Anesth Analg 2006;103:1365-1369
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000242530.81421.cc
CARDIOVASCULAR ANESTHESIA
Pro: Heparin-Coated Circuits Should be Used for Cardiopulmonary Bypass
Michael E. Jessen, MD
From the Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
Address correspondence and reprint requests to Michael E. Jessen, MD, Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX. Address e-mail to michael.jessen{at}utsouthwestern.edu.
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Introduction
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The use of cardiopulmonary bypass (CPB) for cardiac surgical operations, first performed over half a century ago, enabled the correction of previously untreatable cardiac defects and heralded revolutionary advances in the treatment of ischemic heart disease, valvular disorders, and congenital cardiac malformations. Experience with this innovative technology, however, led to the realization that extracorporeal circulation can also produce adverse effects. The most prominent deleterious feature of CPB relates to its intense stimulation of the inflammatory response, which, when severe, is believed by many to be associated with an increase in patient morbidity and mortality (1). This response includes activation of complement (2), initiation of fibrinolytic (3), kallikrein-kinin (4), and coagulation cascades (5), an increase in cytokine levels (6), and activation of neutrophils and platelets. Neutrophil activation during CPB is evidenced by fluctuations in polymorphonuclear cell counts (7), an increase in circulating neutrophil elastase levels (8), and increased expression of adhesive glycoproteins which facilitate neutrophil binding to endothelium (9). Activation of neutrophils are believed to contribute to postoperative complications, including capillary-leak syndrome (10), microvascular lung injury (11), and others (12). The effects of CPB on inflammatory cascades and activation of platelets (13) may also contribute to bleeding problems encountered after cardiac surgery.
A variety of measures have been used clinically to reduce the intensity of the inflammatory response, including administration of glucocorticoids (14), nonsteroidal inflammatory drugs (15), or prostaglandin E1 (16). Many investigations have examined the use of the serine protease inhibitor, aprotinin (17), or other antifibrinolytic drugs (18) to reduce inflammation and improve outcomes. Other strategies have included leukocyte depletion (19) or administration of monoclonal antibodies directed against endothelial adhesion antigens (20) or against the complement cascade (21). In perhaps the most extreme form, some surgeons alter the operation to avoid CPB altogether by using an "off-pump" technique for coronary bypass surgery (22).
Surgeons, anesthesiologists, perfusionists, and manufacturers have developed additional methods to alter some of the factors which can incite the inflammatory process. Membrane oxygenators have replaced bubble oxygenators, centrifugal pumps have replaced roller pumps, and less profound hypothermia is now used during CPB. But probably, the largest impact from a CPB materials standpoint has come by way of modifications to the synthetic surfaces of the CPB circuitry.
Although multiple surface modifications have been developed, the largest experience is with CPB surfaces that have been coated with heparin. Heparin-coated surfaces were first described in 1963 when Gott (23) reported an ionic linkage of heparin to a surface rinsed with a cationic surface-active agent. In 1983, Larm et al. (24) described an alterative method of heparin attachment through a covalent bonding process. The evolution of these processes and their associated manufacturing techniques has led to the development of the two main forms of heparin-coated circuits (HCC) in clinical use today: the Carmeda BioActive Surface (Medtronic, Minneapolis, MN), which uses a covalent endpoint-attached heparin, and the Duraflo II system (Edwards Lifesciences, Irvine, CA), which maintains a heparin coating on circuit components through an ionic linkage. The different forms of heparin attachment may lead to different degrees of attenuation of the inflammatory response (25) but, in general, clinical outcomes are similar with both forms of HCCs (26). As a result, the two forms will be considered equivalent in this discussion.
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EFFECTS ON THE INFLAMMATORY RESPONSE
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Studies examining the effect of HCCs on the inflammatory response are consistent: HCCs reduce inflammation as measured by a wide array of biochemical markers. Use of HCC leads to reduction in complement activation (27), suppression of leukocyte activation (28), decreased release of inflammatory cytokines (29), and reduction in leukocyte CD11b expression and leukocyte-platelet conjugate formation (30).
Much of the early emphasis in the development of HCC centered on the potential for reducing bleeding complications after extracorporeal circulation. Altering the surface characteristics of CPB equipment can reduce bleeding complications by several mechanisms. They may diminish platelet activation during extracorporeal support (31), leaving more functional platelets after the perfusion period. A more biocompatible surface may incite less fibrinolysis (32). As well, surface modifications may decrease the need for heparin during CPB, resulting in improved postoperative hemostasis.
But do these reductions in the inflammatory response translate into a meaningful clinical benefit? And, if so, does the benefit warrant the increased cost of the coated circuits? Here the answer is more difficult, as most studies have been conducted in low-risk patients in whom benefits from reduced inflammation are difficult to demonstrate. Nevertheless, a growing body of evidence supports the concept that HCCs lead to significant improvements in clinical outcomes.
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POSTOPERATIVE BLOOD LOSS AND TRANSFUSION
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A number of studies have examined the role of HCCs in reducing blood loss after cardiac surgery. Investigators have taken different approaches in their use of systemic heparin. Those using high-dose heparin (targeting activated clotting time levels >400 s) have generally not observed differences in blood loss or transfusion requirements in groups of patients undergoing surgery with HCCs when compared with those undergoing operations with control circuits (33–35). However, Sinci et al. (36) reported significantly less blood loss and transfusion requirements in patients undergoing cardiac surgery with HCCs despite the use of full systemic heparinization.
Use of HCCs provides the option of using lower doses of systemic heparin during CPB. When HCCs are used in combination with reduced heparin (targeting activated clotting times of only 180–280 s), investigators have consistently reported significant reductions in postoperative blood loss (37–43). In several studies, this decrease in bleeding has translated into a significant reduction in blood transfusion (40,44–46), a clinically desirable outcome. Many of these studies were performed in low-risk patients in whom clinical benefits are difficult to demonstrate. Use of HCCs in higher-risk groups may lead to greater advantages. This concept is supported by the observation by McCarthy et al. (47) that there were fewer major bleeding episodes in cardiac reoperations when the Duraflo II HCC was used. As well, a large multicenter European study in female patients (48) found a reduction in transfusion requirements using HCC. Overall, the evidence suggests that the use of HCCs for CPB reduces blood loss and transfusion requirements, especially when used with lower intensity heparin protocols.
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POSTOPERATIVE PULMONARY FUNCTION
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Activation of the inflammatory response by CPB can increase capillary permeability, leading to accumulation of edema in the lungs and compromising pulmonary function. Several studies have tested the hypothesis that the use of HCCs diminishes the inflammatory response and leads to improved lung function after CPB. Well-controlled studies in experimental animals, where perfusion conditions and duration of CPB can be precisely regulated, have shown improved oxygenation, lower pulmonary vascular resistance, and increased static compliance 2 h after separation from CPB, when HCCs were used (49). Clinical studies have also demonstrated improvements in pulmonary function after CPB, although the results have been more subtle. Ranucci et al. (50) identified an increase in intrapulmonary shunt and respiratory index immediately after CPB that was attenuated with the use of HCCs. These differences had disappeared when measured in the intensive care unit (ICU), and the postoperative clinical course, including intubation time, was not affected by the use of HCC. This is perhaps not surprising, as all patients had relatively normal preoperative lung function.
Several investigators have studied the use of HCC in the setting of pediatric cardiac surgery. The inflammatory response is believed to be particularly deleterious in neonates and children (51), and the surface area of the oxygenator is relatively increased when compared with the patient’s body surface area, further exaggerating the inflammatory stimulus. Even in studies with few patients, the use of HCCs has been shown to reduce peak airway pressures early after CPB (52) and to improve respiratory index and body weight ratios in the early postoperative interval (53). A larger retrospective study in pediatric patients found a significant reduction in the duration of postoperative mechanical ventilation (54). Thus, HCC use appears to be associated with improved pulmonary function after CPB, especially in the pediatric population.
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NEUROCOGNITIVE DYSFUNCTION
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Considerable interest has centered on neurologic changes after cardiac surgery. These can range from frank stroke to more subtle neurocognitive changes that can significantly impact quality of life (55). As some neurocognitive changes may be related to the inflammatory response, the use of HCCs may improve neurologic outcomes. One piece of supporting evidence comes from the observation by Svenmarker et al. (56) that the release of the astroglial protein S-100 is decreased in patients after coronary artery bypass graft surgery (CABG), when HCCs are used. Although the specificity of this protein as a marker for brain damage has been questioned (57), Svenmarker et al. also observed a reduced incidence of neurologic complications. However, a follow-up study in low-risk patients by the same group failed to confirm an effect on neurocognitive function (44).
Two prospective randomized trials from NY Presbyterian Medical Center examined this question using sensitive tests of neuropsychometric performance (58,59). These authors found fewer abnormalities on neuropsychometric tests on postoperative Day 5 in patients undergoing surgery with HCCs. The mechanism behind this finding is unknown, and long-term cognitive function was not described. Nevertheless, these results and those of a nonrandomized study by Aldea et al. (60) support the concept that HCCs confer a benefit on postoperative neurologic outcomes. Further research of the effects of HCCs on neurologic sequelae appears warranted.
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LENGTH OF ICU OR HOSPITAL STAY
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Multiple factors contribute to the length of stay in the ICU and the total duration of hospitalization after cardiac surgery. It is therefore not surprising that studies comparing these outcomes in patients undergoing cardiac surgery, with and without HCCs, have not consistently found a reduction in length of stay, even when other clinical benefits are identified (47,50,53,54). Jansen et al. (61) randomized 102 patients undergoing CABG to CPB with and without HCCs. All patients received aprotinin in the CPB priming solution. The median ICU stay was reduced by 1 day in the heparin-coated group. The cost saving of this shorter stay more than compensated for the increased cost of the HCC.
Two large multicenter trials, each enrolling over 800 patients, provide an interesting perspective on the value of HCC on hospital stay. The European Working Group (48) randomized 805 low-risk patients to receive HCCs or conventional circuits for elective CABG. Overall, no reduction in adverse events or ICU stay was identified. However, subgroup analysis of patients with aortic cross-clamp time exceeding 60 min revealed a decreased ICU stay with the use of HCCs. Ranucci et al. (62) randomized 886 patients with at least one risk factor for adverse outcome to surgery with HCCs or conventional circuits. In this higher risk population, both ICU stay and hospital stay were significantly reduced with the use of HCC. Thus, it appears that HCCs may lead to improved outcomes in high-risk patients, but clinical benefits may be hard to demonstrate in low-risk populations.
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OTHER EFFECTS
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Reducing the inflammatory response may have beneficial effects in other organs. Randomized studies by Wan et al. (63) and Belboul et al. (64) reported decreased myocardial injury based on cardiac enzyme release, when HCCs were used. Postoperative creatinine elevation was diminished with use of HCCs in one study (44), and the incidence of renal dysfunction in patients with diabetes was reduced with this technology in another (62). Curiously, the incidence of postoperative atrial fibrillation has been found to be significantly reduced when HCCs are used (33,44,65), although the mechanism responsible for this effect is not understood.
Overall, the evidence supporting significant clinical benefit with the use of HCCs is substantial. Low-risk patients are less likely to reap major benefits, although a demonstrable reduction in the inflammatory response occurs and blood loss and transfusion requirements are decreased, particularly when reduced-heparin protocols are applied. The largest clinical improvements are found with higher-risk patients, and it is in this population, where clinical advances are most needed. HCCs represent an important part in our surgical armamentarium to improve outcomes in these challenging patients. As the proportion of higher-risk patients continues to increase, the value of HCCs is likely to continue to rise in the future. Further research and development of biocompatible surface modifications for CPB circuitry is warranted, and the use of coated circuitry should be encouraged in cardiac surgery.
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Footnotes
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Accepted for publication: August 9, 2006.
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Introduction
EFFECTS ON THE INFLAMMATORY...
