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.

Extracorporeal photopheresis to attenuate decline in lung function due to refractory obstructive allograft dysfunction.

BACKGROUND: This study was designed to prospectively evaluate the efficacy of extracorporeal photopheresis (ECP) to attenuate the rate of decline of FEV1 in lung transplant recipients with refractory bronchiolitis obliterans. Due to an observed higher than expected early mortality, a preliminary analysis was performed. STUDY DESIGN AND METHODS: Subjects from 10 lung transplant centres were assigned to ECP treatment or to observation based on spirometric criteria, with potential crossover for those under observation. The primary endpoint of this study was to assess response to ECP (i.e., greater than a 50% decrease in the rate of FEV1 decline) before and 6 months after initiation of ECP. Mortality was also evaluated 6 and 12 months after enrolment as a secondary endpoint. RESULTS: Of 44 enrolled subjects, 31 were assigned to ECP treatment while 13 were initially assigned to observation on a non-random basis using specific spirometric inclusion criteria (seven of the observation patients subsequently crossed over to receive ECP). Of evaluable patients, 95% of patients initially assigned to treatment responded to ECP with rates of FEV1 decline that were reduced by 93% in evaluable ECP-treated patients. Mortality rates (percentages) at 6 and 12 months after enrolment was 32% and 41%, respectively. The most common (92%) primary cause of death was respiratory or graft failure. Significantly (p = 0.002) higher rates of FEV1 decline were observed in the non-survivors (-212 ± 177 ml/month) when compared to the survivors (-95 ± 117 ml/month) 12 months after enrolment. In addition, 18 patients with bronchiolitis obliterans syndrome (BOS) diagnosis within 6 months of enrolment had lost 38% of their baseline lung function at BOS diagnosis and 50% of their lung function at enrolment. CONCLUSIONS: These analyses suggest that earlier detection and treatment of BOS should be considered to appreciate improved outcomes with ECP.

The CELLEX is comparable to the UVAR-XTS for the treatment of acute and chronic graft versus host disease (GVHD).

BACKGROUND: Two extracorporeal photopheresis (ECP) instruments, the CELLEX and the UVARXTS are currently being used "off-label" in the US for treatment of graft versus host disease (GVHD). Our study compared the performance of the two instruments in the setting of acute and chronic GVHD. STUDY DESIGN AND METHODS: We retrospectively analyzed the outcomes of patients with steroid refractory or steroid resistant GVHD undergoing ECP at Barnes Jewish Hospital. Multivariate logistic regression was used to evaluate the comparative efficacy of the two instruments with respect to steroid dose reduction (≥50% from baseline) and clinical improvement in GVHD. Chi-square/Fisher exact tests were used to compare the incidence of adverse events, while multivariate Cox regression was employed to assess a potential difference in mortality between the two instrument treatment cohorts. RESULTS: After adjusting for potential confounders, there was no significant difference in the odds of steroid dose reduction (OR = 1.41, 95% confidence interval [CI]: 0.51-3.90, p = 0.50) or clinical improvement (OR 2.0, 95% CI: 0.63-6.41, p = 0.24) between the two instrument treatment cohorts. The frequency of adverse events (CELLEX 45.4%; UVAR XTS 40.5%, p = 0.55) was also comparable between the cohorts. There was no significant difference in mortality of either acute or chronic GVHD patients when treated by the CELLEX as compared to the UVAR-XTS (aHR 0.66, 95% CI: 0.35-1.25, p = 0.20). CONCLUSION: The efficacy and safety of the two ECP instruments, the CELLEX and the UVAR-XTS, are comparable for the treatment of acute and chronic GVHD.

Optimizing management of replacement fluids for therapeutic plasma exchange: Use of an automated mathematical model to predict post-procedure fibrinogen and antithrombin levels in high-risk patients.

BACKGROUND: Therapeutic plasma exchange (TPE) utilizes an extracorporeal circuit to remove pathologic proteins causing serious illness. When processing a patient's entire blood volume through an extracorporeal circuit, proteins responsible for maintaining hemostatic system homeostasis can reach critically low levels if replacement fluid types and volumes are not carefully titrated, which may increase complications. METHODS: The charts from 27 patients undergoing 46 TPE procedures were reviewed to evaluate the accuracy of our predictive mathematical model, utilizing the following patient information: weight, hematocrit, pre- and post-TPE factor levels (fibrinogen, n = 46, and antithrombin, n = 23), process volume and volumes of fluids (eg, plasma, albumin, and normal saline) administered during TPE and adverse events during and after TPE. RESULTS: Altogether, 25% of patients experienced minor adverse events that resolved spontaneously or with management. There were no bleeding or thrombotic complications. The mean difference between predicted and measured post-TPE fibrinogen concentrations was -0.29 mg/dL (SD ±23.0, range -59 to 37), while percent difference between measured and predicted fibrinogen concentration was 0.94% (SD ±10.8, range of -22 to 19). The mean difference between predicted and measured post-TPE antithrombin concentrations were 0.89% activity (SD ±10.0, range -23 to 14), while mean percent difference between predicted and measured antithrombin concentrations was 3.87% (SD ±14.5, range -25 to 38). CONCLUSIONS: Our model reliably predicts post-TPE fibrinogen and antithrombin concentrations, and may help optimize patient management and attenuate complications.

Acute graft-versus-host disease following lung transplantation in a patient with a novel TERT mutation.

Familial pulmonary fibrosis is associated with loss-of-function mutations in telomerase reverse transcriptase (TERT) and short telomeres. Interstitial lung diseases have become the leading indication for lung transplantation in the USA, and recent data indicate that pathogenic mutations in telomerase may cause unfavourable outcomes following lung transplantation. Although a rare occurrence, solid organ transplant recipients who develop acute graft-versus-host disease (GVHD) have very poor survival. This case report describes the detection of a novel mutation in TERT in a patient who had lung transplantation for familial pulmonary fibrosis and died from complications of acute GVHD.

An ex vivo comparison of vascular access devices used in extracorporeal photopheresis.

BACKGROUND: Central venous access devices are commonly used in extracorporeal photopheresis, but their performance has not been systematically evaluated. The primary objective of this study was to compare pressures at various flow rates for central venous access devices in an ex vivo simulation of photopheresis. STUDY DESIGN AND METHODS: Diluted, heparinized red blood cells were circulated through central access devices in series with a photopheresis system, and pressures at several flow rates were recorded. The devices tested were the Trifusion catheter (Hickman), the Vortex single-lumen and dual-lumen ports (Angiodynamics), and the TidalPort device (Norfolk). Flow rates were also compared for silicone and polyurethane catheters and for different catheter internal diameters. RESULTS: The Vortex dual-lumen port generated pressure alarms above flow rates of 60 mL/minute. Throughout flow rates from 5 to 100 mL/minute, the Trifusion catheter and the TidalPort device operated at lower pressures than the Vortex ports. Within typical clinical flow rates, neither catheter material nor internal diameter substantially affected pressure. CONCLUSION: Central venous access devices show large differences in pressure within flow rates used routinely in clinical settings. These differences cannot be fully attributed to catheter material composition or catheter internal diameter.

The efficacy of extracorporeal photopheresis to arrest bronchiolitis obliterans in lung allograft recipients was compared between two automated photopheresis instruments.

BACKGROUND: The most common instruments used for extracorporeal photopheresis (ECP) treatment in the United States are the UVAR XTS and the CELLEX devices (Therakos, West Chester, PA). When compared to the UVAR XTS instrument, the efficacy of the CELLEX instrument to arrest the decline in lung function in patients with chronic lung allograft dysfunction (CLAD) related to bronchiolitis obliterans (BOS) has not been previously evaluated. METHODS: The relative efficacy of the CELLEX vs UVAR XTS ECP instruments was assessed by comparing the difference in rates of FEV1 decline before and after ECP treatment and survival in two series of lung allograft recipients with BOS who had been treated with these instruments. RESULTS: Similar Slope Difference values for change in rate of decline (6 months Post ECP - Pre ECP) were observed between the two cohorts (UVAR XTS: 85 ± 109 mL/month vs CELLEX: 76 ± 128 mL/month, p=0.72). A similar percentage of patients responded to ECP (UVAR XTS: 77% vs CELLEX: 89%; p=0.36) i.e., as defined as a positive difference in slope between the rate of decline of FEV1 before and 6 months after ECP. Survival at either 6 (p=0.89) or 12 (p=0.8) months after the start of ECP was not associated with instrument used despite a trend in higher early mortality (34% vs 17%, p=0.054) in the patients who were predominately treated with the CELLEX. CONCLUSIONS: Our data support the use of the CELLEX for prospective studies designed to evaluate the merits of ECP in this population.

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.

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.

Factors Associated With Mortality and Response to Extracorporeal Photopheresis in Lung Allograft Recipients With Bronchiolitis Obliterans Syndrome.

BACKGROUND: This study was designed to identify factors associated with clinical response to extracorporeal photopheresis (ECP) and mortality after ECP in lung allograft recipients with bronchiolitis obliterans. METHODS: Forced expiratory volume in 1 second (FEV1) values obtained 6 months before (baseline) and 6 months after initiation of ECP were used to plot the linear relationship between FEV1 versus time before and after ECP. Response to ECP was assigned when a positive integer was derived after subtracting the baseline rate of decline from the rate of decline 6 months after ECP. Univariate and multivariate logistic regression analyses were used to identify demographic, treatment-related factors or spirometric parameters that may be associated with response to ECP or mortality at either 6 or 16 months after initiation of ECP. RESULTS: Forced expiratory volume in 1 second just before ECP was associated with mortality (P = 0.007) at 16 months after ECP initiation. An FEV1 of 1.50 L or less had a sensitivity of 87% and specificity of 60% to identify patients who died within 16 months after ECP initiation. Patients whose FEV1 decline exceeded 40 mL/month were 12 times more likely to have a response to ECP (P = 0.0001). Patients whose decline in FEV1 before ECP was statistically significant (P < 0.05) were nearly 10 times (P = 0.008) more likely to respond to ECP. CONCLUSIONS: Forced expiratory volume in 1 second is an important predictor of mortality, and the response to ECP is influenced by both the extent (>40 mL/mo) and statistical significance of the relationship between FEV1 versus time before ECP initiation. Therefore, earlier bronchiolitis obliterans detection and more timely implementation of ECP (ie, when FEV1 values >1.5 L) should be considered especially in patients with a more aggressive rate of decline of lung function.

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.

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.

Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery.

OBJECTIVE: The purpose of this report is to describe the clinical use of antithrombin III concentrate in 53 patients who were found, in the operating room before cardiopulmonary bypass, to be heparin resistant. METHOD: Resistance to heparin was determined to be present when greater than 600 U/kg body weight of heparin failed to prolong the kaolin-activated clotting time to more than 600 seconds in 53 aprotinin-treated patients. Blood samples were obtained for subsequent antithrombin III activity determination. Patients were then administered 500 U of antithrombin III concentrate, and the activated clotting time was remeasured. If the activated clotting time remained less than 600 seconds, a second 500-U dose was given. RESULTS: Of the 53 patients, 45 (85%) had subnormal measured antithrombin III activity, and the mean plasma antithrombin III activity level for the entire group was 67% (normal 80%-120%). Administration of antithrombin III concentrate (500 U in 45 patients and 1000 U in 8 patients) resulted in prolongation of the mean activated clotting time from 492 to 789 seconds without additional heparin. The mean heparin dose response increased from 36.5 to 69.3 s x U(-1) x mL(-1) with antithrombin III treatment. Only one patient did not achieve the target activated clotting time, despite administration of greater than 600 U/kg heparin and 1000 U of antithrombin III concentrate, and was treated with fresh-frozen plasma. CONCLUSIONS: On the basis of the criterion used in this report, most of the patients defined as being heparin resistant had subnormal plasma antithrombin III activity. Treatment with antithrombin III concentrate resulted in potentiation of the heparin effect to meet predetermined activated clotting time thresholds and allow for cardiopulmonary bypass.

Coronary artery bypass grafting in 2 thrombophilic patients with protein s deficiency.

In this report, we review 2 cases of coronary revascularization in patients with a diagnosis of coronary artery disease and preoperative protein S deficiency, an established hypercoagulable condition. In an attempt to normalize protein S levels, fresh frozen plasma was used as the priming fluid for the cardiopulmonary bypass circuit before the initiation of extracorporeal circulation. On the basis of a low risk of bleeding and the theoretical risk of thrombosis, neither patient received intraoperative antifibrinolytic treatment nor did they develop perioperative thrombotic complications.

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.