Finding a common definition of heparin resistance in adult cardiac surgery: communication from the ISTH SSC subcommittee on perioperative and critical care thrombosis and hemostasis.

Ensuring adequate anticoagulation for patients requiring cardiac surgery and cardiopulmonary bypass (CPB) is important due to the adverse consequences of inadequate anticoagulation with respect to bleeding and thrombosis. When target anticoagulation is not achieved with typical doses, the term heparin resistance is routinely used despite the lack of uniform diagnostic criteria. Prior reports and guidance documents that define heparin resistance in patients requiring CPB and guidance documents remain variable based on the lack of standardized criteria. As a result, we conducted a review of clinical trials and reports to evaluate the various heparin resistance definitions employed in this clinical setting and to identify potential standards for future clinical trials and clinical management. In addition, we also aimed to characterize the differences in the reported incidence of heparin resistance in the adult cardiac surgical literature based on the variability of both target-activated clotting (ACT) values and unfractionated heparin doses. Our findings suggest that the most extensively reported ACT target for CPB is 480 seconds or higher. Although most publications define heparin resistance as a failure to achieve this target after a weight-based dose of either 400 U/kg or 500 U/kg of heparin, a standardized definition would be useful to guide future clinical trials and help improve clinical management. We propose the inability to obtain an ACT target for CPB of 480 seconds or more after 500 U/kg as a standardized definition for heparin resistance in this setting.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Preoperative Antithrombin Supplementation in Patients at Risk for Antithrombin Deficiency After Cardiac Surgery.

BACKGROUND: Antithrombin (AT) activity is reduced during cardiac operations with cardiopulmonary bypass (CPB), which is associated with adverse outcomes. Preoperative AT supplementation, to achieve >58% and <100% AT activity, may potentially reduce postoperative morbidity and mortality in cardiac operations with CPB. This prospective, multicenter, randomized, double-blind, placebo-controlled study was designed to evaluate the safety and efficacy of preoperative treatment with AT supplementation in patients at risk for low AT activity after undergoing cardiac surgery with CPB. METHODS: A total of 425 adult patients were randomized (1:1) to receive either a single dose of AT (n = 213) to achieve an absolute increase of 20% above pretreatment AT activity or placebo (n = 212) before surgery. The study duration was approximately 7 weeks. The primary efficacy end point was the percentage of patients with any component of a major morbidity composite (postoperative mortality, stroke, acute kidney injury [AKI], surgical reexploration, arterial or venous thromboembolic events, prolonged mechanical ventilation, and infection) in the 2 groups. Secondary end points included AT activity, blood loss, transfusion requirements, duration of intensive care unit (ICU), and hospital stays. Safety was also assessed. RESULTS: Overall, 399 patients (men, n = 300, 75.2%) with a mean (standard deviation [SD]) age of 66.1 (11.7) years, with the majority undergoing complex surgical procedures (n = 266, 67.9%), were analyzed. No differences in the percentage of patients experiencing morbidity composite outcomes between groups were observed (AT-treated 68/198 [34.3%] versus placebo 58/194 [29.9%]; P = .332; relative risk, 1.15). After AT infusion, AT activity was significantly higher in the AT group (108% [42-143]) versus placebo group (76% [40-110]), and lasted up to postoperative day 2. At ICU, the frequency of patients with AT activity ≥58% in the AT group (81.5%) was significantly higher ( P < .001) versus placebo group (43.2%). Secondary end point analysis did not show any advantage of AT over placebo group. There were significantly more patients with AKI ( P < .001) in the AT group (23/198; 11.6%) than in the placebo group (5/194, 2.6%). Safety results showed no differences in treatment-emergent adverse events nor bleeding events between groups. CONCLUSIONS: AT supplementation did not attenuate adverse postoperative outcomes in our cohort of patients undergoing cardiac surgery with CPB.

The occurrence of antibodies to heparin-platelet factor 4 in cardiac and thoracic surgical patients receiving desirudin or heparin for postoperative venous thrombosis prophylaxis.

INTRODUCTION: This randomized, exploratory study compared the incidence of heparin-dependent antibodies associated with subcutaneous (SC) desirudin or heparin given for deep-vein thrombosis prophylaxis following cardiac and thoracic surgery. MATERIALS AND METHODS: Adult patients scheduled for elective cardiac or thoracic surgery received desirudin 15 mg SC twice daily or unfractionated heparin 5000 units SC thrice daily. Duration of thrombosis prophylaxis was determined by the treating physician. Primary outcome measure was the incidence of new antibody formation directed against platelet factor 4 (PF4)/heparin complex. Secondary outcomes included bleeding and thrombotic complications. Blood was tested for anti-PF4/heparin antibodies at baseline, after surgery prior to study drug administration, postdrug day (PDD) 2, PDD 7, and at 1 month. Doppler studies were done before discharge. RESULTS: Of 120 patients, 61 received desirudin, 59 received heparin. New PF4/heparin antibodies occurred in 10.2% and 13.6% of desirudin- and heparin-treated patients, respectively. Among desirudin patients with no heparin exposure, none (0/36) developed PF4/heparin antibodies versus 17.1% with heparin exposure. Incidence of deep venous thrombosis was 4.9% and 3.4% in the desirudin and heparin groups, respectively. Two heparin-group patients developed pulmonary embolism. Two patients per group had bleeding events; no patients required re-exploration for bleeding complications. Median chest tube output was similar with desirudin (900 mL) and heparin (692 mL) as was blood transfusion requirements of more than 2 units (5/61, desirudin; 2/59 heparin). CONCLUSIONS: The incidence of thrombotic events was low in both groups. There were no safety concerns, and desirudin was not associated with anti-PF4/heparin antibodies.

2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.

BACKGROUND: Practice guidelines reflect published literature. Because of the ever changing literature base, it is necessary to update and revise guideline recommendations from time to time. The Society of Thoracic Surgeons recommends review and possible update of previously published guidelines at least every three years. This summary is an update of the blood conservation guideline published in 2007. METHODS: The search methods used in the current version differ compared to the previously published guideline. Literature searches were conducted using standardized MeSH terms from the National Library of Medicine PUBMED database list of search terms. The following terms comprised the standard baseline search terms for all topics and were connected with the logical 'OR' connector--Extracorporeal circulation (MeSH number E04.292), cardiovascular surgical procedures (MeSH number E04.100), and vascular diseases (MeSH number C14.907). Use of these broad search terms allowed specific topics to be added to the search with the logical 'AND' connector. RESULTS: In this 2011 guideline update, areas of major revision include: 1) management of dual anti-platelet therapy before operation, 2) use of drugs that augment red blood cell volume or limit blood loss, 3) use of blood derivatives including fresh frozen plasma, Factor XIII, leukoreduced red blood cells, platelet plasmapheresis, recombinant Factor VII, antithrombin III, and Factor IX concentrates, 4) changes in management of blood salvage, 5) use of minimally invasive procedures to limit perioperative bleeding and blood transfusion, 6) recommendations for blood conservation related to extracorporeal membrane oxygenation and cardiopulmonary perfusion, 7) use of topical hemostatic agents, and 8) new insights into the value of team interventions in blood management. CONCLUSIONS: Much has changed since the previously published 2007 STS blood management guidelines and this document contains new and revised recommendations.

Heparin concentration-based anticoagulation for cardiac surgery fails to reliably predict heparin bolus dose requirements.

BACKGROUND: Hemostasis management has evolved to include sophisticated point-of-care systems that provide individualized dosing through heparin concentration-based anticoagulation. The Hepcon HMS Plus system (Medtronic, Minneapolis, MN) estimates heparin dose, activated clotting time (ACT), and heparin dose response (HDR). However, the accuracy of this test has not been systematically evaluated in large cohorts. METHODS: We examined institutional databases for all patients who underwent cardiac surgery with cardiopulmonary bypass (CPB) at our institution from February 2005 to July 2008. During this period, the Hepcon HMS Plus was used exclusively for assessment of heparin dosing and coagulation monitoring. Detailed demographic, surgical, laboratory, and heparin dosing data were recorded. ACT, calculated and measured HDR, and heparin concentrations were recorded. Performance of the Hepcon HMS Plus was assessed by comparison of actual and target ACT values and calculated and measured HDR. RESULTS: In 3880 patients undergoing cardiac surgery, heparin bolus dosing to a target ACT resulted in wide variation in the postheparin ACT (r(2) = 0.03). The postheparin ACT did not reach the target ACT threshold in 7.4%(i.e., when target ACT was 300 s) and 16.9% (i.e., when target ACT was 350 s) of patients. Similarly, the target heparin level calculated from the HDR did not correlate with the postbolus heparin level, with 18.5% of samples differing by more than 2 levels of the assay. Calculated and measured HDR were not linearly related at any heparin level. CONCLUSIONS: The Hepcon HMS Plus system poorly estimates heparin bolus requirements in the pre-CPB period. Further prospective studies are needed to elucidate what constitutes adequate anticoagulation for CPB and how clinicians can reliably and practically assess anticoagulation in the operating room.

Use of activated recombinant factor VII for severe coagulopathy post ventricular assist device or orthotopic heart transplant.

BACKGROUND: Ventricular assist devices(VAD) implantation/removal is a complex surgical procedure with perioperative bleeding complications occurring in nearly half of the cases. Recombinant activated factor VII (rFVIIa) has been used off-label to control severe hemorrhage in surgery and trauma. We report here our experience with rFVIIa as a rescue therapy to achieve hemostasis in patients undergoing orthotopic heart transplant (OHT) and/or VAD implantation. METHODS: A retrospective review was conducted from Jan 03 to Aug 05 for patients who received rFVIIa for the management of intractable bleeding unresponsive to standard hemostatic blood component therapy. Blood loss and the quantity of blood products, prior to, and for at least 12 hours after, administration of rFVIIa were recorded. RESULTS: Mean patient age was 53, (38-64 yrs), mean dose of rFVIIa administered was 78.3 microg/kg (24-189 microg/kg) in 1-3 doses. All patients received the drug either intraoperatively or within 6 hours of arrival in ICU. Mean transfusion requirements and blood loss were significantly reduced after rFVIIa administration (PRBC's; 16.9 +/- 13.3 to 7.1 +/- 6.9 units, FFP; 13.1 +/- 8.2 to 4.1 +/- 4.9 units, platelets; 4.0 +/- 2.8 to 2.1 +/- 2.2 units, p < 0.04 for all). 5 patients expired including 3 with thromboembolic cause. One patient developed a lower extremity arterial thrombus, and another deep vein thrombosis. CONCLUSION: In this review, there was a significant decrease in transfusion requirement and blood loss after rFVIIa administration. Although, 5/17 developed thromboembolic complications, these patients may have been at higher risk based on the multiple modality therapy used to manage intractable bleeding. Nevertheless, the exact role of rFVIIa with respect to development of thromboembolic complications cannot be clearly determined. Further investigation is needed to determine rFVIIa's safety and its effectiveness in improving postoperative morbidity and mortality.

Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline.

BACKGROUND: A minority of patients having cardiac procedures (15% to 20%) consume more than 80% of the blood products transfused at operation. Blood must be viewed as a scarce resource that carries risks and benefits. A careful review of available evidence can provide guidelines to allocate this valuable resource and improve patient outcomes. METHODS: We reviewed all available published evidence related to blood conservation during cardiac operations, including randomized controlled trials, published observational information, and case reports. Conventional methods identified the level of evidence available for each of the blood conservation interventions. After considering the level of evidence, recommendations were made regarding each intervention using the American Heart Association/American College of Cardiology classification scheme. RESULTS: Review of published reports identified a high-risk profile associated with increased postoperative blood transfusion. Six variables stand out as important indicators of risk: (1) advanced age, (2) low preoperative red blood cell volume (preoperative anemia or small body size), (3) preoperative antiplatelet or antithrombotic drugs, (4) reoperative or complex procedures, (5) emergency operations, and (6) noncardiac patient comorbidities. Careful review revealed preoperative and perioperative interventions that are likely to reduce bleeding and postoperative blood transfusion. Preoperative interventions that are likely to reduce blood transfusion include identification of high-risk patients who should receive all available preoperative and perioperative blood conservation interventions and limitation of antithrombotic drugs. Perioperative blood conservation interventions include use of antifibrinolytic drugs, selective use of off-pump coronary artery bypass graft surgery, routine use of a cell-saving device, and implementation of appropriate transfusion indications. An important intervention is application of a multimodality blood conservation program that is institution based, accepted by all health care providers, and that involves well thought out transfusion algorithms to guide transfusion decisions. CONCLUSIONS: Based on available evidence, institution-specific protocols should screen for high-risk patients, as blood conservation interventions are likely to be most productive for this high-risk subset. Available evidence-based blood conservation techniques include (1) drugs that increase preoperative blood volume (eg, erythropoietin) or decrease postoperative bleeding (eg, antifibrinolytics), (2) devices that conserve blood (eg, intraoperative blood salvage and blood sparing interventions), (3) interventions that protect the patient's own blood from the stress of operation (eg, autologous predonation and normovolemic hemodilution), (4) consensus, institution-specific blood transfusion algorithms supplemented with point-of-care testing, and most importantly, (5) a multimodality approach to blood conservation combining all of the above.

Transfusion risks and transfusion-related pro-inflammatory responses.

Despite improvements in blood screening and administration techniques, serious adverse events related to transfusion continue to occur, albeit at a much lower incidence. In addition to the development and implementation of new screening and blood purification/modification techniques and implementation of an optimal blood management program, the incidence and consequences of transfusion reactions can be reduced by a basic understanding of transfusion-related complications. Although acute hemolytic transfusion reactions, transfusion-associated anaphylaxis and sepsis, and transfusion-associated acute lung injury occur infrequently, diligence in administration of blood and monitoring for development of respective signs/symptoms can minimize the severity of these potentially life-threatening complications. In addition, emerging blood-banking techniques such as psoralen-UV inactivation of pathogens and use of patient identification systems may attenuate the incidence of adverse events related to transfusion. With respect to optimizing blood management by means of an effective blood management program involving pharmacologic and nonpharmacologic strategies, the ability to reduce use of blood products and to decrease operative time or re-exploration rates has important implications for disease prevention, blood inventory and costs, and overall health care costs.

Transfusion algorithms and how they apply to blood conservation: the high-risk cardiac surgical patient.

Considerable blood product support is administered to the cardiac surgery population. Due to the multifactorial etiology of bleeding in the cardiac bypass patient, blood products frequently and empirically are infused to correct bleeding, with varying success. Several studies have demonstrated the benefit of algorithm-guided transfusion in reducing blood loss, transfusion exposure, or rate of surgical re-exploration for bleeding. Some transfusion algorithms also incorporate laboratory-based decision points in their guidelines. Despite published success with standardized transfusion practices, generalized change in blood use has not been realized, and it is evident that current laboratory-guided hemostasis measures are inadequate to define and address the bleeding etiology in these patients.

Preoperative use of enoxaparin increases the risk of postoperative bleeding and re-exploration in cardiac surgery patients.

OBJECTIVE: The purpose of this study was to investigate if the preoperative use of new platelet inhibitors and low-molecular-weight heparins may contribute to bleeding after cardiac surgery. DESIGN: Retrospective data review. SETTING: University teaching hospital. PARTICIPANTS: One hundred eleven patients divided in 5 groups. INTERVENTIONS: Patients were grouped according to preoperative antithrombotic regimen: group 1, control, no agents (n=55); group 2, clopidogrel (n=9); group 3, enoxaparin (n=17); group 4, any GP IIb/IIIa inhibitor (n=14); and group 5, any drug combination (n=15). Data included cumulative mediastinal chest tube drainage, allogeneic blood transfusions, total blood donor exposures, and re-exploration. MEASUREMENTS AND MAIN RESULTS: Use of any drug (groups 2-5) resulted in greater total blood transfusions and donor exposure (p=0.0003) than control, especially red cells (p=0.002) and platelets (p=0.006). A greater percentage of patients on enoxaparin required mediastinal re-exploration for nonsurgical bleeding versus control (3/17 v 0/55, p=0.001). The use of enoxaparin was associated with significantly higher chest tube output after the first 24 hours postoperatively (p=0.048). CONCLUSION: Newer antithrombotic agents were associated with greater transfusion rates and total donor exposures. Enoxaparin use was associated with greater overall blood loss and with higher incidence of mediastinal re-exploration. The relative risk-benefit ratio of reduced periprocedure morbidity versus increased bleeding complications has yet to be determined.

A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass.

BACKGROUND: The study evaluated the efficacy of recombinant human antithrombin (rhAT) for restoring heparin responsiveness in heparin resistant patients undergoing cardiac surgery. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing cardiac surgery with cardiopulmonary bypass. Heparin resistance was diagnosed when the activated clotting time was less than 480 s after 400 U/kg heparin. Fifty-four heparin-resistant patients were randomized. One cohort received 75 U/kg rhAT, and the other received normal saline. If the activated clotting time remained less than 480 s, this was considered treatment failure, and 2 units fresh frozen plasma was transfused. Patients were monitored for adverse events. RESULTS: Only 19% of patients in the rhAT group received fresh frozen plasma, compared with 81% of patients in the placebo group (P < 0.001). During their hospitalization, 48% of patients in the rhAT group received fresh frozen plasma, compared with 85% of patients in the placebo group (P = 0.009). Patients in the placebo group required higher heparin doses (P < 0.005) for anticoagulation. There was no increase in serious adverse events associated with rhAT. There was increased blood loss 12 h postoperatively (P = 0.05) with a trend toward increased 24-h bleeding in the rhAT group (P = 0.06). There was no difference between the groups in blood and platelet transfusions. CONCLUSION: Treatment with 75 U/kg rhAT is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation in the majority of heparin-resistant patients. Treating heparin-resistant patients with rhAT may decrease the requirement for heparin and fresh frozen plasma.

Guidelines and alternatives for neuraxial anesthesia and venous thromboembolism prophylaxis in major orthopedic surgery.

Neuraxial anesthesia during major orthopedic surgery, combined with venous thromboembolism prophylaxis, is generally safe and well tolerated, with potential benefits over general anesthesia. The risk of spinal/epidural hematoma, a rare but very serious complication, can be minimized by careful patient selection and attention to anesthetic technique. This risk is further reduced with the use of peripheral nerve blocks in place of neuraxial anesthesia.