Heparin-coated blood oxygenator
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For most cardiothoracic operations such as coronary artery bypass grafting, the cardiopulmonary bypass is performed using a heart-lung machine (or cardiopulmonary bypass machine). The heart-lung machine serves to replace the work of the heart during the open bypass surgery. The machine replaces both the heart's pumping action, and adds oxygen to the blood. Since the heart is stopped during the operation, this permits the surgeon to operate on a bloodless, stationary heart.
One component of the heart-lung machine is the oxygenator. The oxygenator component serves as the lung, and is designed to expose the blood to oxygen. It is disposable, and contains about 2-4 m² of a membrane permeable to gas but impermeable to blood, in the form of hollow fibers. Blood flows on the outside of the hollow fibers, while oxygen flows in the opposite direction on the inside of the fibers. As the blood passes through the oxygenator, the blood comes into intimate contact with the fine surfaces of the device itself. Oxygen gas is delivered to the interface between the blood and the device, permitting the blood cells to absorb oxygen molecules directly.
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[edit] Rationale
Operations which involve uncoated oxygenators require a high dose of systemic heparinization. There are a number of side effects associated with this. The primary side effect can be post-operative hemorrhage. Systemic heparin does not completely prevent clotting or the activation of complement, neutrophils, and monocytes, which are the principal mediators of the inflammatory response. This response produces a wide range of cytotoxins, and cell-signaling proteins that circulate throughout the patient's body during surgery and disrupt homeostasis. Both the thrombotic and inflammatory responses produce thousands of microembolic particles. Microparticles obstruct arterioles that supply small nests of cells throughout the body and, together with cytotoxins, damage organs and tissues and temporarily disturb organ function. Additionally, bare oxygenators are often associated with neurological symptoms following perfusion. Physicians refer to such temporary neurological deficits as “pumphead syndrome.” Heparin-coated blood oxygenators are one option available to a surgeon and a perfusionist.
Heparin-coated oxygenators are thought to:
• Improve overall biocompatibility and host homeostasis
• Mimic the natural endothelial lining of the vasculature
• Reduce systemic anticoagulation
• Better maintain platelet count
• Reduce adhesion of plasma proteins
• Prevent denaturation and activation of adhered proteins and blood cells
• Avoid complications resulting from an abnormal pressure gradient across the oxygenator
[edit] Technology
There are several methods for the binding mechanism of heparin to the oxygenator membranes. Carmeda Bioactive Surface (CBAS), developed by Carmeda, involves the irreversible adsorption of a priming layer (polyethyleneimine). Alternating layers of PEI are treated with dextran sulfate and the crosslinking agent glutaraldehyde. After treating the coating, which includes heparin, with nitrous acid, the coating process is completed, and the result is an “end-point immobilization” of heparin.
CBAS mimics the only truly blood compatible surface - the endothelial lining of blood vessels. The heparin molecules on the CBAS-coated surface may be described as “swaying in the bloodstream like seaweed in water”, thereby enabling their active sequence to interact with substances in the flowing blood. In addition, the substrates on which the coating is attached can be a variety of polymers, glass, and metals.
The following steps show the mechanism by which the CBAS system anticoagulates blood perfusion. It is a good representation of how all heparin-coated oxygenators function:
• CBAS heparin "active sequence" binds with antithrombin.
• Antithrombin conforms to accelerate binding with thrombin and other coagulation factors.
• Coagulation effect of thrombin is neutralized by formation of thrombin-antithrombin complex.
• Thrombin-antithrombin complex washes away.
• CBAS heparin "active sequence" remains intact and is repeatedly available to bind with antithrombin.
The coating remains attached long-term and is considered permanent, so therefore there is no leaching and release-rate associated with heparin on this device. As a result, there is no significant systemic heparinization.
[edit] Surgical outcomes
Heparin coating is reported to result in similar characteristics to the native endothelium. It has been shown to inhibit intrinsic coagulation, inhibit host responses to extracorporeal circulation, and lessen postperfusion, or “pumphead,” syndrome. Several studies have examined the clinical efficacy of these oxygenators.
Mirow et al 2001 examined the effects of heparin-coated cardiopulmonary bypass systems combined with full and low dose systemic heparinization in coronary artery bypass patients. The researchers concluded that:
• Heparin-coated extracorporeal circuits with reduced systemic heparinization lead to significantly increased thrombin generation.
• Postoperative bleeding was reduced with low systemic heparinization, but the reduction was not significant.
Ovrum et al 2001 compared the clinical outcomes of 1336 patients with the Carmeda Bioactive Surface and Duraflo II coatings. The researchers concluded that:
• Duraflo II patients required less heparin to keep the target activated clotting time
• Effects on renal function and platelets were similar
• Incidences of perioperative MI, stroke, and hospital mortality were similar
• Reduced incidence of postoperative atrial fibrillation compared to identical uncoated controls
• Overall clinical results were favorable in both groups
Statistics and conclusions from more studies are available here. Clearly, heparin-coated blood oxygenators exhibit some advantages over non-coated oxygenators. Most hospitals now use heparin-coated oxygenators for the large majority of their cases requiring cardiopulmonary bypass. It is unclear whether most surgeons actually reduce the amount of systemic heparin used when their patients are being perfused with heparin-coated oxygenators. Ultimately, each surgeon makes this decision based upon the needs of individual patient.
Although they offer advantages, these oxygenators are not widely regarded by surgeons as revolutionary breakthroughs in cardiopulmonary bypass. Surgeons are instead looking to off-pump cardiothoracic procedures, wherein surgery is performed on beating hearts, as the next “big thing” in open heart surgery.
[edit] Current products
Currently available heparin-coated blood oxygenators include:
• Medtronic - Carmeda Bioactive Surface
• Medtronic - Trillium Biopassive Surface (licensed from Biointeractions, LTD)
• Baxter - Duraflo II
More information on each of these products, including manufacturing methods and efficacy, can be found on the Heparin-Coated Blood Oxygenators website created at Brown University for BI 108: Organ Replacement, taught by Professor Lysaght.
[edit] See also
• Coronary artery bypass surgery
• Thrombin
[edit] External links
• BI 108: Heparin-Coated Blood Oxygenators
