which systems are also within the scope of the present invention.)

The venous reservoir is desirably adapted to accommodate fluctuations in pooled blood volume brought about by relative variations in the rate of blood inflow (e.g. changes in venous return or cardiotomy blood volume) and/or the rate of blood outflow (e.g. changes in the rate of the bypass system pump). One means of accommodating such fluctuations in pooled blood volume is to provide a flexible bag-like venous reservoir which is capable of expanding and contracting in accordance with the normal variations in pooled blood volume with the reservoir.

The cardiotomy reservoir reclaims blood drawn from the surgical site by defoaming and filtering the blood to remove foreign matter. More particularly, during a cardiopulmonary bypass operation, it is essential to suction away the various fluids, which fluids may contain, for example, air, debris such as bone chips, blood, saline solution, liquids applied to the heart and the like. This must be accomplished as quickly and efficiently as possible without causing injury to the patient. Such "reclaimed" fluids are generally termed cardiotomy blood and require filtration prior to reinfusion. A cardiotomy reservoir is normally used in conjunction with relatively high vacuum suction in order to remove and collect cardiotomy blood and other liquids as quickly as possible. Typically, before the patient's blood is oxygenated and returned to the body, blood which has been defoamed and filtered in a cardiotomy reservoir is combined with blood extracted from the patient's venous system.

To simplify the components and connections and to reduce the volume of such extracorporeal blood circuits, it has been proposed that cardiotomy blood and venous blood be combined in a single reservoir which replaces the separate cardiotomy reservoir and separate venous reservoir formerly used and that the combined fractions be directly fed to an oxygenator.

This creates some problems, however, since the flow rate of venous blood into the extracorporeal circuit is several times (on the order of three times) greater than the flow of cardiotomy blood. Moreover, the venous blood is substantially clean requiring only minimal defoaming and filtration. When venous blood is subjected to the same filtration as that used for cardiotomy blood, it is detrimental to the blood cells. Indeed, the depth filter media used in modern cardiotomy reservoirs can damage healthy cells, especially under high pressures and, therefore, blood obtained directly from a venous shunt which is uncontaminated by foreign matter should not be forced through such filter media, if possible. Thus, the combining of cardiotomy blood and venous blood into a single reservoir not only fails to correct problems associated with typically high prime volumes, it introduces additional problems - e.g., the stagnation of blood or the entrapment of gas bubbles in the blood. Returning to the discussion of "conventional" CPB systems, in contrast to the suction within the cardiotomy and vent lines, the venous return cannula is positioned in a vein in contact with a relatively constant stream of blood. Thus, the conventional venous drain method is to place the reservoir under the patient and allow blood to drain by gravity. This method is facilitated by the relatively large-bore venous return cannulas of 36 French OD or more used in open heart surgery. A major drawback to the gravity drain, however, is that the system must be primed before a return pump can take effect. The only means of enhancing venous return is by increasing the head height between the cannula and the venous reservoir. This is achieved either by lowering the location of the reservoir (which is limited by the floor) and/or by raising the level of the operating table, which is also limited.

In general, blood is pumped by a centrifugal or roller pump, for example, from the venous/cardiotomy reservoir through a blood oxygenator and back to the patient. The pump assumes the pumping task of the heart and perfuses the patient's circulatory system. The oxygenator typically directs a flow of blood across a plurality of permeable filters which are capable of transferring oxygen to and carbon dioxide from the blood. The oxygenator also usually includes a heat exchange system to regulate the extracorporeal blood temperature. Before reaching the patient, the blood may pass through a temperature control monitoring system and along a conduit through an arterial filter and bubble detector, before reaching an arterial cannula positioned in a main artery of the patient.

The perfusion system is typically mounted on a table positioned some distance form the operating table. Thus, the conduits leading from the patient to the various components of the perfusion system contain a significant volume of blood. In addition, the various components such as the venous cardiotomy reservoir and arterial filter also require a certain volume of blood to function properly. All of these components put together require a certain "prime" or volume of blood from the patient (or a blood substitute) to function. The prime volume in some instances may be defined as the volume of blood that is outside the patient, or extracorporeal. In other instances, the prime may include blood substitutes or biocompatible (e.g. blood-compatible) physiological fluids in said extracorporeal circulation. The need for a large hemodilutional prime volume (HPV) is contrary to the best interests of the patient who is undergoing the surgery and is in need of a full supply of fully-oxygenated blood. Therefore, a significant amount of research and development has been directed toward reducing the hemodilutional prime volume within CPB systems, with limited success. The typical CPB system (or circuit) comprises a complex interlinkage of numerous separate components, including, for example, a pump, oxygenator, heat exchanger, arterial blood filter, and dynamic reservoir. The components are usually connected together by lengths of tubing or "lines" (generally a synthetic material, e.g. plastic) through which blood and other fluids flow. The disadvantages of the present, conventional circuits are numerous and include the requirement for an inordinately large priming volume. Priming volume refers to the amount of blood or blood substitute required to fill the device prior to use. For example, even for a young child, the typical prime volume is about 1200cc, which is not an insubstantial amount. For a full-size adult patient, the typical prime volume is about 1600cc - 2 liters. When compared with the normal volume of blood circulating in a patient's cardiovascular system, the use of such large amounts of blood to prime a CPB system is arguably risky to the patient's health. It is thus quite is important to reduce the introduction of donor blood to the patient for a number of reasons, as will be discussed at greater length hereinbelow. Suffice it to say for the moment that the motivation for minimizing prime volume and thus reducing the need for the introduction of donor blood ranges from expanding the options for patients whose religious beliefs cause them to refuse transfusion to minimizing the danger of exposing any patient to infectious diseases such as hepatitis and HIV infection.

The economic costs of blood and fluid are also important reasons to reduce the priming volume of extracorporeal circuits. Normal adults can typically only tolerate the loss of 500 to 1,000 ml (milliliters) of blood during operation but cannot sustain losing an additional 1 ,250 to 2,500 ml to prime the device. It is therefore common for patients undergoing open heart surgery to receive multiple transfusions of blood. The cost of filling the priming volume with a mixture of blood or blood substitutes can be as much as $1,000 (blood processing, saline solution, plasma, hydroxyethyl starch cost between $40 and $330 for each 500 ml required).

While some have proposed to reduce the hemodilutional prime volume via reducing the volume of some of the components of the CPB system - e.g. reducing the size of the venous cardiotomy reservoir or the blood oxygenator - there is a limit to the amount of prime volume reduction that can be reduced in this manner without impairing or sacrificing the functionality of such devices.

Similarly, positioning the perfusion setup closer to the patient has been proposed as a means of reducing prime volume (see e.g. U.S. Pat. No. 5,300,015 to Runge). The Runge circuit eliminates conventional blood reservoirs and utilizes a pulsatile pump which compresses a flexible blood conduit to urge blood through that conduit. While this does appear to reduce the prime volume somewhat, the system is inherently hazardous to the patient, as the perfusionist cannot view a reservoir level to assist in the regulation of the proper flow of blood to and from the patient. Another type of perfusion system employing a vacuum in conjunction with gravity for venous drainage has also been proposed (see, e.g., published European patent application no. EP 0 786 261 A2 of Nomura and Hiroura). The application describes a system in which a wall vacuum generates a negative pressure within a main reservoir, which is connected to a plurality of individual suction reservoirs and to a venous return line, but gravity is still relied upon to draw blood into the main reservoir. Cardiotomy and other suction lines from the patient are attached to the individual suction reservoirs, and the vacuum pressure within each one of the suction reservoirs can be regulated independently. The system further includes a centrifugal pump under the main reservoir for pumping blood through the rest of the CPB system and to the patient. However, a significant amount of hardware is needed for this system to regulate and connect the various pressure chambers, making the system expensive to operate and maintain and impractical from a variety of perspectives, including impaired ability to monitor and correct fluctuations in the steady flow of blood to and from the patient. Moreover, it uses a combination of gravity drainage and negative pressure which appears to make the system difficult to operate and stabilize. Still others have proposed reducing hemodilutional prime volume by slowly draining the cardiopulmonary bypass circuit into a cell-saving device before the initiation of bypass (see, e.g., Shapira et aλ.,Ann. Thorαc. Surg. 65(3): 724-30 (1998)) or by using of retrograde autologous priming (RAP) (see, e.g., DeBois, Proc. Am. Cαrdiovαsc. Perfusion 18: 81-83 (1997); Cromer and Wolk, Perfusion 13: 311-313 (1998)). However, the foregoing methods still require the use of a significant amount of the patient's blood as prime for the circuit, which may trigger a host of problems (discussed below) and the clinical outcomes of patients on which such techniques are used are not noticeably improved (see, e.g., Shapira et al., itf. (1998)).

Thus, a practical means of reducing the hemodilutional prime volume - without compromising the health and safety of the patient - would be of immense benefit to patients and practitioners alike. With the advent of the within-disclosed low-prime circuit and its attendant components and methods, it is believed that such practical means have now been achieved. SUMMARY OF THE INVENTION

Therefore, in one embodiment, the invention discloses an extracorporeal blood circulation system comprising a circuit having one or more components through which a patient's blood circulates, the one or more components including an inlet line adapted to receive blood from the patient; an outlet line adapted to return blood to the patient; a fluid circuit for fluid communication between the inlet and the outlet line; a reservoir for receiving blood from the venous system of the patient; a source of vacuum; a vacuum conduit extending between the source of vacuum and the reservoir and configured to create a negative pressure within the reservoir; and a pressure regulator in the vacuum conduit, wherein one or more of the circuit components has a reduced blood-contacting surface area, thereby reducing the hemodilutional prime volume (HPV) by 10-20%. In another embodiment, the HPV is reduced 20-30%. In still another, the HPV is reduced 30-40%. In other embodiments, the HPV is reduced 40-50%, 50-60%, or 60% and more.

In one disclosed embodiment of the invention, the component through which a patient's blood circulates is a segment of tubing. In various alternative embodiments, the blood-contacting surface area is reduced by decreasing the length of the segment, by decreasing the internal diameter of the segment, or both. It should be understood that any combination of the foregoing is contemplated by the present invention — that is, in various embodiments, the length of one component may be reduced, while another component has a reduced internal diameter, and/or while another component has a reduced internal diameter and a decreased length.

In another embodiment of the present invention, the patient is an adult (e.g. a "full-size" adult) and the hemodilutional prime volume is less than one liter. In other variations, the patient is a small adult or adolescent, and the HPV is not only less than one liter, it is 25% less, more preferably 35% less, and even more preferably at least 50% less than the prime volume would be if conventional CPB circuits were used. In still other embodiments, e.g. where the patient is a newborn or 1-2 years of age, the prime volume is substantially less than a liter and is at least 25% less, more preferably 35% less, and even more preferably, at least 50% less that the prime volume would be if a conventional CPB circuit were used.

The present invention also discloses that the foregoing system may further comprise a number and variety of components. One such component is a device adapted for use in monitoring the pressure at which blood is being pulled from the patient, thereby monitoring the function of the system. Such a device may comprise a sensor that generates a decipherable signal which is transmitted to said device, thereby allowing the monitoring of venous or negative pressure. The invention also discloses a number of useful methods. In one such embodiment, a method for performing a therapeutic surgical procedure on a patient is disclosed, wherein the procedure comprises passing circulating blood from a first blood vessel of the patient through an extracorporeal blood circulation system having a reduced blood-contacting surface area and back to a second blood vessel of the patient, wherein the hemodilutional prime volume of blood circulated through the system is at least 20% less than the hemodilutional prime volume of blood circulated through conventional gravity-assisted cardiopulmonary bypass systems. In an alternative embodiment, the hemodilutional prime volume is at least 35% less than the hemodilutional prime volume of blood circulated through conventional gravity-assisted cardiopulmonary bypass systems. In other embodiments, the HPV is at least 50% less than the HPV of blood circulated through conventional gravity-assisted cardiopulmonary bypass systems.

In another embodiment, the invention discloses a method for performing a therapeutic surgical procedure on a patient comprising passing circulating blood from a first blood vessel of the patient through an extracorporeal blood circulation system having a reduced blood-contacting surface area and back to a second blood vessel of the patient, wherein the hemodilutional prime volume of blood circulated through the system is at least 20% less than the hemodilutional prime volume of blood circulated through conventional vacuum-assisted cardiopulmonary bypass systems. In yet another embodiment, the HPV is at least 35% less than the hemodilutional prime volume of blood circulated through conventional vacuum-assisted cardiopulmonary bypass systems. In still another embodiment, the hemodilutional prime volume is at least 50% less than the hemodilutional prime volume of blood circulated through conventional vacuum- assisted cardiopulmonary bypass systems.

The invention also discloses and encompasses a variety of low-prime volume cardiopulmonary bypass circuits. In one embodiment, the circuit (or system) comprises a conduit through which physiological fluid is received from and returned to a patient, the conduit comprising one or more segments of tubing, wherein the tubing has a reduced blood-contacting surface area, thereby reducing the volume of prime needed; a vacuum-assisted venous drainage system comprising a hard-shelled venous reservoir closed to the atmosphere and having a blood inlet for supplying blood removed under negative pressure during cardiopulmonary bypass to the reservoir, a blood outlet for removing blood from the reservoir, and a vacuum inlet for supplying a vacuum to the reservoir; a vacuum supply for providing a predetermined desired vacuum to the venous reservoir via the vacuum inlet; and a patient support unit for receiving blood from the reservoir blood outlet, treating and returning revitalized removed blood under positive pressure; and a device adapted for use in monitoring the pressure at which blood is being pulled from the patient, thereby monitoring the function of the system. In various embodiments, the length of components in the circuit are shorter than in conventional circuits. For example, in one embodiment, no segment of tubing exceeds 58 inches in length. In other embodiments, segments of tubing are substantially shorter, as disclosed and discussed in detail in subsequent sections.

The circuits of the present invention may be designed and described in various ways, as various parameters are adjusted to suit the patient's needs. Thus, in one disclosed embodiment, the foregoing circuit requires 1 liter or less of prime volume. Substantially smaller volumes of prime (i.e., less than one liter) are required when the patient is small — e.g. a neonate or a pediatric patient — as provided in various embodiments herein.

The invention also discloses methods for reducing the risk of surgically- exacerbated injury to a patient undergoing cardiovascular surgery comprising passing circulating blood from a first blood vessel of the patient through a vacuum-assisted extracorporeal blood circulation system having a reduced blood- contacting surface area and back to a second blood vessel of the patient, thereby minimizing the hemodilutional prime volume of blood circulated through the system. For example, in various embodiments, the surgically-exacerbated injury may be reduction in hematocrit, complement activation, platelet activation, leukocyte activation, platelet-leukocyte adhesion, inflammation, or some combination of the foregoing.

In one variation, the patient is an adult and the hemodilutional prime volume is less than one liter. In other variations, the patient is a neonate, an infant, a small child, a young adult, or a small adult; in such embodiments, the HPV is substantially less than one liter and may readily comprise half or less than half that amount. In another embodiment, the extracorporeal blood circulation system comprises one or more segments of tubing and the internal surface area is reduced via decreasing the length of one or more of the segments. In an alternative embodiment, the internal surface area is reduced via decreasing the internal diameter of one or more of the segments. In still other embodiments, some combination of length reduction and reduction of internal diameter — either in the same component or in different components — may apply.

It should thus be understood that the present circuit and methods may be useful not only in connection with minimally invasive cardiovascular surgery, but with any surgical procedure using the CPB system. A further understanding of the nature and advantages of the invention may be realized by reference to the figures, specification and claims which form additional parts of the present invention disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates one exemplary cardiopulmonary bypass system or circuit.

Figure 2 illustrates a second exemplary cardiopulmonary bypass system or circuit.

Figure 3 is a schematic illustration of a cardiopulmonary bypass system with the low-prime volume system of the present invention.

Figure 4 is a schematic illustration of one portion of the exemplary low- prime volume system shown in Figure 3.

Figure 5 is a schematic illustration of an alternative embodiment of a cardiopulmonary bypass system with the low-prime volume system of the present invention.

DETAILED DESCRIPTION OF THE INVENTION A. Extracorporeal Circulation

Extracorporeal circulation (ECC) of the blood is an important medical technology that is used in a variety of life saving medical procedures. Such procedures include hemodialysis, plasmapheresis, plateletpheresis, leukopheresis, extracorporeal membrane oxygenation (ECMO) heparin-induced extracorporeal LDL precipitation (HELP), and cardiopulmonary bypass (CPB). As such, ECC is widely used in modern medical practice. One of ECC's most common uses is in CPB. Nearly 400,000 CPB surgical procedures are carried out in the United States each year (Rin , A., N. Engl. J. Med. 312: 119 (1985)). The primary medical application of CPB is the facilitation of coronary artery bypass grafting, but it is also utilized during other types of surgery, including cardiovascular applications (e.g. transplants, open heart surgery, procedures to correct congenital heart defects, heart valve disease, and other heart defects) and surgical applications involving vascular injuries that do not directly compromise the heart (e.g. cerebral aneurysms). With improvements in surgical techniques and extracorporeal oxygenation, the overall mortality for this procedure is quite low (see, e.g., Allen C. M., Br. Med. J. 297: 1485 (1988)). Because the most extensive research to date on the effects of ECC on the immune and hemostatic systems has been in the area of CPB, much of the discussion of the detailed effects of ECC presented herein is in connection with CPB. The invention, however, should not be interpreted as being limited to CPB, albeit the improvement of a patient's surgical and post-surgical health (as well as the patient's prognosis following surgery) is a primary goal of the present invention. B. Medical Problems Caused by Extracorporeal Circulation

Although death during ECC procedures is rare, several acute and chronic complications during and subsequent to these procedures result in potentially life- threatening medical problems and cause significant expense to the health care system. Many of these complications have been associated with activation of the immune system, with the complement arm of the immune system playing a particularly important role in the development of inflammation, platelet dysfunction, thrombocytopenia, and other ECC complications. Hemostatic problems during and after ECC can be attributed to several factors, including complement-mediated platelet dysfunction, and can result in both excessive thrombosis and excessive bleeding as platelets first become activated and then become spent and non-functional, and are removed from the circulation. Management of abnormal bleeding associated with CPB often requires re- operation and is frequently associated with excessive, and sometimes inappropriate, blood product administration, occasionally exceeding the available blood supply. In some hospitals, open heart surgery accounts for more than 25% of the total blood product use (Woodman and Harker, Blood 76: 1690 (1990)). 1. Thrombosis

As used herein, the term "thrombosis" generally encompasses the formation, development or presence of a blood clot or a blood coagulation which is located inside of a patient or inside of an extracorporeal life support system which circulates blood of the patient. Thrombosis also encompasses the presence of a thrombus which includes a blood clot occluding a blood vessel or formed in a heart cavity. Thrombosis also encompasses the activation of a plasmatic coagulation system in a patient which includes the production of cross-linked fibrin degradation product, protein C, free protein S, coagulation factor II, immunoglobulin G or albumin in the patient. Thrombosis also encompasses the formation of a white thrombus which may be composed of platelets and fibrin and is relatively poor in erythrocytes, a disseminated fibrin deposit thrombus or a red thrombus which may be composed of red cells and fibrin. Thrombosis may also include a thromboembolism which is the blocking of a blood vessel by a thrombus which may have been dislodged from a vein.

Thrombosis may occur in areas of retarded blood flow in the patient, at a site of injury or at an abnormal vessel wall in conjunction with an initiating platelet plug. Initiation of clot formation in response to tissue injury is carried out by the extrinsic pathway of clotting. Formation of a pure red thrombus in an area of restricted blood flow or in response to an abnormal vessel wall without tissue injury is carried out by the intrinsic pathway. Intrinsic and extrinsic pathways may converge in a final common pathway characterized by the activation of prothrombin to thrombin and the thrombin-catalyzed conversion of fibrinogen to the fibrin clot.

2. Decreased Hematocrit

Blood is often directed to a conventional hemoconcentrator or cell saver during or at the end of surgery to increase the hematocrit and decrease the fluid volume of the blood being reperfused into the patient. As is well known in the art, hematocrit is the percentage volume of blood occupied by cells. The hematocrit of a patient - particularly one about to undergo surgery - is routinely determined prior to surgery and may be readily monitored throughout the surgical procedure and thereafter. Thus, the impact of a particular procedure or composition upon an individual patient's hematocrit may readily (and objectively) be determined. During cardiopulmonary bypass, the blood of the patient is often diluted with saline solution to increase blood volume without or with minimum donated blood. For example, the extracorporeal support circuit may be primed with saline solution before the patient is supported by that circuit; as a result, the saline prime dilutes the patient's blood. Accordingly, cell savers or hemoconcentrators are conventionally provided to increase the hematocrit of the otherwise diluted blood. Studies have shown that the routine use of cell savers or hemoconcentrators does not result in a significant improvement in hematocrit or in the quality of care, however. (See, e.g., Babke et al., Perfusion 12: 187-192 (1997); Sakert and Rosenburg, Perfusion 11: 11-11 (1996).) Moreover, it has also been shown that cell savers disrupt normal blood chemistry and components, e.g., via removing clotting factors from the blood . While hemoconcentrators do not disrupt clotting factors to the degree that cell savers do, they do withdraw heparin and electrolytes from the blood. Clearly, conventional means of increasing a surgical patient's hematocrit - including those described above - are not as effective as the methods and devices of the present invention. Further benefits of using the methods and apparatus disclosed herein will be reviewed at greater detail in subsequent sections.

3. Activation of the Complement System

Activation of the complement system is another means by which a patient's recovery from the surgery may be impaired. Activation of the complement system occurs when blood plasma contacts foreign surfaces during ECC. Activated complement components can initiate inflammatory responses, with associated vasoconstriction, capillary leakage and platelet activation.

The many previous approaches taken in pursuit of controlling activation of the complement system and associated problems arising during ECC illustrate the perceived importance in the medical research community of accomplishing these goals. These approaches have included attempts to alter the mechanical components of CPB circuits, including the use of membrane (as opposed to bubble) oxygenators, and of heparin-coated bypass circuits, as well as various approaches to pharmacological modulation of complement activation. Unfortunately, these efforts have not eliminated the immune and hemostatic system problems associated with ECC, and have, in many cases, themselves been responsible for additional adverse effects.

While ECC clearly causes complement activation, it is also associated with other problems, including kinin generation, loss of coagulation factors by hemodilution, fibrinolysis, liberation of thromboxane A₂, and the activation of platelets and neutrophils. Many of these phenomena are, at least in part, secondary consequences of complement activation. Current therapies used to address these specific phenomena have, to date, relied on rather ineffective, broad-based antifibrinolytics and hemostatic agents, examples of which include those described in the following section. 4. Limitations of Conventional Treatments

Aprotinin, a broad-based serine proteinase inhibitor has recently been studied for its effects on CPB-associated pathology. Aprotinin inhibits kallikrein, a proteolytic enzyme that attenuates the release of neutrophil elastase, another protease, and diminishes the production of complement component C3a. However, CPB-induced activation of platelets, which is (at least in part) secondary to complement activation, is unaffected by aprotinin therapy (Bidstrup, et al., J. Thorac. Cardiovasc. Surg. 973: 364 (1989)), and it is clear that platelet dysfunction is directly involved in the pathogenesis of ECC-associated hemostatic problems.

Moreover, enthusiasm for aprotinin use during CPB has been further dampened by recent clinical results showing an increased incidence of perioperative myocardial infarction (16.9% vs. 8.9% for placebo) and a significant incidence of postoperative renal dysfunction associated with aprotinin administration during CPB (Cosgrove, et al., Ann. Thorac. Surg. 54: 1031

(1992)). Thus, the use of aprotinin for the treatment of patients receiving CPB does not address or solve the majority of problems associated with CPB.

The synthetic lysine analogue EACA has been used often as an antifibrinolytic agent during CPB. Although EACA is effective in reducing bleeding in a variety of clinical circumstances, its use in CPB has been controversial with regard to its potential to reduce postoperative blood loss (Copeland, et al., Ann. Thorac. Surg. 47: 88 (1989)). Additionally, both arterial and venous thrombosis have complicated EACA therapy in a number of clinical trials and have generally discouraged its clinical use (Sonntag and Stein, J. Neurosurg. 40: 480 (1974)). Tranexeamic acid has also been used for its antifibrinolytic effect, but has also been associated with excessive thrombotic complications (Orum, et al., J. Thorac. Cardiovasc. Surg. 105: 78 (1993)).

The relatively non-specific hemostatic properties of the synthetic vasopressin analogue, desmopressin acetate, have made it a candidate pharmaceutical agent for treating the hemodynamic alterations associated with CPB. However, randomized double-blind studies of 150 consecutive patients undergoing elective CPB found no significant differences in blood loss or postoperative transfusion requirements in patients receiving desmopressin (Hackmann, et al., N. Engl. J. Med. 321: 1437 (1989); Rocha, et al., Circulation 77: 1319 (1988)).

As described above, the present invention relates to inhibition of dysfunctions of the immune and hemostatic systems during ECC. To provide background for the description of the preferred embodiments and the examples presented below, general discussions in the context of ECC of the relevant aspects of the immune and hemostatic systems may be helpful. C. Pathophysiology Associated With ECC

A key pathophysiologic change in the blood that is associated with ECC is the rapid activation of the complement cascade. Activation of complement components that mediate inflammation and impact the hemostatic properties of the blood occurs when blood comes in direct contact with the various non- biological components of the ECC circuit (Videm, et al., J. Thorac. Cardiovasc. Surg. 97: 764-770, 1989), and can be inhibited to some extent by certain drugs, particularly heparin and protamine, that are administered to patients during ECC procedures (Jones, et al., Anaesthesia 37: 629-633, 1982). Interdependent disturbances in both the immune system and the hemostatic system are seen during CPB and other types of ECC. Many of these changes intersect at the level of platelet function, as the actions of the complement arm of the immune system can result in platelet activation. In addition to its effects on platelets and the complement arm of the immune system, ECC also effects the cellular arm of the immune system both through effects on leukocytes and through effects on platelet-leukocyte interactions. 1. Effects of ECC on Platelets

Platelets are anuclear, cellular elements of the blood that are vitally important for the formation of blood clots and the prevention of excessive bleeding. An abnormally, severely low platelet count in the blood, a condition known as thrombocytopenia, often results in severe bruising, hemorrhage from mucosal membranes, and considerable loss of blood following surgery or other injury.

Platelet dysfunction has been linked with the contact of platelets with the non-biological surfaces of the extracorporeal oxygenator and the hypothermia associated with CPB. Platelet dysfunction may also be exacerbated by contact with the non-biological surfaces elsewhere in the circuit, i.e., in addition to - or other than - the oxygenator. Several other mechanisms, alone or in combination, have also been implicated as contributing to platelet dysfunction. For example, mechanical trauma due to shear stress, surface adherence, and turbulence within the extracorporeal oxygenator may cause fragmentation of platelet membranes.

CPB adversely affects platelet count as well as function, particularly when prime volume is taken into consideration. Hemodilution during CPB causes platelet counts to rapidly decrease soon after starting CPB, declining to about 50% of preoperative levels. This level of circulating platelets, if occurring in the context of normal individual platelet function, is unlikely to contribute to clinical bleeding. Of greater significance to the development of CPB associated morbidity, however, is the progressive loss of platelet function seen during and after CPB. Within minutes after initiating CPB, bleeding time is prolonged significantly and platelet aggregation is impaired. These changes in bleeding time are independent of platelet count and worsen as CPB progresses. Bleeding times, normally less than 10 minutes, can approach 30 minutes after 2 hours of CPB.

A related problem merits mention at this juncture. As those of skill in the art are aware, heparin is often administered to the patient to preclude the formation of thrombi during surgery. However, if the heparin is not subsequently removed from the patient's blood at the end of the surgical procedure, excessive bleeding may result; thus, palliatives such as protamine are generally administered to counteract such a result. Clearly, CPB and related procedures disrupt normal blood functioning on a number of levels. Platelets undergo profound biochemical and morphological alterations when activated by certain stimuli. When caused by stimuli associated with conditions calling for rapid hemostasis, these alterations are associated with the normal functions of platelets. When caused by ECC, pathophysiologic outcomes result. Activation-induced alterations in platelet characteristics include exocytotic degranulation with the release of the contents of various storage organelles, shape changes, and the induction of adhesiveness, aggregation, and thromboxane production.

Effects of ECC on platelets are particularly significant because platelets can only be activated once, i.e., activation of platelets decreases the number of functional platelets available when platelet functions are subsequently required. The importance of the effects of ECC on platelets is demonstrated by the finding that the impaired hemostasis observed after cardiac operations is mainly attributable to platelet dysfunction (Mohr, et al., J. Thorac. Cardiovasc. Surg. 96: 530, 1988). 2. Platelet-Leukocyte Interactions Associated with ECC

The P-selectin molecule, which appears on the membrane surface of activated platelets, is known to mediate the binding of platelets to various types of white blood cells (WBCs or leukocytes) without requiring the activation of the WBCs for such binding to occur. These WBCs include polymorphonuclear leukocytes (PMNs, neutrophils, granulocytes), and monocytes, and the P-selectin mediated binding results in platelet-PMN, and platelet-monocyte conjugate formation. (See, e.g., Larsen, et al., J. Biol. Chem. 267: 11104-11110 (1992); Corral, et al., Biochem. Biophys. Res. Commun. 172: 1349-1353 (1990).) One result of such conjugate formation is the removal of platelets from the circulation, a phenomenon that can contribute to the development of thrombocytopenia (Rinde, et al., Transfusion 31: 408-414 (1991)).

Such leukocyte-platelet adhesion is also believed to be of physiologic importance in the targeting of leukocytes to appropriate inflammatory and/or hemostatic sites and in modulating leukocyte function. The relevance of such targeting has been recently demonstrated in vivo in a baboon model where blockade of P-selectin with a monoclonal antibody resulted in decreased monocyte accumulation on an artificial vascular graft and decreased procoagulant activity (Palabrica, et al., Nature 359: 848-851, 1992). Such leukocyte-platelet adhesion caused by P-selectin has been found to be induced by CPB (Rinder, et al., Blood 79: 1201-1205, (1992)).

The modulation of leukocyte function mediated by ECC-associated platelet-leukocyte binding includes the upregulation of the major monocyte procoagulant molecule known as tissue factor (TF). Data reported by Catalett, et al. (Blood 78 (Suppl 1) : 279a, ( 1991 )), suggests that P-selectin induces TF upregulation on monocytes over a four hour period. Such TF upregulation enhances the procoagulatory effects of leukocytes (Altieri, Blood 81: 569-579 (1993)). In a simulated closed-loop CPB model, Kappelmayer, et al. (Circ. Res. 72: 1075-1081 (1993)), have recently demonstrated CPB-associated upregulation of both the quantity and activity of TF on circulating monocytes. The expression of monocyte tissue factor several hours after the conclusion of a CPB procedure, combined with other procoagulatory events occurring during CPB (Evangelista, et al., Blood 77: 2379-2388 (1991); Higuchi, et al., Blood 79: 1712-1719 (1992); Weitz, et al., J. Exp. Med. 166: 1836-1850 (1987)) is believed to predispose the patient to late thrombotic events, such as vascular graft re-occlusion. 3. Other Effects of ECC on Leukocytes In addition to upregulation of TF on monocytes, CPB-associated upregulation of cell adhesion ligands that contain the β₂ integrin CD 18, in particular, the heterodimeric adhesive ligand that contains CD 18 and CD1 lb (known as CD1 lb/CD 18 or MAC-1) has been described on monocytes and neutrophils (Rinder, et al., Blood 79: 1201-1205 (1992)). Such upregulation is particularly relevant to CPB-induced injury since CD1 lb/CD18 is responsible for leukocyte adherence to and penetration (diapedesis) through the endothelium via binding to the intercellular adhesion molecules ICAM-1 and ICAM-3 on

"activated" endothelium (Staunton, et al., Cell 52: 925-933 (1988); Staunton, et al., Nature 339: 61-64 (1989); Furie, et al., J. Immunol. 148: 2395-2404 (1992)).

In experimental systems, administration of monoclonal antibodies blocking the activity of CD1 lb/CD 18 has been shown to prevent reperfusion injury (Simpson, et al., J. Clin. Invest. 81: 624-629 (1988); Arnaout, Blood 75:1037-1050 (1990); Dreyer, et al., Circ 84: 400-411 (1991)). In addition, increased CD1 lb/CD 18 expression on leukocytes has been linked to complications associated with hemodialysis (Arnaout, et al., N. Engl. J. Med. 312: 457 (1985)). Thus, CD1 lb/CD18 may contribute to ECC associated medical problems.

4. Complement and Platelet Function and ECC The activation and consumption of complement components during ECC, specifically CPB, is evidenced by levels of hemolytic complement activity that are much lower at the end of CPB than can be explained by hemodilution alone. A rapid effect on complement components accompanies the initiation of extracorporeal circulation; evidence of alternative pathway activation is observed minutes after the onset of CPB. Classical pathway activation has also been observed during CPB (Haslam, et al., Anaesthesia 35:22 (1980)).

The levels of C3a anaphylatoxin have been found to increase dramatically during CPB, and there is a strong statistical association between elevated C3a levels and postoperative organ system dysfunction manifest by impairment and/or failure of cardiac, renal and pulmonary systems, bleeding diathesis, and the need for artificial ventilation (Kirklin, et al., J. Thorac. Cardiovasc Surg 86: 845-847 (1983)). This association has led to the belief that C3a is a key mediator of the deleterious effects linked to complement activation during CPB.

It is well established that platelets can be activated by the assembly of terminal complement components C5b-9 on their surfaces. The assembly of these complement components on platelets is known to occur during ECC (Finn, et al., J. Thorac. Cardiovasc. Surg. 105: 234 (1993)). Complement-mediated platelet activation, in turn, leads to alpha-granule release, increased expression of P- selectin, and the loss of GPIb. The generation of products of complement activation such as C3a, C5a, and C5b-9 further results in platelet membrane vesiculation and consequent microparticle formation.

Other damaging effects of complement activation during CPB can include the activation of granulocytes, which leads to partial degranulation, up-regulation of CD1 lb/CD18, and to organ damage. Such injurious effects are largely due to the actions of certain products of complement activation, specifically the anaphylatoxins C3a and C5a, which, in turn, can be converted to desArg forms with altered activity levels by plasma carboxypeptidase. These activated complement components cause activation and aggregation of neutrophils. Such activated cells, in turn, accumulate in the pulmonary vessels and vascular beds, as has been demonstrated by serial biopsies of lung tissue before and after CPB (Howard, et al., Arch. Surg. 123: 1496-1501 (1988)). Liver, brain and pancreas, also suffer such damage, which can result in postoperative dysfunction of these organs.

5. Thrombogenic Response to ECC (or CPB)

As those of skill in the relevant art are aware, direct contact between the synthetic materials used in cannulas, ECC components, CPB circuits, and other such devices and a patient's blood often results in the occurrence of thrombosis on the surfaces of the device. The thrombus so formed results from the undesired accumulation or adsorption of blood proteins and platelets onto said surfaces. These deposited formations may increase in size, thereby increasing the risk of circulatory blockage to a patient. The clots may also break and migrate downstream, creating additional risks of other dangerous conditions such as a pulmonary or a cerebral embolus, or myocardial infarction. Protein deposition on the surfaces of such devices also acts as an attractive growth medium for invading microbes, and thus the hazards to the patient are further increased.

In view of the continuing development of synthetic materials such as composites, ceramics, and resins, a patient's tissues and fluids will likely be exposed to a wide variety of different substances during surgery and other therapeutic procedures. Because many of the surfaces of the components of medical devices, including implants, will directly contact the patient's tissues and bodily fluids and may have a tendency to attract protein deposits, the combined effect on a patient of exposure to a variety of surfaces may pose a complex problem and may create a substantial risk of protein deposition and thrombosis in that patient. The adsorption of protein onto a surface - e.g., any surface in a CPB circuit with which the patient's blood comes in contact - is basically the result of two dynamic forces, electrostatic attraction and hydrophobic interaction. Proteins generally have positively-charged and negatively-charged hydrophilic regions and neutral hydrophobic regions. Because many artificial surfaces are negatively charged, the positively-charged regions of the proteins are electrostatically attracted toward the substrate surfaces. Artificial surfaces also have hydrophobic regions which attract the proteins by hydrophobic interaction with the hydrophobic regions of the proteins. Moreover, the hydrophobic nature of some of the most common substrate materials, such as polystyrene or polypropylene, may actually denature or break apart some biopolymers and contribute to the buildup of deposits.

As deposits accumulate, they invite compounding problems, such as calcification and bacterial infection. Subsequent bacterial infection can be particularly problematic as infectious bacteria adhering to the surface of a medical device are sequestered from the body's normal immune response. Even more serious problems can arise when the predominant physiological fluid contacting the surface of a medical device is blood. As discussed above, a complex process of blood protein deposition, absorption and replacement precipitates a cascading mechanism, turning the body's natural defense against bleeding into a dangerous clot formation process.

These same clot-forming or thrombogenic mechanisms also negatively impact the utility of surgical devices relying on extracorporeal blood-conducting circuitry to direct a surgical patient's blood to oxygenators, reservoirs, defoamers, filters and heaters during lengthy surgical procedures. These extracorporeal devices are essential to the success of such procedures as open heart surgery, yet they expose the patient's blood to large synthetic material surface areas which may precipitate protein deposition and clot formation.

Conventional medical practices aimed at preventing thrombosis include the direct administration of anticoagulant agents such as heparin to patients who are exposed to blood-contacting medical devices and apparatus. However, while the direct administration of heparin or other anticoagulants is effective at reducing blood coagulation, it also presents the undesirable risk of uncontrollable patient bleeding. Thus, until the advent of the present invention, the options available for reducing the risks incident to ECC and CPB via exposure of a patient's blood to artificial surfaces were limited.

6. Inflammatory Response to ECC or CPB Extracorporeal circulation of a patient's blood causes bleeding and thrombotic complications, fluid retention and temporary dysfunction of every organ system. The reason is because contact of the blood with the foreign surfaces of the extravascular circuit triggers a massive defense reaction in blood proteins and cells that has been called the "whole body inflammatory response." The problem has especially been documented in connection with CPB surgery. See Blackstone E. H. et al., "The Damaging Effects of Cardiopulmonary Bypass," in Wu K. K., Roxy E. C. (eds), Prostaglandins in Clinical Medicine: Cardiovascular and Thrombotic Disorders, Chicago, Yearbook Medical Publishers (1982), pp. 355-369.

In the whole body inflammatory response, platelets are activated by contact with surfaces other than the endothelial cells that line the circulatory system of the body. The activated platelets adhere to non-endothelial cell surfaces, then aggregate and release granule contents and synthesize powerful vasoconstrictor substances. These granules in turn release coagulation proteins, substances that increase capillary permeability and attract neutrophils, substances that enhance platelet adhesion and aggregation, and numerous other substances including vasoconstrictors norepinephrine, serotonin and histamine, and potent hydrolases and proteases.

These granule products contribute to systemic inflammatory response associated with extracorporeal blood circulation. Deficiencies of platelet number and function after extracorporeal circulation such as in CPB are a major cause of postoperative bleeding. Neutrophils are strongly activated by extracorporeal circulation and release many cytotoxic chemicals and powerful enzymes that mediate much of the inflammatory response associated with extracorporeal circulation. Interstitial fluid accumulates rapidly especially during CPB caused by increased capillary permeability, increased central venous pressure and decreased colloid osmotic pressure due to hemodilution. Vasoactive substances released by the defense reaction cause endothelial cells or vascular smooth muscle cells to contract or relax or alter the contractile strength of cardiac myocytes. Circulation of these substances contributes to fluid retention and the whole body inflammatory response. Microemboli including fibrin, denatured protein and platelet aggregates too small for capture by extracorporeal circulation filters bombard the organs and may be responsible in CPB procedures for subtle central nervous system deficits that afflict over 50% of patients and can persist for more than a year.

In order to prevent blood from clotting in extracorporeal circulation procedures, heparin is systemically administered to the patient, but heparin does not prevent the whole body inflammatory reaction. This is because heparin acts primarily at the end of the coagulation cascade and does not prevent activation of at least five plasma protein systems (contact; intrinsic coagulation pathway; extrinsic coagulation pathway; complement; and fibrinolysis) and five blood cells (platelets, neutrophils, monocytes, endothelial cells and lymphocytes) which act to produce more than two dozen vasoactive substances that alter the vascular tone, capillary permeability and cardiac myocyte contractability. Heart-lung machines often have heparin coated surfaces, and these seem to be thromboresistant, apparently because they are instantly covered with layers of plasma proteins which isolate the surface from direct contact with flowing blood. However, attempts to produce nonthrombogenic synthetic materials have generally failed. Although some materials are less thrombogenic than others, all activate blood elements to initiate clotting and activate the body's defense reaction. (See generally, J. H. Gorman and L. Henry Edmunds, Jr., "Blood Anesthesia for Cardiopulmonary bypass," J. Card. Surg. 10: 270-279 (1995).) Although the search for a bioactive material that does not activate blood elements during extracorporeal circulation such as CPB is one approach, and the administration of anticoagulants and/or compositions which interfere with complement or platelet activation are other approaches, the most practical and useful approach is that disclosed herein, namely, the reduction of the surface area to which a patient's blood will be exposed and the reduction in the amount of blood that must circulate extracorporeally. D. The Low-Prime CPB Circuit

As illustrated in Figs. 1 or 2, cardiopulmonary bypass (CPB) systems or circuits include an array of chambers, tubes, cannulas, pumps, and monitors. With the advent of vacuum-assisted venous drainage, it has been possible to improve surgical procedures and patient outcomes, partially through the reduction in prime volume needed in a vacuum-assisted system when compared with gravity-based drainage systems. However, it has until now been considered too expensive, impractical or risky to substantially alter the arrangement, volume, size and/or length of the components of the circuit in an effort to further reduce the prime, thereby improving the post-surgical prognosis of the patient and reducing the health-care costs incident to the relevant surgical procedures. As noted above, the present invention reduces the amount of prime needed, thereby reducing the need for the use of blood substitutes or other biocompatible physiological fluids which may restore the patient's circulatory volume but which create other complications. By applying a novel approach and new designs, the present invention not only maintains the patient's circulatory volume, it tends to obviate the need to administer blood substitutes or other compositions which disrupt normal blood function, just as it eliminates the need to use devices such as cell savers (which remove clotting factors) and hemoconcentrators (which deplete electrolytes), which reduce the patient's chances for a complete recovery within a reasonable period of time. 1. Reduction of Prime Volume It has already been explained that a certain amount of fluid - generally the patient's blood and/or another biocompatible (or blood-compatible) fluid - is necessary to prime the CPB circuit. In particular, such priming is necessary to avoid the entrapment of even microscopic air bubbles in the circuit, as the return of such bubbles to the patient's circulatory system can produce exceedingly harmful results.

The low-prime volume (LPV) system or circuit comprises a CPB circuit that has been designed and modified in an effort to substantially reduce the fluid volume needed to prime the CPB circuit. Since CPB systems (and other cardiovascular circuits) include an array of components including a variety of lines (or tubing), connectors, pumps, reservoirs, manifolds, clamps, valves, plugs, filters, and assemblies, it was thought to be almost impossible, until the advent of the present invention, to redesign this complicated system in such a manner that the prime volume can be reduced without sacrificing the proper functioning of the entire circuit.

After a significant amount of design and testing work, however, a low- prime volume circuit has now been prepared which is not only functional, it actually functions significantly better than conventional CPB systems - whether or not said systems include vacuum-assist. Moreover, the LPV system enhances surgical procedures from the perspective of all parties involved.

For example, in the various embodiments of the present invention, extracorporeal blood contact volume, hemodilutional volume, and total circuit volume are reduced substantially in comparison to either conventional gravity or vacuum-assisted venous return (VAVR) systems. In one embodiment, total circuit volume and extracorporeal blood contact volume are reduced by 5-10%; in another embodiment, those volumes are decreased by 10-20%; in yet another embodiment, those volumes are reduced 20-30%; in a preferred embodiment, total circuit volume and extracorporeal blood contact volume are reduced by 30- 40%; in a more preferred embodiment, those volumes are reduced by 40-50%; and in even more preferred embodiments, those volumes are reduced by 50% or more. As noted previously, the more the volume is reduced, the greater the benefit to the patient.

In one instance in which conventional gravity-assisted, vacuum-assisted venous return (VAVR), and LPV systems were compared, significant reductions were seen in hemodilutional volume (e.g. the blood that goes through the circuit and is returned to the patient), consistent with the foregoing percentages. For example, in one series of tests, hemodilutional volume in the gravity-assist system was measured at 1352cc, compared to 104 lcc using the VAVR system. Amazingly, the hemodilutional volume was only 866 in the LPV system in that procedure. Thus, in that example, the hemodilutional volume was reduced at least 35% using the LPV system compared with the conventional gravity-assist system and at least 17% using the LPV system compared with the conventional VAVR system. Thus, the data indicate that for adult patients, prime volumes and hemodilutional volumes may be dropped to a level significantly below the conventional usage of 1600-2000cc's and may reasonably be expected to remain at lOOOcc or less. Similar reductions in other patients - e.g. pediatric patients and neonates - are achieved as well with the use of the LPV system. For example, a 50%) reduction in prime volume in a neonate drops the volume from 600-700cc - as seen using conventional systems - to 300-350cc or less.

As discussed elsewhere herein, there are other means of illustrating the beneficial effects and outcomes achieved using the LPV system. For example, significant benefits to the patient are achieved by the use of the LPV circuit in that the surface area of the circuit and its components is smaller than in conventional systems and less injury to the patient's blood and circulatory system results therefrom. Review of the data set forth in Tables 1 and 2 and the methods of calculating surface areas to which the blood is exposed - as well as the volumes passing therethrough - clearly enables the skilled artisan to follow the teachings of the present invention and to design similar LPV systems and circuits which achieve the disclosed reductions in prime volume, hemodilutional volume, extracorporeal volume, and total circuit volume, and which also reduce the surface area with which the blood comes into contact. Thus, it should be emphasized that the invention is not limited to the percentages, volumes, etc. which are provided as examples. Thus, in various embodiments of the present invention, lengths of line

(tubing) may be reduced or eliminated, and/or components of the circuit may be modified to facilitate a substantial reduction in the overall length and complexity of the circuit, which allows one to require and use a much lower prime volume. Not only does the LPV system have a significantly lesser amount of tubing, the venous reservoir can be raised up off the floor and the blood oxygenation and heat exchange unit has as well, which confers the added benefit of allowing the surgeon and perfusionist to more easily monitor the condition of the patient and the functioning of the circuit. It may be helpful to further highlight various aspects of the invention. As already noted, the amount and length of tubing in the LPV system is significantly less than that of conventional systems. The LPV circuit is not merely a "pruned" version of conventional gravity-assisted or vacuum-assisted CPB circuits, however. Not only can ancillary loops of tubing be removed - without compromise to the function of the system - the various components of the entire circuit can be rearranged to produce a more efficient flow, as well as to reduce prime volume.

What is perhaps more difficult to observe is the reduction in surface area of various components of the LPV system that has also been achieved with the advent of the present invention. Further reductions in surface area to which the patient's blood is exposed are feasible with the LPV system, which accommodates further such refinements depending on the needs of the surgeon and the individual patient. For example, one may not be able to observe from the Figures that smaller cannulas may be used with the LPV system, as the flow through the circuit is much more efficient than in conventional circuits; this is especially beneficial to neonatal and pediatric patients (as well as to adult patients). The ID (inner diameter) and/or length of various sections of tubing and/or various components of the LPV system is readily modified as well, thereby reducing the prime volume required and reducing the likelihood of injury to the patient's blood via exposure to synthetic surfaces. Such modifications and refinements are well within the scope and purpose of the present invention.

In one example, an LPV circuit has been designed so that when the circuit includes components comprising one or more segments (or lengths) of tubing, the longest segment of tubing in that circuit is less than 5 feet in length. In conventional circuits including standard A-V lines, for instance, the length of any one of the segments of tubing can easily extend to nearly 8 feet in length. Referring to Table 2, for example, one may readily observe the differences in lengths (as well as volumes and surface areas, when the appropriate calculations are applied) between components of conventional systems and LPV systems. Thus, the preferred circuits of the present invention may alternatively be described as having reductions in the length of components thereof of at least 10- 20%), preferably 10-30%), more preferably 25-35%, even more preferably 35% or more. As shown in Table 2, some components have been reduced in length at least 40%), some 50% and greater, and in at least one instance, an 80% reduction in length was achieved. Similar reductions in surface areas to which the patient's blood is exposed are also observed and preferred. Clearly, a wide range of reductions in volumes, surface areas, lengths and diameters (i.e. of various tubes and other essentially-cylindrical components) are achieved via using the methods and devices of the present invention. As those of skill in the art will appreciate, the invention is not limited in scope to the specific embodiments exemplified herein.

In another example, then, it is preferable that the LPV circuits of the present invention have surface areas - i.e. areas with which a patient's blood comes into contact during CPB or other procedures involving ECC - that are reduced by at least 5%, preferably by at least 10%, more preferably by at least 15%), and even more preferably by 20% or more, when compared with the surface areas of conventional gravity-assisted and vacuum-assisted circuits. It should also be appreciated by those of skill in the art that certain components of the circuit are more amenable to surface-area reduction than are others; that is, reduction in surface area preferably does not interfere with the function of either the component or the circuit. Reduction in the size of the lumen(s) of the tubing, as well as reductions in length of the lines (tubing) also facilitates the use of lower prime volumes. These aspects of the invention are also described in greater detail in subsection 2 below. a. Volume Reduction Using LPV Circuit

As discussed previously, a cardiopulmonary bypass circuit is normally composed of numerous components, with the oxygenator and other components interconnected by significant lengths of sterile tubing. Additional lengths of tubing are connected to the patient's vascular system and are utilized to direct the patient's venous blood into the extracoφoreal circuit, and to return the arterialized blood to the patient's arterial circulation. This circuit must be completely filled with an appropriate physiologic fluid, prior to connection into the patient's vascular system to prevent catastrophic embolization of gas into the circulatory system of the patient. Obviously, the larger the total fluid volume of the bypass circuit, the greater the hemodilutional effect on the patient. As one progressively dilutes the patient's blood, a critical point will be reached at which the patient's blood will not be able to transport sufficient oxygen to support tissue requirements without excessive blood flow rates. Such extreme hemodilution will then require transfusion of homologous blood into the circuit to increase the blood's oxygen- carrying capacity. Consequently, the optimal design of an oxygenator would be to minimize the fluid priming volume required for safe operation.

With the use of the LPV system, significant reduction in priming volume and significant improvement in patient response and recovery have been observed in clinical situations. Some specific examples, for the puφose of further illustrating - and not limiting - the within-disclosed invention may prove helpful.

As those of skill in the art are aware, the use of conventional procedures requires approximately these amounts of prime volume for the following "classes" of patients: newborn infants, 600-700cc; infants 6mos-l yr in age, 1200cc; children 1-5 yrs of age, 1200cc; adults of small stature, 1400cc; and full- size adults, 1600cc - 2 liters. With use of the LPV system, however, the amount of prime needed to perform CPB surgery has been reduced by as much as 50%) to date and may be further reduced as the system is further modified pursuant to the teachings of the within-disclosed invention.

For example, the following comparisons may be helpful to an understanding of the invention. Conventional gravity-assist and vacuum-assist systems were compared with an LPV system with respect to the degree of volume reduction in total circuit volume, hemodilutional volume, and extracoφoreal volume. Measurements of the relative lengths of various components in these systems were also made for the puφose of comparison.

Although data was gathered for all three systems and with respect to all three volumetric parameters, in order to simply and clearly show the significant reduction in prime volume (particularly the volume that is ultimately returned to the patient — the hemodilutional volume or HDV) and circuit length, the following table presents the data for seven (7) different components of a CPB circuit. (Data regarding total circuit volume and extracoφoreal circuit volume was also gathered but is not illustrated in the following tables.) Data gathered using a conventional VAVR system and using an LPV system of the present invention are shown in Tables 1-2 following.

Table 1

Comparison of HDV in Conventional and LPV Systems

Conventional Systems LPV System Component Gravity- VAVR LPV¹ Reduction in

Assisted Assisted¹ Vol. ^!

(LPV vs Gravity)

A-V line 476 165 105 -371

Arterial line 51 51 11 -40

Arterial filter 290 290 277 -13

Arterial trimed 23 23 15 -8 line

Pump header 169 169 127 -42

Arterial filter 11 11 7 -4 purge line

Sample 17 17 9 -8 manifold

Total 1352² 1041² 866² -486

= all numbers in table are expressed in cc's = total includes HDV from two other components (totaling 315cc)

Table 2

Conventional System LPV System

Component Device Lengths' * Device Lengths*

A-V line 4, 78, 73, 3, 91 3, 54, 49, 2, 58

Arterial line 3,3,31,4 2,3,3,9,2

Arterial filter 4,6,4 2.5,5.5,2.5 redesigned with fewer

Arterial trimed line N/A segments and surfaces

Pump header 12,18 3,3

Arterial filter 27,28 16,16 purge line

Sample manifold 36,12,30 16, 12, 12

Cardioplegia line 41,68,24 35,36,16

Cardioplegia line 15,3 9,3

* Multiple numbers for any component indicate segments that are joined together to complete said component. All measurements reported in inches.

b. Advantages of LPV Consistent with the foregoing, the use of a low-prime volume (LPV) circuit confers a number of advantages, including the following, non-limiting list. First of all, reducing the prime volume means that a greater proportion or volume of the patient's blood will be in the reservoir than in the circuit, which enhances blood volume management and provides substantial safety benefits to the patient. Increased blood volume in the reservoir as opposed to the circuit (e.g. the various lengths of tubing) means that there is a significantly reduced chance of getting air in the system. Second, as mentioned previously, there is decreased hemodilution with the use of the LPV system. Not only does this reduce the risks to the patient and improve the patient's recovery from surgery, it often makes it unnecessary to transfuse the patient during or after surgery, as the hematocrit is not substantially reduced as with conventional (non-low-prime) systems. Typically, a patient's hematocrit drops about 10% during surgery when conventional systems (gravity- or vacuum-assisted drainage systems) are used, whereas the hematocrit tends to drop not more than about 5% during surgery when the low-prime volume system is used.

Third, the patient's blood pressure does not drop as much on initiation of bypass, as the volume of blood held in the tubing in the circuit is substantially reduced - and this facilitates blood volume management as well, as previously noted. This also gives the surgeon and perfusionists an increased ability to stabilize the patient during and after surgery. In addition, use of the LPV circuit enables one to raise various components - particularly the reservoir - off the floor and closer to the patient, which allows the perfusionists to more readily monitor the volume of blood in the reservoir, which enhances blood volume management.

Fourth, with the use of the LPV system, there is less need to use a cell saver or a hemoconcentrator. The former strips the patient's blood of clotting factors, not to mention the fact that it provides yet another expanse of synthetic surface areas into which the patient's blood comes into contact, further increasing the likelihood of cellular damage, platelet activation and injury, and the like. Similarly, hemoconcentrators provide another source of cellular damage, platelet activation and injury, etc., and they are known to extract electrolytes and heparin (needed to prevent the undesired clotting of blood during surgery) from the patient's blood.

Fifth, more of the patient's own blood can be transfused back to the patient when the patient is coming off pump. In some instances, use of the LPV system has maintained the patient's pre-op hematocrit so well that not all of the blood in the reservoir is returned to the patient as he/she comes off pump; on various occasions, the blood is saved for return to the patient at a subsequent time, e.g. in the recovery room or upon return of the patient to his/her hospital room.

Sixth, the decreased hemodilution that results from use of the LPV circuit makes it possible to administer less protamine to the patient. (As noted previously, protamine is generally administered to assist in the removal of excess heparin from the patient's blood at the close of surgery.)

Seventh, as mentioned previously, the risks of injury to the patient resulting from activation of the complement system and the like is decreased with the use of the LPV circuit. The improved prognosis tends to result in a shorter recovery time and a reduced hospital stay for the patient. It has also been reported that fewer incidents of atrial fibrillation are observed during surgery when the LPN/NANR system is in use, as smaller cannulas may be used in conjunction therewith.

Measurement of all the aforementioned physical parameters provides still other objective means of assessing the effectiveness of the present invention. Reduction of the size of the circuit - whether one is talking about the length of the tubing and other components, the size of the lumens, the size of the surface area to which the patient's blood is exposed, or all the above - produces quantifiable results, not only with respect to patient outcomes and the reduced risk of injury to the patient, but in ancillary benefits, such as the reduced need for transfusion, etc. Finally, the use of the LPV circuit allows health care providers to reduce costs as well as to significantly improve patient outcomes and shorten recovery times. It has been noted that many institutions now use cell savers, which are significantly more expensive than hemoconcentrators; the two tend not to be used together in a single procedure. However, with the use of the LPV system, there is a reduced need to use either a hemoconcentrator or a cell saver, as most of the patient's extracoφoreal blood volume is held in the reservoir rather than in the circuit.

c. Calculating Volumes and Surface Areas

As discussed previously, there are numerous components of the LPN system/circuit that come into contact with the patient's blood and thus have relevant priming volumes. Examples of such components include tubing ("lines"), connectors, reservoirs, filters and the like.

Component volumes may readily be determined via mathematical calculations. All of these calculations can be performed from the analysis of the component geometry and the use of simple formulas to calculate the volumes. The components' geometry can be placed into three basic categories, each having its own sub-methodology for volume determination. In general, the components can be classified as either tubing, connectors and fixed-length tubing, or as Y- connectors.

(1) Calculations for Tubing As those of skill in the art will appreciate, tubes are essentially cylinders.

Since tubing can have variable lengths, the cross-sectional area of the tubing is an important calculation. To calculate the volumes, the following assumptions are made: ifN = A/ and A = ^² ' 4 where N = volume; A = cross-sectional area of the tubing; / = the length of the tubing; and d = the inner diameter of the tubing, then:

V = ™£ I ■ To obtain volume per unit length, rearrange the equation as follows: ⁴

N = πi I 4 Running a sample calculation for 3/8-inch tubing, one obtains the following, using a factor of (2.54 cm)³ to accommodate for the desired units: in

V ₌ π£ = π (0.375m)² ₌ o.llOin² (2.54 cm)³ = 1.810 mVin. / 4 4 in

Multiplying this cross-sectional area by the length of the tubing (in inches) gives one the volume of the tubing.

(2) Calculations for Connectors and Fixed-Length Tubing

Connectors and fixed-length tubing can have their volumes derived as complete cylinders. Their volume is a function of two variables: ID (inner diameter) and length. The following methodology is used: the same assumptions are made as in (1), plus a few others, as follows. N = A/ and A = ^ ' where N = volume; / = the length of the fixed-length tubing or connector (pref. w/o barbed connections); A = the cross-sectional area; and d = ID of the component. Thus, one has the following:

4 It was also assumed that all connectors would always be connected and all connections would be "all the way up" (i.e. fully joined together). The length of barbed connections would therefore not be included in the volume calculation for all connectors; only the portion not overlapping lengths of tubing (or devices) connected would be included in the calculation. Thus, for a connector whose overall length is, say, 2.79in but whose non-overlapping portion is 1.25in, the calculation would be as follows:

N = _π i = _π (0.375m)² (i.25in) = 0.138m³ ( ^4 cm)³ _{= 2 26ml} in

(3) Calculations for Y-Type Components

These calculations were performed with the same assumptions as above, with the added assumption that the volumes of these component types are the summation of three cylinders. The formulas already provided are readily adaptable for use in such calculations.

(4) Surface Area Calculations

Although reduction in surface area within the LPN system is discussed in detail elsewhere, it should be noted that the calculation of the surface area to which the patient's blood is exposed in conventional systems as opposed to the LPN system is readily performed. Standard geometrical calculations appropriate for such determinations are known to those of skill in the art and include, for example, the formula for the calculation of the surface area of a cylinder (e.g. a container or a length of tubing) is as follows: 2πr x /, where 2πr = the circumference of the cylinder and / = the length of the cylinder.

Determination of the surface area with which the patient's blood comes into contact represents another parameter that is used herein in the design, preparation and use of the LPN systems/circuits of the present invention. As disclosed herein, reduction of the surface area to which the patient's blood is exposed is another significant benefit of the use of the LPN system, in addition to the reduction of prime volume.

2. Use of a Vacuum in the Circuit a. Vacuum- Assisted Venous Return Systems in General

The present LPV circuit provides improved venous drainage in a CPB system and enhanced patient outcomes. Suφrisingly, the LPV circuit used in conjunction with a vacuum-assisted venous drainage system enhances the performance of the latter system beyond expectations and provides benefits to the patient (as well as to the health-care provider) that could not be achieved via use of conventional gravity-drainage or even vacuum-assisted drainage systems alone. Before remarking on the unexpected advantages of using an LPV circuit, it may be helpful to provide a general overview of conventional vacuum-assisted venous return (VAVR) systems. (Such systems may alternatively be referred to herein as vacuum-assisted venous drainage, or NAND, systems.)

An exemplary vacuum-assisted venous drainage system preferably includes a sealed venous reservoir interconnected with a vacuum regulator assembly, a valve subassembly, and a vacuum supply. The reservoir is preferably supplied via cannulas (including reduced-diameter cannulas, as discussed elsewhere herein) and may be interconnected with either a heart/lung machine or to a combination of components used in the heart/lung machine - for example, positive pressure pumps, a blood oxygenation unit, a filtration unit and a heat exchange unit. Use of a NANR system enables numerous advantages over other known CPB systems - e.g. "gravity drainage" systems - used in both standard and minimally-invasive cardiovascular surgical procedures.

Eliminating the use of a gravity system to provide venous blood flow from the patient results in numerous advantages. Some of the advantages include decreased size of the holes in the heart, as one may use smaller venous cannulas in conjunction with the use of vacuum assist. Other advantages include a somewhat- reduced venous priming volume; reduced system tubing requirements; reduced cannula size while maintaining desired venous flow rates (which also enables increased access to the operative field during cardiovascular procedures); reduction in the use of centrifugal or roller pumps previously used for venous flow (resulting in reduced hemolysis and reduced system costs); some reduction in the occurrence of air locks in the lines; and increased flexibility in patient positioning and system location in the operating room, since the patient need not be elevated above the reservoir as high as previously required.

Using a vacuum-assisted venous return system, venous blood flow from the patient is provided directly to the sealed venous reservoir. Additionally, intermittent cardiotomy blood flow from the vent and suction lines may be provided to the reservoir. One preferred reservoir is a conventional design sealed, hard-shell cardiotomy and venous reservoir. Where an alternate cardiotomy reservoir is provided for the vent and suction lines, the vent and suction ports to the reservoir are occluded with a conventional capping kit to seal the unit. Additional modifications to the reservoir, such as additional sealing, may be required to be made to ensure that adequate sealing is obtained to maintain the reservoir under negative pressure.

The reservoir is interconnected with a conventional heart/lung machine, or, alternatively, positive pressure or roller pumps interconnected with a conventional blood oxygenation unit and heat exchange unit, either or any of which may be used, and which are referred to collectively herein as the CPB circuit or as the patient support unit. The patient support unit receives blood pumped from the reservoir for removal of carbon dioxide, and for the addition of oxygen. It also provides appropriate temperature adjustment and returns the blood supplied to the patient, preferably directly into the aorta.

The heart/lung machine typically includes four roller pumps, one for pumping arterial blood back to the body, one for pumping blood cardioplegia to the body, one for venting additional blood form the patient and one for suctioning blood from the patient. In an embodiment of the present invention where a heart/lung machine or patient support unit is used, four pumps are used. Still further, in the event cardioplegia is not required to be provided to the patient via the patient support unit, only three pumps are used.

A vacuum source or supply is interconnected with the reservoir to apply a negative pressure or vacuum to the system. The vacuum source used is preferably a conventional house or wall vacuum supply having a constant pressure of about -24 kPas or -450 mmHg. However, it should be understood that any vacuum supply may be used as a source for the system. A conventional negative pressure monitor is generally provided at a venous entry port to the reservoir to constantly monitor the negative pressure within the reservoir. The preferred negative pressure measured at the reservoir entry port of the present system is approximately -25 to - 70 mmHg. It will be understood by those of skill in the relevant art that during a CPB procedure it is the rate of venous blood flow through the system which is monitored, and not the venous blood pressure levels, since the goal of the CPB system is to reduce the pressure as low as possible, while continuing to maintain adequate blood flow to and from the patient via the system. Intermediate the venous reservoir and the vacuum supply, a regulator subassembly and valve subassemblies are generally provided. The reservoir is interconnected with the subassemblies via a short length (approximately 12 inches) of %-inch sterile tubing. The regulator subassembly includes a vacuum gauge to monitor the negative pressure supplied to the system, and a vacuum regulator, having a delivery gauge, enabling increasing or decreasing adjustment of the pressure level as may be required during the surgery to maintain desired blood flow from and to the patient. A manifold is connected between the vacuum gauge and the vacuum regulator to ensure supply of the desired vacuum level upon adjustment.

The vacuum regulator is preferably preset prior to the surgery procedure at the estimated desired pressure level. The desired vacuum level is estimated based upon numerous patient characteristics and surgical factors, such as size of the patient, the procedure being performed, the cannulas being used, and so on, as will be appreciated by those of skill in the art. The vacuum regulator includes an

"on/off valve so that when it is desired to initiate the venous drainage, the vacuum regulator may simply be moved from the "off position to the "on" position. The regulator subassembly and manifold may be bracketed to the pump hardware of the patient support unit. The valve subassembly of a vacuum-assisted venous drainage system preferably includes a vacuum relief valve, vacuum relief controls, a positive pressure relief valve, a high negative pressure relief valve and first and second water vapor relief traps. The reservoir is interconnected with the vacuum relief controls to enable a quick disconnect of the negative pressure if the suction increases too rapidly, or other conditions require termination of the vacuum. In one embodiment, the vacuum relief controls comprise an open tube extending form the tubing interconnecting the reservoir and the vacuum regulator, which is clamped to a closed condition during operation using surgical tubing clamps or other conventional clamping means. In the clamped or closed condition, the system operates under the desired negative pressure level. However, release of the clamped condition opens the system to atmosphere to remove any negative pressure.

Once the patient is prepared, following heparinization, the bypass may be initiated. After confirming the preset desired negative pressure on the pressure regulator, the vacuum relief controls are clamped closed, and the vacuum regulator is moved to the "on" position. An arterial pump of the patient support unit is then activated. The vacuum levels are confirmed on a negative pressure monitor, and the system vacuum levels are confirmed using the vacuum gauge and delivery gauge. The application of the desired negative pressure to the system immediately, and without priming of the venous lines, provides venous blood flow to the reservoir. Because the VAVR system does not rely solely on gravity for venous drainage, the system does not require increasing the distance of the patient from the floor during use of the circuit, nor must the venous drainage system be located on or near the floor. In fact, the system is preferably located near the patient support unit, but it may be positioned as desired by the surgical team. For example, the reservoir, regulator and valve subassemblies may be supported on brackets extending form the patient support unit, or they may extend from, and be movable with, the surgical table supporting the patient, and thus may be moved with the patient, particularly where a heart/lung machine is not used and a modified combination of pumps and heat exchangers, as set forth herein, are used. Such positioning provides increased flexibility for the surgery team during a procedure. b. Various VAVR Systems May Be Enhanced Via Use of LPN Circuit The present invention is compatible with and improves the function of - and the patient outcome as a result of the use of - a variety of cardiovascular procedures. In particular, the modification of any venous drainage system - particularly those that are vacuum-assisted - according to the within-disclosed methods and using the within-disclosed techniques and devices will result in the use of significantly lower hemodilutional prime volumes, will cause less damage to the patient's own blood, and will result in an improved surgical and post-surgical prognosis and recovery.

For example, the present methods and devices may readily be used with a vacuum-assisted venous drainage system including a reservoir for receiving blood from a venous system of a patient; a source of vacuum; a conduit extending between the source of vacuum and configured to create a negative pressure within the reservoir; a pressure regulator in the conduit; and a vacuum stabilizer positioned in the conduit between the pressure regulator and the reservoir, the vacuum stabilizer allowing air into the conduit from the exterior thereof to modulate extreme changes in pressure within the conduit, but preventing air from escaping from the conduit. Regardless of the type or configuration of the sealed reservoir, use of the within-disclosed methods and devices provides significant enhancements over the prior art.

The low-prime volume circuit of the present invention may also be used in conjunction with a vacuum assisted venous drainage system comprising a hard shell venous reservoir for receiving blood from a venous system of a patient; a source of vacuum; a conduit extending between the source of vacuum and configured to create a negative pressure within the reservoir; a pressure regulator in the conduit; and a moisture trap in fluid communication with the conduit between the pressure regulator and the hard shell reservoir, the moisture trap serving to collect fluids drawn from the reservoir before reaching the pressure regulator. As further described herein, the length and/or size - and thereby the surface area - of various components is modified to reduce the prime volume and to produce a host of other beneficial results, as well.

The low-prime volume circuit of the present invention may also be used in conjunction with a reservoir that comprises a reduced blood/air interface venous reservoir, e.g. one comprising a rigid container having an inlet adapted to receive venous blood into an interior space sealed from the atmosphere, the container shaped to contain the blood and form a blood surface; an outlet in the rigid container adapted to drain blood to an extracoφoreal oxygenation circuit; a vacuum port in the reservoir adapted to be connected to a source of vacuum; and a flexible air impermeable membrane mounted within the container and defining a closed space sealed from the interior space of the container, the membrane having sufficient flexibility so that the closed space expands into the interior space upon a vacuum being drawn within the container, the membrane configured to expand and contact the blood surface.

Similarly, the low-prime volume circuit enhances the usefulness of a vacuum assisted venous reservoir such as one comprising a rigid, sealed outer housing; a flexible, blood-impermeable reservoir within the housing; an inlet port in the reservoir; a conduit attached to the inlet port and in communication with the interior of the reservoir, the conduit passing through a sealed opening in the housing and being connected to a source of venous blood; a vacuum conduit extending between a source of vacuum and the interior of the housing through a sealed opening; and a pressure regulator between the vacuum conduit and vacuum source. The use of the low-prime volume circuit and the methods disclosed herein also enhances various methods of surgery and significantly improves patient outcomes. For example, one such surgical method comprises securing a first cannula percutaneously in a patient; securing a second cannula percutaneously in a patient; connecting the first cannula to a venous reservoir blood inlet port; creating a negative pressure in the venous reservoir; regulating the pressure within the venous reservoir; and pumping blood from the venous reservoir through a blood oxygenator and to the second cannula back to the patient. Use of the within- described methods and apparatus in conjunction with such methods and apparatus causes less injury to the patient's blood and enhances the surgical procedures themselves, in that use of a low-prime volume circuit - particularly in conjunction with vacuum-assisted venous drainage - allows the perfusionist to insert the cannulas at any point in any available blood vessel in the patient, which is not true if conventional methods and apparatus (e.g. "gravity drainage") are used. c. Venous or Negative Pressure Monitor

In conventional VAVR systems, negative pressure is monitored prior to entry of blood into the reservoir, in order to confirm the vacuum level within the reservoir. In an LPV/VAVR system, a negative pressure monitor is also employed, albeit it is utilized for a variety of other, more novel, reasons. In particular, in accordance with various preferred embodiments of the present invention, a negative pressure monitor is utilized (a) to monitor the condition of the cannula in the vena cava; (b) to monitor the pressure at which blood is being pulled from the patient; and (c) to monitor the function of the low-prime system.

A useful venous pressure monitor according to the present invention, such as the DLP device available from Medtronic DLP, Inc. (Grand Rapids, MI), is appropriate for use with the within-described LPV system and with alternative embodiments thereof. In conjunction with the use of an LPV circuit, the venous pressure monitor is utilized to measure the pressure at which one is pulling blood from the patient. That is, it measures the pressure in the venous line.

Moreover, the monitor (or an equivalent device) is used herein to monitor the condition of the cannula in the patient's vena cava — in essence, it measuring the "pulse pressure." Measurements are taken via a sensing apparatus (sensor) that is preferably located at any location along the venous line between the cannula tip inserted into the patient's blood vessel and the venous reservoir. In the exemplary system illustrated in Figure 3, the sensor is located on the venous line proximal to where it connects to the reservoir at the "Y" junction, as the hydrostatic differential appears to be minimal there. As noted previously, however, the sensing means can be located anywhere along the venous line between the cannula terminus and the reservoir.

We have discovered that if there are significant fluctuations or "jumps" in the readout (or display) on the monitor, then the skilled practitioner will know whether (1 ) the cannula is properly placed in the vein; (2) whether or not the patient's tissue is being sucked into the cannula; and (3) whether the pressure is too high, and to what degree. This novel use and inteφretation of the readout allows a skilled practitioner to have an "early warning" of potential problems. For example, the monitor display instantaneously tells the perfusionist how much pressure there is. If negative numbers are "jumping" in the readout, this indicates that there is too much pressure. If the fluctuations in numbers are small, this indicates that the pressure is correct. If the numbers are fixed or not changing, the perfusionists know they do not have the cannula properly placed or that there is too much pressure, as tissue is being drawn into the mouth of the cannula. While a visual readout is typically employed in such a monitor, an auditory signal may also be produced for similar reasons — i.e. to alert the person(s) monitoring venous pressure to potential problems or to confirm proper placement and functioning of the cannula and related equipment. Many useful signaling devices useful in such an apparatus are known to those of skill in the art and are adaptable for use as disclosed herein. d. Advantages of Combined LPV/NANR Use A number of advantages have been noted with the combined use of the low- prime circuit and vacuum-assisted venous return. While some of these improvements may be largely - or exclusively - due to one device/methodology more than the other, they nonetheless show that the use of the within-disclosed invention confers unexpected benefits upon the patient as well as health practitioners and the health-care system itself.

For example, venous return flow rates no longer depend on the physical location of the reservoir with respect to the operating table. Use of LPN/NANR also provides quicker responses within the system which do not impair the safety of the patient but actually enhance it. In combination with the increased blood volume in the reservoir due to the use of LPV circuits, the margin of safety to the patient is further enhanced.

The use of LPN/NANR also makes it possible - and even preferable - to use smaller cannulas. This provides surgeons with even greater access to the surgical site. The use of NANR means there is no such thing as an 'air lock' in the CPB system, as there is with non-vacuum systems. Enhancement of NANR with LPN also reduces the risk that air bubbles will be introduced from the reservoir, as the majority of the extracoφoreal blood volume is maintained in the reservoir.

Again, the foregoing represent just a few of the improvements observed and expected with the use of the methods and devices of the present invention. 3. Reduction of Surface Area

Another method of reducing complications during and after surgery (e.g. activation of the complement system), thereby improving the patient outcome, is through the reduction of the surface area of blood-contacting devices in the circuit. One means of accomplishing this goal is via the reduction in the length of the circuit, concomitant with the reduction of the prime volume, as discussed at length in subsection 1 above.

Another means of accomplishing this goal is via the reduction in size, number and volume of the various pumps and reservoirs used in the circuit. For example, the use of a combined venous reservoir / cardiotomy reservoir reduces the surface area of the circuit to which the patient's blood is exposed, thereby decreasing the risk of complications (e.g. thrombogenesis). Reduction of the need for use of a hemoconcentrator or cell saver via use of the low-prime circuit disclosed herein also results in the reduction of surface area with which the patient's blood might otherwise come into contact, thereby improving the patient's prognosis during and after surgery significantly.

Still another method of reducing the surface area of the circuit is via the use of smaller-bore tubes and cannulas. For example, cannula sizes for older children and teens range from about 18-26 Fr, although larger sizes may also be used (e.g. 36 Fr). Smaller cannulas tend to be used for pediatric applications, particularly for infants and children. Cannulas of varying sizes are readily obtainable from commercial sources; for example, cannulas down to 8 Fr in size may be obtained from Baxter Research Medical, Inc. (Salt Lake City, UT).

French (Fr) is a term for the outside diameter - or OD - of the cannula, and the conversion to metric is: 1mm = πFr. Thus, an 8 Fr cannula has an OD of 2.54 mm. The bore size of a particular Fr cannula will depend on the thickness of the cannula wall. For example, Baxter Research Medical has developed an extrusion process which brings the wall thickness of an 18 Fr cannula down to 0.18 inches (0.457 mm) from between 0.022- 0.027 inches (0.559 - 0.686 mm) for earlier designs fabricated by conventional dipping methods. An 18 Fr cannula has an OD of 5.73 mm. With a wall thickness of 0.457 mm, the ID (inner diameter) is 4.816 mm. Conventional 18 Fr cannulas would have a maximum ID of 4.612 mm. The increase in the cross-sectional flow area through extruded cannulas is thus 9%. This increase, in combination with drawing a negative pressure in the cannula, greatly facilitates the use of smaller and smaller cannulas.

It should be emphasized that cannulas smaller than the currently available 8 Fr size may become viable for neonatal care, for example, with the vacuum-assisted drainage and thin- walled cannulas. In other words, the benefits of the present invention will be realized by patients of all sizes. Moreover, the reduction in extracoφoreal blood prime volume which is realized by locating the reservoir closer to the vein and by reducing the length of the entire circuit is particularly significant for neonates and infants, who have a much lower blood volume in their cardiovascular systems than older children, adolescents, and adults.

Thus, an improved LPV circuit of the present invention also makes use of cannulas having a reduced diameter over those used in conventional cardiovascular surgery and CPB systems. The reduced diameter cannulas may be inserted directly into the right atrium of the heart or to the vena cava. Alternatively, the cannulas may be inserted into other vessels of the patient's circulatory system when and where appropriate, as use of the LPV circuit - particularly in conjunction with VAVR - makes it unnecessary to restrict placement of cannulas as is required with gravity-drainage systems. The flow rates for venous drainage using the present system are preferably in the range of about 0.0 to 7.0 L/min, depending on the procedure used, albeit other flow rates are contemplated for use in conjunction with the disclosed devices and methods. Thus, it will be apparent to one of ordinary skill in the art that the present system obtains CPB flow rates that are compatible with conventional ones (and which may be further enhanced), while at the same time providing numerous other advantages over prior systems which make use of expensive positive pressure pumps and/or which require increased priming volumes, while still obtaining the desired reduced cannula diameters. E. Detailed Description of an Illustrative Embodiment

The following detailed description and the accompanying drawings are provided for puφoses of describing one (1) embodiment of the present invention and are not intended to limit the scope of the invention in any way. Moreover, it should be emphasized that much of the tubing illustrated in Figures 11-13 is actually shorter than it appears in the drawings — that is, the drawings are not to scale. Lengths and proportions of various components of the LPN circuit are exaggerated in order to allow the reader to identify said components. Referring now to the drawings, the present low-prime volume (LPN) system used in a cardiopulmonary by-pass system, preferably a vacuum assisted venous drainage system, is generally illustrated in Figure 3 and bears reference numeral 10. The arrows that appear alongside various lengths of tubing in the drawings are intended to indicate the desired direction of fluid flow. The present system preferably includes a sealed reservoir 12, interconnected with a vacuum regulator subassembly 14, a valve subassembly 16, and a vacuum supply line 18 interconnected with a vacuum wall source 20. The reservoir 12 is preferably supplied with blood flow from the patient P via reduced diameter cannulas 22 (not shown), and may be interconnected with either a heart/lung machine 24, partially illustrated in Figure 3, or to a combination of components used in the heart/lung machine, such as roller pumps 26, 26a, 26b, 26c a blood oxygenation and heat exchange unit 28 and a filtration unit 30. It will be understood by one of ordinary skill in the art that each of these components is conventional, and readily available from numerous well known sources.

The improved system preferably uses cannulas having diameters of approximately 20F to 28F, but it is anticipated that even smaller diameters may be used. As schematically illustrated, these are either inserted directly into the right atrium RA of the heart, as shown in Figure 3, to the vena cava, or may alternatively be inserted as desired. The cannulas are conventional single stage venous cannulas (available, for example, from Medtronic DLP, Inc., Grand Rapids, MI). The cannulas 34 are interconnected with conventional 3/8 inch surgical tubing 36, which is interconnected with an inlet port of the reservoir 12. In the preferred embodiment, the reservoir 12 is an HSR-4000 Gold hard-shelled venous reservoir which is closed to the atmosphere and has a fixed volume, or is not flexible. (The reservoir is available, for example, from Baxter Healthcare Coφoration, Bentley Division, Irvine, CA.) The reservoir 12 includes various inlet and outlet ports described as follows: vacuum inlet 40 indirectly connected to the vacuum supply line 18 and vacuum wall source 20 which supplies a vacuum to the reservoir; a venous blood inlet 42 which supplies venous blood flow from the patient via tubing 36, and a blood outlet 44 which supplies blood from the reservoir to the blood oxygenation and heat exchange unit 28, the blood filtration unit 30 and the patient P, using the roller pump 26. An additional optional venous blood supply line may also be provided, but is not illustrated in use in Figure 3, as a clamp C is provided on tubing 36b. The additional cardiotomy blood inlets 46, 46a may also be used, as in the illustrated embodiment, but may also be sealed using conventional caps or plugs in these connectors. In the alternate embodiment of Figure 5, cardiotomy blood inlet 46' may be used to supply cardiotomy blood via vent line 47' and suction line 48' to be combined with the venous blood supply of the reservoir 12'. Referring back to Figure 3, the vent and suction lines 47, 48 are manually operated by the surgical staff to remove blood from the patient P.

It is noted that where similar or duplicate elements are referred to they will be referred to with an additional alphanumeric designation, and where they are present in an alternate embodiment of the present system, the elements will be referred to with a prime designation. In either case, duplicate elements will not be described in further detail to the extent their performance is substantially similar to the embodiments previously described. For example, the roller pumps illustrated in Figure 3 will be referred to as 26, 26a, 26b, etc., and in Figure 5 as 26', 26a', 26b', etc.

In conventional NANR systems, negative pressure is monitored prior to entry of blood into the reservoir 12, in order to confirm the vacuum level within the reservoir. Thus, in general, a negative pressure monitor 38 (e.g., a digital Series 60000 pressure display momtor available from Medtronic DLP, Inc., Grand Rapids, MI) is positioned to receive blood via tubing 37 from an interconnecting joint 36j intermediate tubing 36 and tubing 36a. A conventional Luer port 39 is also provided at this interconnection so that blood samples may be withdrawn if desired. The preferred negative pressure of blood, which is continuously measured at this point within the system, is approximately -25 to -70 mmHg. In an LPN/NANR system, a negative pressure monitor 38 is also employed, albeit it is utilized for novel puφoses. As discussed in greater detail in subsection 2.c. above, monitor 38 is utilized not simply to confirm the vacuum level within the reservoir, but to monitor the condition of the cannula in the vena cava, the pressure at which blood is being pulled from the patient, and other details. The vacuum inlet connection 40 to the reservoir 12 is interconnected with a reservoir supply line 50, which is indirectly connected with the vacuum wall source 20. This series of interconnections provides a vacuum to the reservoir, to place the reservoir under negative pressure and enable drainage of venous blood from the patient P through the system. In the preferred embodiment, the vacuum wall source 20 used is the conventionally available source of vacuum supplied to many, if not all, U.S. surgical rooms. As previously described, the wall source supplies a vacuum at a constant pressure of approximately -450 mmHg. Attached to the wall source 20 via a conventional fastener, is the vacuum supply line 18.

Intermediate the reservoir supply line 50 and the vacuum supply line 18, a vacuum regulator subassembly 14 and valve subassembly 16 are provided. The regulator subassembly 14 includes a vacuum gauge 60 and a vacuum regulator 62. The vacuum gauge 60 is used to monitor the negative pressure level of the system, and is preferably a conventional Duro-United vacuum gauge, with an inlet port 61. The vacuum regulator 62, has a delivery gauge 64 with an on/off lever 66, and an adjustment knob 68 to enable increasing and or decreasing adjustment of the pressure level as desired. As shown in Figures 11 and 12, the vacuum regulator is a conventional general puφose suction regulator (available from Nellcor Puritan Bennett Inc., Pleasanton, CA), having a first inlet port 69 and a second outlet port 70.

Referring to Figures 11 and 12, a manifold 72 is interconnected between the vacuum gauge inlet port 61, the vacuum regulator first inlet port 69 and the vacuum supply line 18. In the illustrated embodiment of Figure 3, the manifold 72 is a section of hollow steel tubing with first, second and third ports 74, 76, 78, respectively. A threaded interconnection connects the manifold 72 with the inlet port 61 of the vacuum gauge 60 at the first port 74, the first inlet port 69 of the vacuum regulator 62 at the second port 76 and a friction fit engagement with the vacuum supply line 18 at the third port 78. Using this arrangement, the manifold 72 is continuously supplied with negative pressure via the supply line 18. The manifold 72 supplies the vacuum gauge 60 and the vacuum regulator 62. The vacuum gauge 60 provides a reading of the negative pressure level within the system emanating from the wall source 20. Through the vacuum regulator 62, the present system is supplied with negative pressure at the level set using the adjustment knob 68 and the on/off lever 66. In the illustrated embodiment of Figure 3, the manifold 72 is shown clamped within a conventional adjustable support clamp 80. The support clamp is itself clamped within a conventional adjustable horizontal clamp 82. The horizontal clamp 82 is engaged along a vertical pole 84 which is secured to the surgery room floor or other fixed equipment. The vertical pole 84 likewise adjustably supports the negative pressure monitor 38. The reservoir 12 and reservoir supply line 50 are indirectly supplied with negative pressure via the second port. 70 of the vacuum regulator 62. Intermediate the vacuum regulator 62 and the reservoir supply line 50 is a conventional vapor trap 86. The vapor trap 86 protects the regulator subassembly from damage due to vapor return from the direction of the reservoir supply line 50. The valve subassembly 16 is positioned intermediate the regulator subassembly 14 and the reservoir 12. The valve subassembly 16 includes a conventional check valve 88, which is supplied with negative pressure from the vapor trap 86 via tubing 87. The check valve 88 serves as a safety relief valve, which, when the system negative pressure level reaches -80 mmHg, the valve operates to let in room air. A still further vapor trap 90 is provided for protection of the vacuum regulator subassembly 14 which is interconnected with the check valve 88 via tubing 89. The trap 90 may be supported on the roller pump 26, as illustrated, or on other available support structure. From the vapor trap 90, negative pressure is supplied via the vacuum inlet 40 to the reservoir 12 via tubing 50a and through an interconnecting joint 50j intermediate tubing 50a and tubing 50. A manual system disable line 52 also extends from the interconnecting joint 50j. The line 52 is conventional tubing secured with a surgical clamp 54. When the system is in "on" condition, supplying negative pressure to the reservoir 12 for drainage of venous blood from the patient P, the clamp 54 is clamped on the tubing 52 as shown. When the clamp 54 is removed, the system 10 is open to atmosphere, and no vacuum is provided through the system. This manual system disable line 52 provides a convenient "on" to enable the system, as well as an immediate shut off for the system, should this become necessary during system operation.

Prior to operation of the system, the adjustment knob 68 of the vacuum regulator 62 is used to preset the estimated desired vacuum level. The desired vacuum level is estimated based upon numerous patient characteristics and surgery factors, such as size of the patient, the procedure being performed, the cannulas being used, etc., which are well known to those of ordinary skill in the art, and range between -25 and -70 mmHg. Once the patient is prepared, the heart/lung machine 24, or the arterial pump 26 component of the patient support unit, is then activated. Likewise, the cardioplegia supply pump 26a may be activated when it is desired to supply the patient P with additional blood/fluid components. The vent pump 26b and suction pump 26c may also be activated to remove blood from the patient P as desired.

As shown in Figure 3, cardioplegia fluid is supplied to the cardioplegia supply pump 26a from one or more supply bags 120 (containing either blood or other fluids) via tubing 122. Activation of the pump 26a enables the supply of cardioplegia fluid mixed by the pump 26a through a heat exchange unit 124 having a heating/cooling port inlet 106a, and a port outlet 106b. The unit 124 is supplied with hot or cold fluid, typically water, depending on the temperature change desired, via the port inlet 106a, which fluid is removed via the port outlet 106b. Following appropriate heating or cooling, the cardioplegia fluid is pumped via tubing 122a to the patient P as indicated. The activation of the vent pump 26b and/or suction pump 26c, removes blood from the patient via the hand held devices illustrated, or other conventional mechanisms, to the vent line 47 or suction line 48, respectively. The roller pumps 26b, 26c, supply the removed blood to the cardiotomy blood inlets 46a, 46, respectively, via tubing 49, for combination with the direct venous blood flow to the reservoir 12. Turning again to the further operation of the system 10, when the vacuum regulator "on/off lever 66 is in the "on" position, and the manual system disable line 52 is clamped in the closed condition, the system is supplied with negative pressure and venous drainage to the reservoir 12 immediately commences without requiring priming of any of the lines 36, 36a. The application of the desired negative pressure to the system immediately, and without priming of the venous lines, provides venous blood flow to the reservoir 12. The system vacuum levels are confirmed on the negative pressure monitor 38, vacuum gauge 60 and delivery gauge 64.

The venous blood flow B supplied to the filtered reservoir 12 is returned to the patient P via pump 26 of the patient support unit or heart/lung machine 24, as previously described. Blood exits the reservoir 12, through the blood outlet 44, 44' to, and using, the roller pump 26, 26' and tubing 100, 100'. The blood is then pumped in the direction of the arrows illustrated, via tubing 102, to the oxygenation and heat exchange unit 28 for removal of CO₂ and the addition of oxygen. The unit 28 is of a conventional design, with a gas exhaust 104 for CO₂ output, and a gas inlet (not illustrated, but positioned adjacent the gas exhaust 104) for oxygen input. The unit 28 is a conventional device having a stainless steel support structure 32. The unit 28 is supplied with hot or cold water, depending on the temperature change desired, via heating/coolant inlet port 106, and outlet port 106c (not illustrated). As with the cardioplegia heat exchange unit 124, the hot or cold fluid is provided to the inlet port 106 at a rate of approximately 20 l/min, for appropriate temperature adjustment of the blood or fluid between 10° - 37° C. The warmed blood B is then returned to the patient P via outlet 107 and tubing 108, 108a, 108b through the filtration unit 30. Tubing 110 supplies the filtered blood directly to the aorta A via reduced diameter cannulas 34, as illustrated. (As noted earlier, the actual length of tubing 110 — and of various other lengths of tubing — is much shorter than it appears in the illustration.)

The filtration unit 30 is conventionally available, and provides a filter of 20μ for blood passing therethrough. A prime port 130 permits the return of blood, as well as vapor, to the reservoir via prime inlets to the reservoir 134, 134a. The present system provides return blood flow to the patient at approximately 7 l/min. In the event additional blood flow is required, or filtration is not required, blood flow may be provided to tubing 110 for direct return to the patient via tubing 108c. The surgical clamp Ca is manually used to determine the desired flow pattern. As further noted in Figure 3, that conventional prime ports 130, 132 may be provided from the filtration unit 30 and oxygenation and heat exchange unit 28, respectively, to prime inlets 134, 134a in the reservoir 12 via the tubing indicated. The priming fluid may be provided from supply bags 136 via the tubing as indicated in Figure 3. Also as shown, conventional priming of the filtration and oxygenation and heat exchange units may be clamped or valved to prevent or permit flow as may be desired. The availability of such return lines to the reservoir 12 permits recirculation of blood flow during use of the system as may be required.

In the embodiment of Figure 3, it should be understood that four roller pumps 26, 26a, 26b, 26c are used, as blood from the vent line 47 and suction line 48 is removed from the patient using the positive pressure of roller pumps 26b and 26c, respectively. In the embodiment of Figure 5 of the present system, only three pumps are shown in use. The operation of two vent and suction pumps are combined in one pump 26b' to supply blood pumped from the patient to the reservoir 12'. As shown in Figure 5, the present vacuum assist system is used to indirectly connect a single or multiple vent and/or suction tubing lines supplying blood from the patient P to the pump 26b', under a vacuum. It will be understood by one of ordinary skill that any number of vent lines may be used in the present system, as are desired or not, during operation of the system. As illustrated in the embodiment shown in Figure 5, each of the vent and suction tubing lines 47', 48', respectively, supply blood from the patient to an intermediate reservoir subassembly 140', supported on an adjustable bracket 82'. The intermediate reservoir subassemblies 140' are under a predetermined desired negative pressure as illustrated, which is -10 mmHg for the vent lines, and -20 mmHg for the suction lines. As illustrated in Figure 5, between each of the intermediate reservoir subassemblies 140' and the vacuum wall source 20' are elements of the vacuum regulator subassembly 14' substantially as previously described and illustrated. A vacuum gauge 60' monitors system vacuum levels, and individual vacuum regulators 62' for each vacuum line are provided to adjust the negative pressure level as needed. The manifold 72' interconnects each of the respective regulators 62' and the gauge 60'. Vapor traps 86' are additionally used adjacent each of the regulators 62' to protect the regulators from vapor damage.

In addition to the valve subassembly 16' components which are similar to those in Figure 3, the Figure 5 embodiment includes additional check valves 88a positioned between the vapor traps and the intermediate reservoir subassemblies 140' to prevent high negative pressure as previously described. Each of the intermediate reservoirs 140' is a hard shelled, sealed unit, preferably including a replaceable liner or bag 146 (not shown). Due to the use of such liners, the intermediate reservoirs are preferably reusable. As illustrated, once cardiotomy blood is supplied from the vent and suction lines to an inlet 141 of the intermediate reservoir subassemblies 140' under a vacuum, it is removed for providing to the reservoir 12' via the transfer or positive pressure roller pump 26b'. The blood is removed from each of the intermediate reservoirs 140' via reservoir tubing 142 to an outlet 144, which is interconnected with tubing 89a, and by the interconnection illustrated, with tubing 89b.

Other differences illustrated in the embodiment of Figure 5 include the elimination of priming lines to the reservoir 12', as well as the connection of the prime port 132' from the oxygenation and heat exchange unit 28' directly to the input of the cardioplegia pump 26a', at tubing 122', for mixing by the pump 26a'.

Flow rates for venous blood flow both to and from the system using the embodiments illustrated and described are preferably in the range of 0.1 to 7.0 l/min, depending on the procedure used. It should be understood by one of ordinary skill in the art that various modifications to the details of construction, use and operation of the embodiments of the present system may be made, all of which are within the spirit and scope of the claims.

The foregoing specification, including the specific embodiments and examples, is intended to be illustrative of the present invention and is not to be taken as limiting. Numerous other variations and modifications can be effected without departing from the true spirit and scope of the present invention.

Claims

We claim:

1. An extracoφoreal blood circulation system comprising a circuit having one or more components through which a patient's blood circulates, said one or more components including: an inlet line adapted to receive blood from the patient; an outlet line adapted to return blood to the patient; a fluid circuit for fluid communication between the inlet and the outlet line; a reservoir for receiving blood from the venous system of the patient; a source of vacuum; a vacuum conduit extending between the source of vacuum and the reservoir and configured to create a negative pressure within the reservoir; and a pressure regulator in the vacuum conduit, wherein one or more of the circuit components has a reduced blood-contacting surface area, thereby reducing the hemodilutional prime volume by 20-30%.

2. The system of claim 1 , wherein the hemodilutional prime volume is reduced by 30-40%.

3. The system of claim 1 , wherein the hemodilutional prime volume is reduced by 40-50%.

4. The system of claim 1, wherein the hemodilutional prime volume is reduced by 50% or more.

5. The system of claim 1, wherein said component is a segment of tubing and said blood-contacting surface area is reduced by decreasing the length of said segment.

6. The system of claim 1 , wherein said component is a segment of tubing and said blood-contacting surface area is reduced by decreasing the internal diameter of said segment.

7. The system of claim 1 , wherein said patient is an adult and said hemodilutional prime volume is less than one liter.

8. The system of claim 1 , further comprising a device adapted for use in monitoring the pressure at which blood is being pulled from said patient, thereby monitoring the function of the system.

9. A method for performing a therapeutic surgical procedure on a patient comprising passing circulating blood from a first blood vessel of said patient through an extracoφoreal blood circulation system having a reduced blood-contacting surface area and back to a second blood vessel of said patient, wherein the hemodilutional prime volume of blood circulated through said system is at least 20% less than the hemodilutional prime volume of blood circulated through conventional gravity-assisted cardiopulmonary bypass systems.

10. The method of claim 9, wherein said hemodilutional prime volume is at least 35% less than the hemodilutional prime volume of blood circulated through conventional gravity-assisted cardiopulmonary bypass systems.

11. A method for performing a therapeutic surgical procedure on a patient comprising passing circulating blood from a first blood vessel of said patient through an extracoφoreal blood circulation system having a reduced blood-contacting surface area and back to a second blood vessel of said patient, wherein the hemodilutional prime volume of blood circulated through said system is at least 20% less than the hemodilutional prime volume of blood circulated through conventional vacuum-assisted cardiopulmonary bypass systems.

12. The method of claim 11 , wherein said hemodilutional prime volume is at least 35% less than the hemodilutional prime volume of blood circulated through conventional vacuum-assisted cardiopulmonary bypass systems.

13. A low-prime volume cardiopulmonary bypass circuit comprising: a conduit through which physiological fluid is received from and returned to a patient, said conduit comprising one or more segments of tubing, wherein said tubing has a reduced blood-contacting surface area, thereby reducing the volume of prime needed; a vacuum-assisted venous drainage system comprising a hard- shelled venous reservoir closed to the atmosphere and having a blood inlet for supplying blood removed under negative pressure during cardiopulmonary bypass to the reservoir, a blood outlet for removing blood from the reservoir, and a vacuum inlet for supplying a vacuum to the reservoir; a vacuum supply for providing a predetermined desired vacuum to said venous reservoir via said vacuum inlet; and a patient support unit for receiving blood from said reservoir blood outlet, treating and returning revitalized removed blood under positive pressure; and a device adapted for use in monitoring the pressure at which blood is being pulled from said patient, thereby monitoring the function of the system.

14. The circuit of claim 13 , wherein no segment of tubing exceeds 58 inches in length.

15. The circuit of claim 13 , wherein the volume of prime needed is 1 liter or less.

16. A method for reducing the risk of surgically-exacerbated injury to a patient undergoing cardiovascular surgery comprising passing circulating blood from a first blood vessel of said patient through a vacuum-assisted extracoφoreal blood circulation system having a reduced blood-contacting surface area and back to a second blood vessel of said patient, thereby minimizing the hemodilutional prime volume of blood circulated through said system.

17. The method of claim 16, wherein said surgically-exacerbated injury is selected from the group consisting of reduction in hematocrit, complement activation, platelet activation, leukocyte activation, platelet- leukocyte adhesion, and inflammation.

18. The method of claim 16, wherein said patient is an adult and said hemodilutional prime volume is less than one liter.

19. The method of claim 16, wherein said extracoφoreal blood circulation system comprises one or more segments of tubing and said internal surface area is reduced via decreasing the length of one or more of said segments.

20. The method of claim 16, wherein said extracoφoreal blood circulation system comprises one or more segments of tubing and said internal surface area is reduced via decreasing the internal diameter of one or more of said segments.