Hemostatic system and components for extracorporeal circuit

Details Hemostatic system and components for extracorporeal circuit Hemostatic system and components for extracorporeal circuit

2000-09-15

2004-05-11

Bianco, Patricia (Department: 3762)

Surgery

Blood drawn and replaced or treated and returned to body

C604S005010, C604S006090, C422S044000, C128SDIG003, C210S645000, C210S739000, C210S743000, C210S198100, C210S348000

Reexamination Certificate

active

06733471

ABSTRACT:

TECHNICAL FIELD
The present invention relates to surgical and other procedures, such as cardiopulmonary bypass procedures, that involve the use of extracorporeal blood flow. In a related aspect the invention relates to sensors and filters for determining and affecting the presence or level of blood components such as heparin and administered drugs and their metabolites.
BACKGROUND OF THE INVENTION
The heart-lung machine is a system used for cardiopulmonary bypass (“CPB”). Since the development of a prototype system by Dr. John Gibbon in 1953, the use of CPB has evolved to the point where it is now commonplace, and permits major surgical procedures to be performed on the heart.
While on bypass, the blood flow is diverted around the heart and lungs, as a machine takes over the responsibility of both oxygenating the blood and maintaining blood flow. Cardiopulmonary bypass permits the surgeon to operate on the heart while the heart-lung machine sustains circulation throughout the body. Oxygen-poor blood that would normally enter the heart through the superior and inferior vena cavae, is shunted off through the superior vena caval cannula and the inferior vena caval cannula. Once oxygenated, the blood is returned to the body through the aortic cannula.
The typical CPB circuit includes several components, including one or more oxygenators, heat exchangers, tubing sets, filters, pumps and reservoirs. The circuit is often used, in turn, in combination with one or more drugs such as heparin, which is an anticoagulant that is both administered intravenously and can be used to coat blood contacting surfaces. At the conclusion of surgery, the presence and effect of heparin is reversed, typically in a rapid manner, by the administration of a drug such as protamine. Protamine, which is derived from salmon sperm, is highly positively charged and serves to effectively neutralize the negatively charged heparin in a cationic/anionic interaction. Protamine, however, has its own drawbacks, in the form of potential allergenic and inflammatory responses.
Extracorporeal circulation, such as that used during cardiopulmonary bypass, continues to be associated with various drawbacks, however, including both inflammation and excessive bleeding. The inflammatory response is believed to be caused, or exacerbated, by various factors, including the various flow forces (e.g., shear associated with turbulence and suction) involved in CPB, and by the exposure of blood to both foreign surfaces and to air. Exposure of the blood to oxygenators, pumps, and blood salvage and tubing sets, is well documented to activate inflammation responses during and post bypass procedures. In addition, the process of removing the anticoagulant heparin, post bypass, by addition of protamine is also documented to activate inflammatory processes. Inflammation, in turn, can cause both cell damage and diminished organ function, leading to increased morbidity and a longer recovery time with an increase in both length of hospital stay and costs.
Inflammatory injury occurs when the patient's own blood, after circulating through the CPB circuit is returned to the patient. The inflammation reaction induced by extracorporeal circulation also has the potential of increasing patient risk of inducing the “whole body inflammatory response” and ensuing organ failure. Approximately 600,000 cardiac surgical procedures requiring CPB are performed annually in North America and approximately 400,000 in the rest of the world. Most, if not all, of such procedures involve the need to monitor both heparin concentration and whole blood Activated Clotting Time (ACT).
As mentioned above, the use of heparin and protamine may be associated with a number of adverse effects. Close monitoring of the heparin concentration and clotting time is required due to risk of clotting, if the heparin levels drop excessively low. Similarly, excessively high levels of heparin can require correspondingly high dosages of protamine. Although life-threatening, protamine-related reactions occur in less than 5% of cardiac surgical patients. Still, the use of protamine is broadly problematic and severe reactions to protamine complex are idiosyncratic.
Moreover, protamine is difficult to titrate. The existence of many dosing regimes attests to the fact there is no agreement among practitioners as to how best the drug should be used. Protamine may be dosed on the basis of 1) body weight or surface area, 2) by a fixed ratio to the initial dose of heparin, 3) by fixed ratio according to the total heparin dose, or 4) by response to the activated clotting time (ACT). Because protamine itself has anticoagulant properties when given in excess, the ideal protamine dose results in plasma levels just exceeding the heparin concentration. However, there is evidence that fixed-ratio dosing schemes tend to result in excessive protamine administration.
While the ACT is used as a functional test for the adequacy of heparin reversal, it does not provide an index of how much protamine is required to reverse heparin. This is, in part a function of large patient-to-patient variability in heparin pharmacodynamics and pharmacokinetics (e.g., the half-life for heparin may vary for 30 min to 2 hr). While this functional test is used in practice when bleeding is present, additional repeated doses of protamine are often given even when the ACT is normal.
These and other complications associated with heparin and protamine dictate that management of patient's heparin concentration and clotting time be closely monitored. Typically, however, heparin concentration is not accurately recorded during CPB, due largely to the lack of suitable methods and instrumentation. At most, some facilities measure a heparin concentration “range” by removing plasma and performing a heparin determination by protamine titration, using a commercially available device. Such an approach has several drawbacks, however, including the lack of a direct measurement of heparin concentration, the need for manual blood draws, and heparin concentrations that are provided in gross increments.
Another complication of surgical procedures that involve CPG is excessive bleeding. A recently approved drug known as aprotinin can effectively reduce blood loss and decrease the need for transfusions. Aprotinin was studied for use mainly in heart surgery because the circulation of the blood outside the body in this surgery increases the likelihood of excessive bleeding during and after surgery.
Aprotinin (TRAYSL™, Bayer) is a natural protease inhibitor derived from bovine lung, and acts by inhibiting trypsin, chymotrypsin, plasmin, tissue plasminogen activator, and kallikrein, thereby directly affecting fibrinolysis. It also inhibits the contact phase activation of coagulation which initiates coagulation and promotes fibrinolysis. In addition, aprotinin preserves the adhesive glycoproteins in the platelet membrane, rendering them resistant to damage from the increased plasmin levels and mechanical injury that occur during cardiopulmonary bypass. The net effect is to inhibit both fibrinolysis and turnover of coagulation factors and to decrease bleeding. T1/2, IV: 150 min with a terminal elimination phase half-life of 10 hr. Aprotinin is slowly broken down by lysosomal enzymes, although depending on the dose, up to 9% may be excreted through the urine unchanged.
Although aprotinin was studied in the 1960's, low doses were evaluated in an effort to treat bleeding after cardiac surgery rather than to prevent it. However, it was not until the late 1980's that prothylactic use was reported. Royston developed a pharmacologic approach to inhibit inflammatory responses during CPB administering that includes a loading dose of 2 million units of aprotinin following intubation, and a continuous infusion of 500,000 units/hour with a CPB pump prime dose of 2 million units. This has become known as the high dose or “Hammersmith regimen”. In patient's receiving aprotinin, chest tube drainage was 286 ml as compared to 1509 ml in the control.
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