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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.

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.

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.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.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 (P0.05) were nearly 10 times (P = 0.008) more likely to respond to ECP.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 values1.5 L) should be considered especially in patients with a more aggressive rate of decline of lung function.

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.

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.

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.

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.

BACKGROUND: Graft versus host disease (GVHD) is a significant contributor to non-relapse mortality after allogeneic stem cell transplant (SCT). Steroids are first line therapy and extracorporeal photopheresis (ECP) is used as second line therapy for steroid refractory or intolerant patients. ECP has immunomodulatory effects rather than immunosuppressive effect which decreases the risk of infection, and may decreases the risk of disease relapse. There are two ECP instruments approved in the US for the treatment of Cutaneous T Cell Lymphoma (CTLC), however both have been used "off-label" to prevent or treat solid organ transplant rejection, acute and chronic GVHD, and other autoimmune diseases. Until recently the UVAR-XTS instrument has been the most commonly used closed system in the US until the CELLEX was approved in 2009. The CELLEX and the UVAR-XTS procedures are similar in that buffy coat is collected, exposed to methoxsalen (UVADEX®) ex vivo and then UVA light before returning the treated cells back to the patient in a closed looped system. The instruments differ in the collection of the buffy coat; collection is continuous by the CELLEX, and it is intermittent by UVAR-XTS. In addition CELLEX has been shown to be more efficient in collecting mononuclear cells when compared to the UVAR -XTS. Little clinical data is available comparing the clinical efficacy of the two instruments in the setting of GVHD. We designed a single institution retrospective study to compare the efficacy and safety of the two instruments. The primary outcomes analyzed were >/=50% reduction of steroid dose between the initial and final dose during the study period, and the number and type of adverse events that occurred during the ECP procedures. METHODS: Study Population: We reviewed charts of allogeneic stem cell transplant patients who received ECP for the treatment of acute or chronic GVHD between 1/2009 and 12/2015. The patients were divided into two groups based on the type of ECP instrument that was used. One group was exclusively treated with UVAR-XTS while the second group with CELLEX. Patients who received treatments with both instruments were excluded. The frequency of steroid dose reduction by >/=50%, and toxicity was compared between the two instruments while adjusting for age, gender, GVHD severity, number of organs involved by GVHD, type of allogeneic stem cell transplant, conditioning regimen, number of other immunosuppressants, type of anticoagulants (ACDA vs heparin), type of access line, and baseline blood counts. Statistical Analysis: The baseline characteristics of the patients in the two groups were compared using Chi square, Fischer's exact test for categorical variables and one-way analysis of variance (ANOVA) for continuous variables. Chi square analysis was used to determine the difference in frequency of >/=50% steroid dose reduction and adverse events between the two groups. Logistic multivariate regression was used to evaluate the potential interactions of all significant covariates. A p value of less than 0.05 was considered to be statistically significant. Statistical analyses were performed using STATA14 software (StataCorp, College Station, TX). RESULTS: We identified 242 allogeneic SCT recipients who received ECP for acute or chronic GVHD in the study period, 146 of whom met the selection criteria. 69 patients had all procedure performed with UVAR-XTS and 77 patients had all procedures performed with CELLEX. There was no significant difference in age, gender, percent of acute GVHD, anticoagulant used, type of transplant, number of organs involved, number of immunosuppressants, vascular access and baseline blood counts between the two treatment cohorts as shown in table 1. Although year of transplant and conditioning regimen were different between the two cohorts, neither of these covariates influenced the impact of instrument on the primary outcome. In multivariate analysis, the patients who underwent ECP with CELLEX were 3 times more likely to have >/=50% steroid dose reduction (p =0.01). The total number of adverse events was similar between the instruments (p = 0.73). (Table 2) CONCLUSION: More than twice as many patients with GVHD treated with the CELLEX had a steroid dose reduction by >/=50% reflecting clinical improvement when compared to the patients treated with the UVAR-XTS. Similar safety profile was observed between the two instruments based on a similar number of adverse events. Disclosures No relevant conflicts of interest to declare.

Background Extracorporeal photopheresis (ECP) has been used to treat acute and chronic rejection after solid organ transplantation. However, data supporting the use of ECP for bronchiolitis obliterans syndrome (BOS) after lung transplantation are limited. Methods We retrospectively analyzed the efficacy and safety of ECP for progressive BOS at our institution. Between January 1, 2000, and December 31, 2007, 60 lung allograft recipients were treated with ECP for progressive BOS. Results During the 6-month period before the initiation of ECP, the average rate of decline in forced expiratory volume in 1 second (FEV 1 ) was −116.0 ml/month, but the slope decreased to −28.9 ml/month during the 6-month period after the initiation of ECP, and the mean difference in the rate of decline was 87.1 ml/month (95% confidence interval, 57.3–116.9; p 1 improved in 25.0% of patients after the initiation of ECP, with a mean increase of 20.1 ml/month. Conclusions ECP is associated with a reduction in the rate of decline in lung function associated with progressive BOS.

Excessive bleeding after cardiac surgery can result in increased morbidity and mortality related to transfusion- and hypoperfusion-related injuries to critical organ systems. Our objective was to review mechanisms that result in bleeding after cardiac surgery as well as current and emerging interventions to reduce bleeding and transfusion. We discovered that of point-of-care (POC) tests of hemostatic function can facilitate the optimal management of excessive bleeding and reduce transfusion by facilitating administration of specific pharmacologic or transfusion-based therapy and by allowing physicians to better differentiate between microvascular bleeding and surgical bleeding. Emerging interventions like recombinant FVIIa have the potential to reduce bleeding and transfusion-related sequelae and may be life-saving; however, randomized, controlled trials are needed to confirm safety before they can be used as either first-line therapies for bleeding or bleeding prophylaxis. In conclusion, careful investigation of the role of new interventions is essential as the ability to reduce use of blood products, to decrease operative time and/or re-exploration rates has important implications for overall patient safety and health care costs.

Background and objectives: The main aim of this review is to summarize the literature with respect to transfusion and bleeding risks and the therapeutic strategies with respect to optimal management of perioperative bleeding. Methods: This review was generated using peer-reviewed manuscripts pertinent to this topic that were identified using a computer-based Medline search. Results: Although the pathophysiology of many transfusion-related complications are well-documented, the incidence of these complications is changing. Transfusion Medicine initiatives are being implemented to reduce complications, however, the literature is describing new potential problems related to transfusion in addition to identification of new potential pathogens while blood shortages may limit our ability to adequately manage our anemic and bleeding patients. Excessive bleeding after cardiac surgery can result in increased morbidity and mortality related to transfusion and hypoperfusion related complications as well as injury to critical organ systems. Seven of eight studies have demonstrated that use of point-of-care (POC) tests of hemostatic function can facilitate the optimal management of excessive bleeding and reduce transfusion after cardiac surgery. Two randomized prospective studies have demonstrated that point-of-care tests that assess platelet function can identify patients at risk for acquired, platelet-related bleeding that may be attenuated with pharmacologic agents such as DDAVP. The current literature contains fifty publications with over 400 patients that describe the fairly consistent efficacy of off-label use of recombinant factor VIIa to manage intractable, life-threatening bleeding. Most of these publications involve either case reports or case series that describe the use of this agent and therefore do not adequately address the safety of this agent. Conclusions: There are substantial risks related to excessive bleeding and transfusion. The literature indicates that use of point-of-care diagnostics with a standardized management algorithm can optimize the management of bleeding and reduce transfusion requirements. Recombinant FVIIa has the potential to reduce transfusion and transfusion-related sequelae and may be life-saving in certain circumstances. However, randomized, controlled trials are warranted to assess both the efficacy and, more importantly, the safety of this intervention (i.e., especially with respect to thrombotic complications) in cardiac surgical patients prior to its use as a first line therapy for bleeding or for bleeding prophylaxis. We must continue to carefully investigate the role of new interventions since the ability to reduce use of blood products, to decrease operative time and/or re-exploration rates has important implications for disease prevention and overall patient safety, blood inventory and associated costs as well as overall health care costs.

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.

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.

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.

ObjectivesWe sought to evaluate the efficacy of recombinant human antithrombin III for restoration of heparin responsiveness in heparin-resistant patients scheduled for cardiac surgery.MethodsThis was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing elective cardiac surgery. Patients were considered heparin resistant if the activated clotting time was less than 480 seconds after 400 U/kg heparin. Fifty-two heparin-resistant patients were randomized into 2 cohorts. One cohort received a single bolus (75 U/kg) of recombinant human antithrombin III (n = 28), and the other, the placebo group (n = 24), received a normal saline bolus. If the activated clotting time remained less than 480 seconds, this was defined as treatment failure, and 2 units of fresh frozen plasma were transfused. Patients were monitored for adverse events during hospitalization.ResultsSix (21%) of the patients in the recombinant human antithrombin III group received fresh frozen plasma transfusions compared with 22 (92%) of the placebo-treated patients (P < .001). Two units of fresh frozen plasma did not restore heparin responsiveness. There was no increased incidence of adverse events associated with recombinant human antithrombin III administration. Postoperative 24-hour chest tube bleeding was not different in the 2 groups. Surrogate measures of hemostatic activation suggested that there was less activation of the hemostatic system during cardiopulmonary bypass in the recombinant human antithrombin III group.ConclusionTreatment with recombinant human antithrombin III in a dose of 75 U/kg is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation for cardiopulmonary bypass in the majority of heparin-resistant patients. Two units of fresh frozen plasma were insufficient to restore heparin responsiveness. There was no apparent increase in bleeding associated with recombinant human antithrombin III.

niversity of Kentucky Chandler Medical Center, Lexington, Kentucky; Loyola University Medical Center, Maywood, Illinois; niversity of Florida, Jacksonville, Florida; Harefield Hospital, London, United Kingdom; Lahey Clinic, Burlington, Massachusetts; Duke niversity Medical Center, Raleigh, North Carolina; University of Pennsylvania Health System, Philadelphia, Pennsylvania; and ashington University Medical Center, St. Louis, Missouri

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.

Recombinant FVIIa (rFVIIa) has been approved for treatment of bleeding in hemophilia patients with inhibitors. It has also been successfully used in nonhemophilia patients with acquired antibodies against FVIII (acquired hemophilia). Pharmacological doses of rFVIIa have been found to enhance the thrombin generation on already activated platelets and, therefore, may also likely be of benefit in providing hemostasis in other situations characterized by profuse bleeding and impaired thrombin generation,1 such as patients with thrombocytopenia and in those with functional platelet defects.2,3 Additionally, it has been used successfully in a variety of less well-characterized bleeding situations,4–7 as well as in patients with impaired liver function.8,9 To date, case reports, anecdotal experience, and limited clinical trials describe these uses; data from randomized clinical trials are limited. Because of the recent trends in rFVIIa usage in non-approved settings among physicians from various disciplines, significant concerns about its safety, efficacy, and costs have arisen. Additionally, dosing of rFVIIa for these potentially broad clinical applications is not standardized. Currently, the decision on when and where to use rFVIIa for patients with uncontrolled bleeding continues to be one that must be made by individual physicians, assisted by their hospital pharmacotherapeutics and transfusion committees.10

Using algorithms based on point of care coagulation tests can decrease blood loss and blood component transfusion after cardiac surgery. We wished to test the hypothesis that a management algorithm based on near-patient tests would reduce blood loss and blood component use after routine coronary artery surgery with cardiopulmonary bypass when compared with an algorithm based on routine laboratory assays or with clinical judgement.Patients (n=102) undergoing elective coronary artery surgery with cardiac bypass were randomized into two groups. In the point of care group, the management algorithm was based on information provided by three devices, the Hepcon, thromboelastography and the PFA-100 platelet function analyser. Management in the laboratory test group depended on rapidly available laboratory clotting tests and transfusion of haemostatic blood components only if specific criteria were met. Blood loss and transfusion was compared between these two groups and with a retrospective case-control group (n=108), in which management of bleeding had been according to the clinician's discretion.All three groups had similar median blood losses. The transfusion of packed red blood cells (PRBCs) and blood components was greater in the clinician discretion group (P0.05) but there was no difference in the transfusion of PRBCs and blood components between the two algorithm-guided groups.Following algorithms based on point of care tests or on structured clinical practice with standard laboratory tests does not decrease blood loss, but reduces the transfusion of PRBCs and blood components after routine cardiac surgery, when compared with clinician discretion. Cardiac surgery services should use transfusion guidelines based on laboratory-guided algorithms, and the possible benefits of point of care testing should be tested against this standard.

HEPARIN-INDUCED thrombocytopenia (HIT) is an immunologically-mediated reaction to unfractionated heparin that can result in life-threatening thrombotic complications. When patients with a history of HIT present for cardiac surgery, anticoagulation for cardiopulmonary bypass (CPB) can be challenging. Recombinant hirudin (r-hirudin) has been reported as a feasible alternative for anticoagulation. 1-8 R-hirudin is a potent direct thrombin inhibitor that works independently of antithrombin-III, offers a rapid onset of anticoagulation, and has a relatively short half-life (60-90 min) in patients with normal renal function. 9 The ability to rapidly and reliably monitor intraoperative levels of r-hirudin anticoagulation, however, has been problematic. The levels of r-hirudin recommended for anticoagulation during CPB (3.5-4.5 μg/ml) 10 exceed those that can be effectively monitored with either the partial thromboplastin time or activated clotting time. 11 The authors described a plasma-modified kaolin-activated clotting time (PM-ACT) assay as a new point-of-care monitoring tool for r-hirudin anticoagulation has been previously described. 12 This assay, accomplished by mixing patient whole blood samples with an equal volume of citrated commercial normal plasma, extends the ACT monitoring range by correcting for hemodilution of coagulation factors and diluting r-hirudin plasma concentrations. The authors present two cases where the PM-ACT was used to monitor r-hirudin anticoagulation during cardiac surgery, and describe the potential for significant perioperative bleeding complications.

Patients undergoing cardiac surgery with cardiopulmonary bypass are at risk for excessive microvascular bleeding, which often leads to transfusion of allogeneic blood and blood components as well as reexploration in a smaller subset of patients. Excessive bleeding after cardiac surgery is generally related to a combination of several alterations in the hemostatic system pertaining to hemodilution, excessive activation of the hemostatic system, and potentially the use of newer, longer-acting antiplatelet or antithrombotic agents. Although several nonpharmacologic strategies have been proposed, this review summarizes the role of pharmacologic interventions as means to attenuate the alterations in the hemostatic system during CPB in an attempt to reduce excessive bleeding, transfusion, and reexploration. Specifically, agents that inhibit platelets, fibrinolysis, factor Xa and thrombin, as well as broad-spectrum agents, have been investigated with respect to their role in reducing consumption of clotting factors and better preservation of platelet function. Prophylactic administration of agents with antifibrinolytic, anticoagulant, and possibly antiinflammatory properties can decrease blood loss and transfusion. Although aprotinin seems to be the most effective blood conservation agent (which is most likely related to its broad-spectrum nature), agents with isolated antifibrinolytic properties may be as effective in low-risk patients. The ability to reduce blood product transfusions and to decrease operative times and reexploration rates favorably affects patient outcomes, availability of blood products, and overall health care costs.

Patients undergoing cardiac surgery with cardiopulmo nary bypass (CPB) are at increased risk for excessive perioperative blood loss requiring transfusion of blood products. Point-of-care evaluation of platelets, coagu lation factors, and fibrinogen can enable physicians to assess bleeding abnormalities rapidly. They also can facilitate the optimal administration of pharmacologic and transfusion-based therapy and allow physicians to identify patients with surgical bleeding. The ability to reduce the unnecessary use of blood products in this setting has important implications for emerging issues in blood inventory and blood costs. The ability to de crease operative time along with re-exploration rates has important consequences for health care costs in an increasingly managed health care environment. Copyright© 2001 by W.B. Saunders Company.

Objective: To assess the incidence of myocardial ischemia in patients receiving radial arterial and left internal thoracic arterial conduits (RA+LITA) during the postrevascularization period. Design: Nonrandomized observational sequential cohort. Setting: University hospital. Participants: Thirty adult patients, scheduled for elective coronary artery bypass graft surgery with RA+LITA, compared with 30 patients who received saphenous vein graft and left internal thoracic arterial conduits. Interventions: None. Measurements and Main Results: Myocardial ischemic episodes were defined as reversible ST-segment depressions or elevations ≥1 mm and ≥2 mm at J +60 msec and lasting ≥1 minute using 2-channel Holter monitoring. During the post-cardiopulmonary bypass period, a significantly higher number of patients with ≥2 mm ischemic episodes (21.7%; p = 0.015) and higher number of ≥2 mm ischemic episodes per hour (0.19 ± 0.4 episodes/hr; p = 0.03) were observed in the radial artery group versus the comparison group (0% of patients and 0 episodes/hr). During the postoperative period (24 hours), a significantly longer duration of ≥2 mm ischemic episodes was observed in the radial artery group (24 ± 33 minutes v 8.4 ± 21 minutes; p = 0.046). Radial artery graft, preoperative calcium antagonists, and pulmonary arterial mean pressure were independent predictors of the duration and area under the ST-segment curve of ≥2 mm ischemic episodes during the postoperative period. Conclusion: There is an association between the use of the radial artery graft and the incidence and severity of ≥2 mm postrevascularization ischemic episodes. Copyright © 2001 by W.B. Saunders Company

Anticoagulation with recombinant hirudin (r-hirudin) (Refludan) has been suggested as an alternative to heparin for patients with heparin-induced thrombocytopenia requiring cardiac surgery. We sought to develop a modified activated coagulation time (ACT) that would allow quantification of the levels of r-hirudin required during cardiopulmonary bypass (CPB). Twenty-one patients scheduled for elective cardiac surgical procedures requiring CPB were enrolled in this IRB-approved study. R-hirudin was added to blood specimens obtained before heparin administration (before CPB) and 30 min after heparin neutralization with protamine (after CPB) to result in concentrations of 0, 2, 4, 6, 7, or 8 microg/mL. Kaolin/ACT and complete blood count measurements were assayed in native specimens (first 10 patients, Phase I) or in specimens mixed with equal volumes of commercial normal plasma (second 11 patients, Phase II). In Phase I, good (r(2) = 0.83) linear relationships between ACT values and r-hirudin concentrations (or =4 microg/mL) were observed in specimens obtained before CPB. However, ACT values were markedly prolonged (P0.0001) by r-hirudin in specimens obtained after CPB, with ACT values generally exceeding the ACT's detection limit (999 s) at hirudin concentrations2 microg/mL. In patient specimens mixed with normal plasma (Phase II), ACT/hirudin relationships (i.e., hirudin/ACT slope values obtained with hirudin concentrationor =4 microg/mL) in the post-CPB period (0.022 +/- 0.004 microg. mL(-1). s(-1)) were similar (P = 0.47) to those (0.019 +/- 0.004 microg. mL(-1). s(-1)) obtained in the pre-CPB period. Accordingly, a significant relationship between normal plasma-supplemented ACT values and predilution hirudin concentration was obtained in the post-CPB (hirudin = 0.039ACT - 4.34, r(2) = 0.91) period. Although our data demonstrate that the ACT test cannot be used to monitor hirudin during CPB, the addition of 50% normal plasma to post-CPB hemodiluted blood specimens yields a consistent linear relationship between hirudin concentration and ACT values up to a predilution concentration of 8 microg/mL. Plasma-modified ACT may be useful in monitoring hirudin anticoagulation during CPB.A modified activated clotting time test system that may be helpful in monitoring hirudin anticoagulation in patients with heparin-induced thrombocytopenia during cardiac surgery with cardiopulmonary bypass is described.

In today’s health care environment, laboratories are cost centers and as such face significant pressures to reduce costs. Laboratorians are constantly faced with the question of whether point-of- care testing is a more cost-effective means of providing laboratory information to the clinician and whether an institution could benefit from converting testing from the central laboratory to near patient testing. This article reviews a number of studies that attempt to determine the cost of decentralized testing versus central laboratory testing.

There is still no alternative that is as effective or as well tolerated as blood; nevertheless, the search for ways to conserve, and even eliminate blood transfusion, continues. Based on hemoglobin levels, practice guidelines for the use of perioperative transfusion of red blood cells in patients undergoing coronary artery bypass grafting have been formulated by the National Institutes of Health and the American Society of Anesthesiologists. However, it has been argued that more physiologic indicators of adequacy of oxygen delivery should be used to assess the need for blood transfusion. Methods used for conserving blood during surgery include autologous blood donation, acute normovolemic hemodilution and intra- and postoperative blood recovery and reinfusion. The guidelines for the use of autologous blood transfusion are controversial and it does not appear to be cost effective compared with allogeneic blood transfusion in patients undergoing cardiac surgery. Similarly, the cost effectiveness of intra- and postoperative blood recovery and reinfusion need further evaluation. Treatment with recombinant human erythropoietin (rhEPO) remains unapproved in the US for patients undergoing cardiac or vascular surgery, but it is a valuable adjunct in Jehovah's Witness patients, for whom blood is unacceptable. The characterization of darbepoetin alfa, a novel erythropoiesis stimulating protein with a 3-fold greater plasma elimination half-life compared with rhEPO, is an important advance in this field. Darbepoetin alfa appears to be effective in treating the anemia in patients with renal failure or cancer and trials in patients with surgical anemia are planned. Desmopressin has been used to effectively reduce intraoperative blood loss. Topical agents to prevent blood loss, such as fibrin glue and fibrin gel, and agents that alter platelet function, such as aspirin (acetylsalicylic acid) or dipyridamole, need further evaluation in patients undergoing cardiac surgery. Aprotinin has been shown to preserve hemostasis and reduce allogeneic blood exposure to a greater extent than the antifibrinolytic agents tranexamic acid and aminocaproic acid. Controlled clinical trials comparing the costs of these agents with clinical outcomes, along with tolerability profiles in patients at risk for substantial perioperative bleeding are needed.

BACKGROUND: The value of acute normovolemic hemodilution (ANH) as compared to preoperative autologous blood donation (PABD) in orthopedic surgery is unknown. Therefore, a prospective, randomized study was conducted to compare these techniques in patients undergoing primary total hip arthroplasty. STUDY DESIGN AND METHODS: ANH patients underwent phlebotomy for up to 3 units, or to a target Hct level of 28 percent after induction of anesthesia. PABD patients were asked to donate up to 3 units before admission. RESULTS: Mean baseline Hct levels were not different in ANH and PABD patients (39.7 ± 4.5 vs. 41.8 ± 3.8%, p = 0.09). No difference was found in allogeneic blood exposure among ANH and PABD cohorts: 4 (17%) of 23 ANH patients received a total of 9 allogeneic blood units, compared to no allogeneic transfusions in the PABD cohort (p = 0.30). Total blood costs associated with ANH were significantly (p

Patients undergoing cardiac surgery with cardiopulmonary bypass are at increased risk for microvascular bleeding that requires perioperative transfusion of blood components. Platelet-related defects have been shown to be the most important hemostatic abnormality in this setting. The exact association between preoperative use of potent platelet inhibitors and either bleeding or transfusion in patients undergoing cardiac surgical procedures is currently being defined. Laboratory evaluation of platelets and coagulation factors can facilitate the optimal administration of pharmacologic and transfusion-based therapy. However, their turnaround time makes laboratory-based methods impractical for concurrent management of surgical patients, which has led many investigators to study the role of point-of-care coagulation tests in this setting. Use of point-of-care tests of hemostatic function can optimize the management of excessive bleeding and reduce transfusion. Accordingly, point-of-care tests that assess platelet function may also identify patients at risk for acquired, platelet-related bleeding. The ability to reduce the unnecessary use of blood products and to decrease operative time or reexploration rates has important consequences for blood inventory, blood costs, and overall health care costs.

This study was designed to compare results obtained with a new point-of-care hemocytometer with those of two established (point-of-care and laboratory-based) instruments.To compare CBC values between established laboratory-based and point-of-care instruments, measurements were performed on routinely obtained blood specimens for CBC analysis in our institutional laboratory (phase I) and on specimens from cardiac surgical patients before initiation of cardiopulmonary bypass and after discontinuation of cardiopulmonary bypass in phase II.Surgical and hospitalized patients at a tertiary care center.Measurements were obtained by using blood specimens obtained from 141 hospitalized patients from different services (phase I) or from a consecutive series of 204 patients undergoing cardiac operations (phase II).Hemoglobin (HGB), platelet count (PLT), red blood cell count, and white blood cell count (WBC) were measured with two on-site and one laboratory-based instruments. Hematocrit (HCT) was calculated by using measured variables. Linear regression demonstrated good correlations between Ichor and T540 HGB (r2 = .95), HCT (r2 = .95), PLT (r2 = .94), and WBC (r2 = .95) results (n = 408); similarly, good correlations were observed with Coulter STKS HGB (r2 = .92), HCT (r2 = .91), and PLT (r2 = .94) results (n = 141). The relationship between Ichor and Coulter STKS WBC (r2 = .27) was poor; however, when two Ichor-derived outlier values (50) were excluded, the relationship was very good (r2 = .99). Bias analysis (mean +/- SD) demonstrated similar results between Ichor and T540 HGB (0.003+/-0.5), HCT (-0.21+/-1.5), WBC (0.79+/-1.3), and PLT values (-9.2+/-16.6) as well as STKS HGB (-0.08+/-0.7), HCT (-0.69+/-2.3), WBC (-0.62+/-5.8), and PLT values (-10.2+/-21.4).The Ichor hemocytometer provides accurate hematologic results that can facilitate rapid quantitative assessment of CBC variables and thus may be clinically useful, especially in critically ill patients.

Accelerated thrombin generation is central to the development of hemostatic abnormalities during cardiopulmonary bypass (CPB) that are associated with both thromboembolic complications and serious, abnormal bleeding. Thrombin not only converts fibrinogen to fibrin, but also activates platelets and coagulation factors V, VIII, and XI and causes release of von Willebrand factor from vascular endothelium. Thrombin can also downregulate the hemostatic system by inducing formation of platelet inhibitory agents, such as nitric oxide and prostacyclin, and release of tissue plasminogen activator, facilitating activation of protein C, and releasing tissue factor pathway inhibitor. Excessive thrombin activity may also result in substantial consumption of platelets, fibrinogen, and labile coagulation factors and abnormal bleeding. Elevated tissue plasminogen activator levels secondary to activation of the contact system and surgery catalyze the formation of plasmin, which also consumes or internalizes platelet glycoprotein receptors and coagulation factors V, VIII, and fibrinogen. Heparin can reduce the generation of and mediate neutralization of excessive and CPB-associated thrombin activity. Heparin anticoagulation is commonly monitored with the activated clotting time (ACT). However, the ACT may be prolonged by factors other than heparin during CPB, such as hemodilution and hypothermia, and therefore may not accurately reflect the extent of anticoagulation by heparin. Aprotinin, a nonspecific serine protease inhibitor used with CPB, can also prolong celite-based ACT values, rendering it less reliable for monitoring heparin anticoagulation. Therefore, several alternative anticoagulation strategies have been recommended when aprotinin is used, such as a higher celite ACT trigger (>750 seconds), monitoring of whole blood heparin concentrations (eg, >2.7 U/mL), or administration of heparin based on a CPB duration-dependent, fixed-dose regimen. Administration of heparin doses higher than those generally recommended, as guided by predetermined, patient-specific whole blood heparin concentration measurements during bypass, can reduce excessive thrombin-mediated consumption of platelets and coagulation factors as well as post-CPB blood loss and blood component transfusions. New modalities of improving suppression of excess thrombin generation during CPB include use of heparin-bonded CPB circuits, heparin cofactor II or related analogs, supplemental antithrombin III, direct thrombin inhibitors (eg, hirudin, argatroban), and inhibitors of the contact and tissue factor pathways. The safety and efficacy of these approaches remains to be established by additional, appropriately powered, prospective studies.

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at increased risk for excessive perioperative blood loss requiring transfusion of blood products. Point-of-care evaluation of platelets, coagulation factors, and fibrinogen can enable physicians to rapidly assess bleeding abnormalities, facilitate the optimal administration of pharmacological and transfusion-based therapy, and also identify patients with surgical bleeding. The ability to reduce the unnecessary use of blood products in this setting has important implications for emerging issues in blood inventory and blood costs. The ability to decrease surgical time, along with exploration rates, has important consequences for health care costs in an increasingly managed health care environment.

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at increased risk for excessive perioperative blood loss requiring transfusion of blood products. The risk is dependent on the status of the patient, the type of procedure, and the duration of CPB. This brief review will summarize (1) the pathophysiology of abnormalities in the hemostatic system during CPB; (2) important pharmacologic interventions currently available to decrease blood loss, including mechanisms by which these agents lead to preservation of hemostasis during CPB; and (3) the optimal management of perioperative bleeding using point-of-care coagulation tests.

Background . We assessed the efficacy of a continuous infusion of nicardipine and nitroglycerin in reducing the incidence and severity of perioperative myocardial ischemia during elective coronary artery bypass grafting procedures in a prospective, randomized, controlled study. Methods . Patients received either nicardipine infusion (0.7 to 1.4 μg · kg · −1 · min −1 ; n=30) or nitroglycerin (0.5 to 1 μg · kg −1 · min −1 ; n=30) or neither medication (n = 17) after aortic occlusion clamp release and for 24 hours postoperatively. Myocardial ischemic episodes (MIE) were considered to have occurred with ST-segment depressions or elevations of at least 1 mm and at least 2 mm (for both depressions or elevations), each at J + 60 ms and lasting at least 1 minute, using a two-channel Holter monitor. Results . Only nicardipine significantly decreased the duration ( p = 0.02) of the 1-mm or greater minutes per hour (3.2 ± 1.2 minutes per hour) and eliminated the number ( p = 0.02) of the 2-mm or greater minutes per hour (zero minutes per hour) when compared with control patients (17.2 ± 5.6 minutes per hour and 0.17 minutes per hour, respectively) during the intraoperative postbypass period. Conclusions . Our results suggest that nicardipine lessened the severity of myocardial ischemia shortly after coronary revascularization and could be considered as an alternative to standard antiischemic therapy.

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at increased risk for excessive perioperative blood loss requiring transfusion of blood products. Strategies to optimize administration of heparin and protamine and the assessment of their effects on coagulation are evolving in cardiac surgical patients. Two recent evaluations have focused on the use of multiple point-of-care (POC) coagulation assays for patient-specific adjustment of heparin and protamine dosage. These studies indicate that blood loss and transfusion requirements in cardiac surgical patients may be reduced with more accurate control of heparin anticoagulation and its reversal. Blood component administration in patients with excessive post-CPB bleeding is generally empiric in part, related to turnaround times of laboratory-based tests. Methods are now available for rapid, POC assessment of coagulation to allow appropriate, targeted therapy for acquired hemostatic abnormalities. Recent studies indicate that a rapid evaluation of thrombocytopenia and coagulation factor deficiencies with POC tests can facilitate the optimal administration of pharmacologic and transfusion-based therapy in patients who exhibit excessive bleeding after CPB. POC tests that assess platelet function have been developed, and their use may facilitate identification of which patients at risk for excessive blood loss may respond to pharmacologic interventions such as desmopressin acetate or antifibrinolytic agents.

benefit for patients with an increased risk for degeneration of the valves. At present it is impossible to assess prospectively which patients are at risk for immunemediated valve degeneration. However, children listed for retransplantation for reasons other than technical failure and children with preformed HLA antibodies are likely candidates. We recommend that for these patients at "high risk" a crossmatch-negative, HLA-matched heart valve allograft be selected.

Background This study was designed to evaluate a new point-of-care test (HemoSTATUS) that assesses acceleration of kaolin-activated clotting time (ACT) by platelet activating factor (PAF) in patients undergoing cardiac surgery. Our specific objectives were to determine whether HemoSTATUS-derived measurements correlate with postoperative blood loss and identify patients at risk for excessive blood loss and to characterize the effect of desmopressin acetate (DDAVP) and/or platelet transfusion on these measurements. Methods Demographic, operative, blood loss and hematologic data were recorded in 150 patients. Two Hepcon instruments were used to analyze ACT values in the absence (channels 1 and 2: Ch1 and Ch2) and in the presence of increasing doses of PAF (1.25, 6.25, 12.5, and 150 nM) in channels 3-6 (Ch3-Ch6). Clot ratio (CR) values were calculated with the following formula for each respective PAF concentration: clot ratio = 1-(ACT/control ACT). These values also were expressed as percent of maximal (%M = clot ratio/0.51 x 100) using the mean CRCh6 (0.51) obtained in a reference population. Results When compared with baseline clot ratios before anesthetic induction, a marked reduction in clot ratios was observed in both Ch5 and Ch6 after protamine administration, despite average platelet counts greater than 100 K/microliter. There was a high degree of correlation between clot ratio values and postoperative blood loss (cumulative chest tube drainage in the first 4 postoperative hours) with higher concentrations of PAF: CRCh6 (r = -0.80), %M of CRCh6 (r = -0.82), CRCh5 (r = -0.70), and %M of CRCh5 (r = -0.85). A significant (P < 0.01) improvement in clot ratios was observed with time after arrival in the intensive care unit in both Ch5 and Ch6, particularly in patients receiving DDAVP and/or platelets. Conclusions Activated clotting time-based clot ratio values correlate significantly with postoperative blood loss and detect recovery of PAF-accelerated coagulation after administration of DDAVP or platelet therapy. The HemoSTATUS assay may be useful in the identification of patients at risk for excessive blood loss and who could benefit from administration of DDAVP and/or platelet transfusion.

Objective To compare point-of-care results obtained from an on-site hemocytometer with values provided by an institutional laboratory instrument. Design A prospective laboratory evaluation. Setting The central laboratory and cardiac surgical intensive care unit of a university-affiliated tertiary care center. Patients Normal range comparison was performed using blood specimens routinely obtained from 48 hospitalized patients for complete blood count analysis. The second evaluation was performed on blood specimens routinely obtained (in the intensive care unit) after cardiac surgery involving extracorporeal circulation in a series of 187 consecutive patients. Measurements and Main Results Hemoglobin concentration, platelet count, mean corpuscular volume, mean platelet volume, and red and white blood cell counts were measured with both on-site (MD 16, Coulter Electronics, Hialeah, FL) and laboratory (STKS, Coulter Electronics) instruments. Hematocrit and red cell distribution width were calculated using measured variables. Blood specimens were obtained from two distinct patients series. To evaluate measurement values within the normal range, a series of 48 routinely obtained blood specimens for complete blood count analysis in our institutional laboratory were utilized for concurrent analysis with the on-site hemocytometer. To evaluate measurement values out of the normal range, a second comparison involved measurements performed on blood specimens obtained in the cardiac surgical intensive care unit for complete blood count analysis. Linear regression demonstrated good correlations between on-site and laboratory hemoglobin concentration (r2 equals .97), hematocrit (r2 equals .95), platelet count (r2 equals .97), mean corpuscular volume (r2 equals .91), red cell distribution width (r2 equals .80), and red (r2 equals .95) and white (r2 equals .96) blood cell count results. A marginal correlation was observed between mean platelet volume values (r2 equals .47). Bias analysis (mean plus minus 2 SD) demonstrated similar measurements between on-site and laboratory hemoglobin concentration, hematocrit, platelet count, red blood cell count, white blood cell count, mean platelet volume, mean corpuscular volume, and red cell distribution width. Conclusions On-site hemoglobin concentration, hematocrit, white blood cell count, red blood cell count, red cell distribution width, and platelet count values compare well with those results obtained from the laboratory. The MD 16 hemocytometer (Coulter Electronics) provides on-site hematologic results that can provide an accurate and rapid quantitative assessment of platelets, and red and white blood cells. Rapid access to information obtained from this type of system may be clinically useful, especially in critically ill patients.

This study was designed to evaluate the effect of aprotinin on activated versus nonactivated whole blood clotting time using two different on-site methods and to quantify these anticoagulant properties when compared to heparin in a controlled, in vitro environment. Blood specimens were obtained prior to heparin administration from 56 patients undergoing cardiac surgery. Specimens obtained from the first consecutive 20 patients were mixed with either normal saline (NS) or aprotinin (400 kallikrein inhibiting units (KIU)/mL), inserted into Hemochron Registered Trademark tubes containing either NS or heparin (0.3 or 0.6 U/mL) and then used to measure celite-activated (celite ACT) and nonactivated whole blood clotting time (WBCT1) using four Hemochron Registered Trademark instruments. Accordingly, specimens obtained from the second consecutive 20 patients were mixed with either NS or aprotinin, inserted into Automated Clot Timer Registered Trademark cartridges containing either NS or heparin (0.06, 0.13, or 0.25 U/mL) and then used to measure kaolin-activated (kaolin ACT) or nonactivated whole blood clotting times (WBCT2) using four Automated Clot Timer Registered Trademark instruments. Specimens obtained from the last 16 patients were mixed with either incrementally larger doses of aprotinin (0, 100, 200, 300, or 400 KIU/mL) or heparin (0, 0.12, 0.24, 0.36, 0.48, or 0.72 U/mL) and were then used for measurement of whole blood clotting time (WBCT2) using six Automated Clot Timer Registered Trademark instruments. Aprotinin significantly prolonged activated or nonactivated whole blood clotting time and potentiated the prolongation of whole blood clotting time by heparin. The linear relationship between whole blood clotting time and either heparin concentration (WBCT2 = H times 357 + 280, mean adjusted r2 = 0.88) or aprotinin concentration (WBCT2 = A times 0.97 + 300, mean adjusted r2 = 0.94) was variable among patients. On average, 200 KIU/mL of aprotinin prolonged WBCT2 to the same extent as 0.69 +/- 0.28 U/mL of heparin using linear regression models within each patient. Aprotinin significantly prolongs activated or nonactivated whole blood clotting time measurements in a dose-dependent manner. Since prolongation of whole blood clotting time by heparin is potentiated by aprotinin in vitro, aprotinin's anticoagulant properties may in part account for the prolonged celite activated clotting time values observed in the presence of aprotinin. (Anesth Analg 1996;82:1126-31)

Background. Because previous reports suggest that the linear relationship between celite activated clotting time (ACT) values and heparin sodium is disrupted if values exceed 500 to 600 seconds, this study was designed to evaluate the relationship of kaolin activated clotting time (ACT) values to high in vitro heparin concentrations. In addition, the relationship of kaolin ACT to heparin concentration as determined manually was compared with that obtained with an automated heparin dose response assay. Methods. Blood specimens were obtained prior to and after heparin administration from 41 cardiac surgical patients requiring cardiopulmonary bypass in this institutional human studies committee-approved study. Five ACT instruments were used to evaluate the response of kaolin ACT to manually added heparin at two anticoagulation levels: low range (ACT values of less than 500 seconds) and high range (ACT values of 500 seconds or greater). Specimens were also used to measure kaolin ACT values at three heparin concentrations with an automated heparin dose response assay (HDR) using a Hepcon instrument. Results. A greater response of kaolin ACT to heparin was seen with high-range ACT values than low-range ACT values as illustrated by greater ( p = 0.002) mean slope values (low range, 99 ± 30 s · U −1 · mL −1 ; high range, 128 ± 50 s · U −1 · mL −1 ). Good correlations were obtained between heparin concentration and either low-or high-range ACT values as demonstrated by mean correlation coefficients (low range, 0.992; high range, 0.982). The response of low-range kaolin ACT values to heparin was greater than that obtained with the automated heparin dose response assay as illustrated by greater ( p = 0.005) mean slope values (low range, 99 ± 30 s · U −1 · mL −1 ; HDR, 82 ± 21 s · U −1 · mL −1 ). Good correlations were observed for the relationship between heparin and ACT values obtained with the HDR assay ( r = 0.998). Conclusions. A variable response of kaolin ACT to heparin among patients was demonstrated in our study, especially when ACT values exceeded 500 seconds. We found that the response of kaolin ACT to higher heparin concentrations was acceptable for clinical monitoring based on good correlations obtained in individual patients. The HDR assay generally overestimates a patient's heparin requirements; most likely, this is due to a lower response of kaolin ACT to heparin concentration that is reflected by this assay. Because an exceptional correlation can be obtained between kaolin ACT values and heparin concentration using the assay, this automated assay can identify heparin-resistant patients who may need further treatment.

SummaryThis study was designed to determine whether the maintenance of higher than usual patient-specific heparin concentrations during cardiopulmonary bypass (CPB) was associated with more effective suppression of hemostasis system activation.Thirty-one patients scheduled for repeat cardiac sugery or combined procedures (i.e., coronary revascularization + valve repair/replacement) were consented and enrolled in this study. All patients received porcine heparin and protamine and were randomly assigned to monitoring of anticoagulation by either celite ACT alone (Control, n = 16) or by kaolin ACT combined with on-site measurements of whole blood heparin concentration (Intervention, n = 15). Blood specimens collected before administration of heparin, before weaning from CPB and after administration of protamine were analyzed with a battery of coagulation assays.Patients in the intervention cohort received appreciably greater heparin doses than control patients, resulting in higher anti-Xa heparin levels at the end of CPB. Fibrinopeptide A and D-dimer levels were higher in the control group before discontinuation of CPB. Percent decrease during CPB were greater in the control group for factors V and VIII, fibrinogen and antithrombin III. Percent decrease in complement 3 was greater in the control group after protamine and bleeding times measured in the Intensive Care Unit were significantly more prolonged in this group.Maintenance of higher patient-specific heparin concentrations during CPB more effectively suppresses excessive hemostatic system activation than do standard heparin doses chosen based on measurement of ACT. These findings may explain, at least in part, the significant reduction in perioperative blood loss and blood product use when higher heparin concentrations are maintained.

Aprotinin is being used increasingly to limit cardiopulmonary bypass (CPB)-induced coagulation derangements. Since whole blood prothrombin time (PT) and activated partial thromboplastin time (APTT) assays are beneficial in the treatment of bleeding after CPB, we studied the potential effect of aprotinin on these whole blood assays. Blood specimens from 151 cardiac surgical patients were obtained in two phases: prior to heparin administration, before CPB, and subsequent to heparin neutralization after CPB. After collection, blood specimens were divided into two aliquots and mixed with either normal saline (NS) or aprotinin (A, 200 or 400 Kallikrein inhibiting units (KIU)/mL). Whole blood specimens were used to measure whole blood PT and APTT using CoaguChek Plus instruments. Whole blood PT results were similar between normal saline. (NS)- and aprotinin-spiked specimens before CPB (A, 12.9 +/- 1.5s; NS, 12.8 +/- 1.5s; P = 0.76) and after CPB (A, 17.5 +/- 2.4s; NS, 17.7 +/- 2.4s; P = 0.58). In contrast, whole blood APTT results were prolonged in aprotinin-spiked specimens prior to CPB (A, 63.3 +/- 32.2s; NS, 38.6 +/- 16.3s; P < 0.0001) and after CPB (A, 65.9 +/- 23.7s; NS, 45.7 +/- 14.4s; P < 0.0001). A dose-dependent prolongation of whole blood APTT by aprotinin was demonstrated by a greater mean difference in APTT (P = 0.0001) between specimens spiked with NS or 200 KIU (17.5 +/- 12.2s) vs 400 KIU (27.8 +/- 21.5s) of aprotinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty cardiac surgical patients requiring cardiopulmonary bypass were enrolled in this study designed to evaluate the effect of aprotinin on activated clotting time (kaolin and celite), whole blood, and laboratory-based plasma (anti-Xa) heparin measurements. Whole blood heparin measurements were not different ( p = 0.98) between aprotinin-treated (3.2 ± 2.8 U/mL) and control (3.2 ± 3.0 U/mL) specimens. Plasma anti-Xa heparin measurements were also not different ( p = 0.95) between aprotinin-treated (2.7 ± 2.5 U/mL) and control (2.8 ± 2.5 U/mL) specimens. The relationship between whole blood (plasma equivalent) and plasma heparin measurements was similar ( p 0 = 0.1) in the presence (slope, 1.04; r 2 =0.89) or absence (slope, 1.11; r 2 = 0.89) of aprotinin. In contrast to weak correlations between celite ( r = 0.50) or kaolin ( r = 0.53) activated clotting time values, whole blood heparin measurements correlated well ( r = 0.93) with plasma heparin measurements during cardiopulmonary bypass in the presence of aprotinin. These findings indicate that whole blood heparin measurements are unaffected by aprotinin and correlate well with plasma anti-Xa heparin measurements even in the presence of aprotinin. Therefore, the automated protamine titration assay can be used to monitor accurately heparin concentrations in patients receiving aprotinin.