Point-of-care testing for tranexamic acid efficacy: a proof-of-concept study in cardiac surgical patients.

BACKGROUND: Low-dose tranexamic acid (TXA) has been recently recommended for cardiopulmonary bypass (CPB) to reduce associated complications. Although point-of-care laboratory tests for TXA concentrations are unavailable, a novel TPA-test on the ClotPro® system can measure TXA-induced inhibition of fibrinolysis. We evaluated the performance of the TPA-test in vitro and in patients undergoing surgery requiring CPB. METHODS: Blood samples were obtained from six volunteers for in vitro evaluation of tissue plasminogen activator (tPA)-triggered fibrinolysis and the effects of TXA. This was followed by an observational study in 20 cardiac surgery patients to assess clinical effects of TXA on the TPA-test. RESULTS: Hyperfibrinolysis induced by tPA was inhibited by TXA ≥2 mg L-1 in a concentration-dependent manner, and was completely inhibited at TXA ≥10 mg L-1. In patients undergoing CPB, antifibrinolytic effect was detectable on TPA-test parameters after a 0.1 g bolus of TXA at the end of CPB, and complete inhibition of fibrinolysis was obtained with TXA ≥0.5 g. The antifibrinolytic effects of 1 g TXA on TPA-test parameters were gradually attenuated over 18 h after surgery. However, the fibrinolytic inhibition continued in four patients with estimated glomerular filtration rate (eGFR) ≤30 ml min-1 1.73 m-2. The eGFR had strong correlations with TPA-test parameters at 18 h after surgery (r=0.86-0.92; P<0.0001). CONCLUSIONS: The TPA-test is sensitive to low concentrations of TXA and serves as a practical monitoring tool for postoperative fibrinolytic activity in cardiac surgery patients. This test might be particularly useful in patients with severe renal impairment.

Antithrombin supplementation attenuates heparin resistance in plasma spiked with Gla-domainless factor Xa S195A in vitro.

BACKGROUND: Andexanet alfa is a Gla-domainless mutant (S195A) factor Xa (GDXa) approved for acute reversal of oral factor Xa inhibitors. Cardiac surgery patients exposed to andexanet before cardiopulmonary bypass often exhibit severe heparin resistance. There is a paucity of data on the effectiveness and optimal dosage of antithrombin use in this setting. The objective of this study was to evaluate the in vitro effect of increased heparin with antithrombin levels on attenuating heparin resistance induced by GDXa. METHODS: Heparinised normal pooled plasma and cardiopulmonary bypass plasma were spiked with GDXa 4 µM. Tissue factor-activated thrombin generation was used to assess heparin reversal effects of GDXa and restoration of anticoagulation with additional heparin with and without antithrombin. Serum thrombin-antithrombin complex, antithrombin activity, and tissue factor pathway inhibitor were also measured in tissue factor-activated, recalcified cardiopulmonary bypass plasma spiked with GDXa. RESULTS: In normal pooled plasma, GDXa-induced heparin reversal was mitigated by maintaining a high heparin concentration (12 U ml-1) and supplementing antithrombin (1.5-4.5 µM) based on peak and velocity of thrombin generation. Heparin reversal by GDXa was also demonstrated in cardiopulmonary bypass plasma, but supplementing both heparin (8 U ml-1) and antithrombin (3 µM) attenuated GDXa-induced changes in peak and velocity of thrombin generation by 72.5% and 72.2%, respectively. High heparin and antithrombin levels attenuated thrombin-antithrombin complex formation in tissue factor-activated, GDXa-spiked cardiopulmonary bypass plasma by 85.7%, but tissue factor pathway inhibitor remained depleted compared with control cardiopulmonary bypass plasma. CONCLUSIONS: Simultaneous supplementation of heparin and antithrombin mitigate GDXa-induced heparin resistance by compensating for the loss of tissue factor pathway inhibitor.

Protamine dosing and its impact in cardiac surgery transfusion practice-A retrospective bi-institutional analysis.

BACKGROUND: Bleeding after cardiac surgery is common and continues to require 10-20% of the national blood supply. Transfusion of allogeneic blood is associated with increased morbidity and mortality. Excessive protamine in the absence of circulating heparin after weaning off CPB can cause anticoagulation and precipitate bleeding. Hence, adequate dose calculation of protamine is crucial yet under evaluated. STUDY DESIGN: Retrospective cohort study. METHODS: We conducted a retrospective bi-institutional analysis of cardiac surgical patients who underwent cardiopulmonary bypass (CPB)-assisted cardiac surgery to assess the impact of protamine dosing in transfusion practice. Total 762 patients were identified from two institutions using electronic medical records and the Society of Thoracic Surgery (STS) database who underwent cardiac surgery using CPB. Patients were similar in demographics and other baseline characteristics. We divided patients into two groups based on mg of protamine administered to neutralize each 100 U of unfractionated heparin (UFH)-low-ratio group (Protamine: UFH ≤ 0.8) and high-ratio group (Protamine: UFH > 0.8). RESULTS: We observed a higher rate of blood transfusion required in high-ratio group (ratio >0.8) compared with low-ratio group (ratio ≤0.8) (p < .001). The increased requirement was consistently demonstrated for intraoperative transfusions of red blood cells, plasma, platelets, and cryoprecipitate. CONCLUSION: High protamine to heparin ratio may cause increased bleeding and transfusion in cardiac surgical patients. Protamine to heparin ratio of 0.8 or lower is sufficient to neutralize circulating heparin after weaning off cardiopulmonary bypass.

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.

Trends and predictions of perioperative transfusion and venous thromboembolism in hepatectomy using a North American Registry.

BACKGROUND: Studies indicate a link between allogeneic blood transfusion and venous thromboembolism (VTE) post-major surgery. Analyzing trends and predictors of these outcomes after hepatectomy can inform risk management. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used for a retrospective analysis. Primary outcomes were perioperative red blood cell (RBC) transfusion and VTE events within 30 days of hepatectomy. Seven-year trends and predictors were evaluated. RESULTS: Among 29,131 hepatectomy patients, transfusion rates showed no statistically significant decreasing trends (p = .122) from 2014 to 2020 (18.13%-16.71%), while VTE rates showed a downward trend over the 7 years (p = .021); 17.2% received RBC transfusion, with higher rates in surgeries lasting ≥282 min (median: 220 min). Calculated RBC mass [hematocrit (%) × body weight (kg) × 10-5 × 70/ √ (body mass index/22)] at or below 1.5 L substantially increased transfusion odds. VTE was reported postoperatively in 2.6% of cases more frequently in longer cases involving transfusions. The adjusted odds ratio (aOR) of VTE escalated from the shortest operative time to the longest (3.17; 95% confidence interval [CI], 2.37-4.22). The adjusted odds of VTE doubled for transfused patients compared to non-transfused patients (aOR, 2.19; 95% CI, 1.86-2.57). CONCLUSIONS: Rates of RBC transfusion and VTE rates hepatectomy have minimally changed in the recent years. VTE prevention is challenging in extended surgeries at increased risk of bleeding and RBC transfusions. Patient-level data on coagulation and thromboprophylaxis can potentially refine risk assessment for postoperative VTE.

Trends and Prediction of Surgical Site Infection After Elective Spine Surgery: An Analysis of the American College of Surgeons National Surgical Quality Improvement Project Database.

Background: Surgical site infection (SSI) is an infrequent but costly complication after elective spine surgery. Identification of important temporal changes and predictive factors may inform targeted prevention efforts. Patients and Methods: A retrospective study of elective spine surgery patients was performed using the National Surgical Quality Improvement Programs (NSQIP) database from 2011 and 2019. Temporal changes in SSI and related factors were examined descriptively. Recursive partitioning and bootstrap forest techniques were used to inform the development of predictive models for SSI. Results: A total of 6,038 (1.66%) of 363,754 patients had an SSI recorded. Peri-operative transfusion and preoperative anemia decreased over the nine-year period, however, obesity and diabetes mellitus increased, whereas the SSI rate remained essentially unchanged. A full model including 15 variables had an area under the curve (AUC) of 0.693 (95% confidence interval [CI], 0.686-0.700) whereas a reduced model with just nine variables had an AUC of 0.690 (95% CI, 0.683-0.697). Adjusted odd ratios (aOR) greater than two were noted for only three variables; a posterior approach (aOR, 2.32; 95% CI, 2.14-2.50), body mass index (BMI) >40 kg/m2 (aOR, 2.63; 95% CI, 2.39-2.90), and surgical duration longer than 350 minutes (aOR, 2.39; 95% CI, 2.14-2.67). Remaining retained variables included albumin <3.5 g/dL, inpatient procedure, peri-operative transfusion, diabetes mellitus (both insulin/non-insulin), anemia, and smoking. Conclusions: Surgical site infection rate remained unchanged over a nine-year period despite the lower rates of allogeneic blood transfusion. Class 3 obesity, long operative times, and a posterior approach mainly for thoracic/lumbar spine procedures seemed more pragmatic, but their predictive performance was only modest in our prediction models for SSI.

Role of Cardiac Anesthesiologists in Intraoperative Enhanced Recovery After Cardiac Surgery (ERACS) Protocol: A Retrospective Single-Center Study Analyzing Preliminary Results of a Yearlong ERACS Protocol Implementation.

INTRODUCTION: Enhanced recovery after cardiac surgery (ERACS) has been gaining rapid acceptance after multiple studies have demonstrated promising results in improved outcomes of enhanced recovery after surgery in other surgical fields (eg, colorectal, orthopedic, thoracic, etc). Cardiac surgery has several unique challenges, including sternotomy, cardiopulmonary bypass and associated coagulopathy, blood transfusion, and postoperative intensive care requirement. Nonetheless, selective cardiac surgical patients can still benefit from ERACS. Guidelines for perioperative care in cardiac surgery, previously published by the ERACS Society, are weighted heavily in preoperative and postoperative management without much focus on intraoperative care provided by anesthesiologists. To address this gap and to explore anesthesiology's contribution in achieving ERACS, the study authors' cardiac anesthesiology division, in collaboration with cardiac surgery, introduced the ERACS protocol in their institution in February 2020. METHODS: The cardiac anesthesiology division, in collaboration with cardiac surgery, introduced the ERACS protocol consisting of multimodal opioid-sparing analgesia, including the introduction of regional blocks, hemostasis management protocol, reversal of neuromuscular blockade, and administration of antiemetics in the authors' institution in February 2020. They have conducted a retrospective chart review study comparing patients who have received ERACS measures with a similar historic cohort who underwent cardiac surgery prior to initiation of an ERACS protocol. The primary outcomes of the study were to determine patients' time to extubation, postoperative opioid consumption, intensive care unit (ICU) length of stay (LOS), and incidence of postoperative complications (eg, postoperative nausea vomiting [PONV], bleeding, ICU readmission, delirium. RESULTS: The ERACS patients showed reduced opioid consumption (intraoperative fentanyl; postoperative fentanyl, as well as oxycodone, in the first 6 hours postoperatively), lesser mechanical ventilation (2.5 hours less), shorter ICU stays (5 hours less), shorter hospital LOS (1 day), and lesser incidence of PONV. None of the ERACS patients required blood transfusion. The study authors performed an anonymous survey among the anesthesiologists and ICU providers to assess providers' satisfaction, which showed 92% of survey takers agreed that the ERACS protocol should be continued for future cardiac patients, and 61% of survey takers reported superior pain control in ERACS group of patients while managing those patients. DISCUSSION: The ERACS is achievable after the careful implementation of a series of measures. It does not signify only fast-track extubation and opioid-sparing analgesia, and must be implemented in the entire perioperative period beginning from preoperative clinic to postoperative rehabilitation. Cardiac anesthesiologists play a vital role in execution of intraoperative ERACS measures. Both providers and patients themselves are key stakeholders. A larger randomized prospective trial is warranted to solidify the inference.

Blood utilization in liver transplantation (BUILT): A multidisciplinary survey of transfusion practices.

BACKGROUND: The purpose of this study was to survey liver transplant centers in the United States to assess baseline practices in blood utilization and identify opportunities for standardization to optimize blood use in these complex cases. STUDY DESIGN AND METHODS: Two surveys, one for transfusion medicine physicians and the other for anesthesiologists, were distributed to high-volume liver transplant centers. RESULTS: The response rate was 52% for both surveys. The majority of respondents (90%) indicated they issue a standardized number of blood products to start surgeries. The most common number of products issued before the start of cases were 10 red blood cells (RBC) and 10 plasma units with no platelets or cryoprecipitate. On average, fewer RBC (7.5) and plasma (7) units were transfused than issued. Decisions to transfuse RhD+ RBCs to RhD- patients and use antigen untested units in alloimmunized patients were mainly handled on a case-by-case basis. Many centers reported utilizing viscoelastic testing (97%) and cell salvage (97%). Most centers reported standardized, laboratory-based intraoperative transfusion goals for RBCs (65%) and fibrinogen replacement (52%) but lacked a standardized approach for plasma (55%) and platelets (58%). DISCUSSION: More blood products are issued during surgery than are transfused. Responses from anesthesiology providers suggest a broad consensus on practice. Almost all respondents use viscoelastic testing in the management of intraoperative coagulopathy, either alone or in combination with classical coagulation tests. The majority of programs do not transfuse clotting factor concentrates, including fibrinogen concentrate, prothrombin complex concentrates, and recombinant activated FVII, and do not use antifibrinolytics prophylactically.

Relationships Between Body Mass Index, Allogeneic Transfusion, and Surgical Site Infection After Knee and Hip Arthroplasty Surgery.

BACKGROUND: Increased body mass index (BMI) is considered as an important factor that affects the need for total knee and hip arthroplasty (TKA/THA) and the rate of perioperative complications. Previous investigations have not fully established the relationship of BMI and perioperative transfusion with surgical site infection (SSI) or the relationship of BMI and perioperative transfusion after TKA or THA. METHODS: The National Surgical Quality Improvement Program database was used to perform a retrospective cohort study involving 333,223 TKA and 41,157 THA cases between 2011 and 2018. Multivariable regression assessed the associations of BMI (5 standard categories) and transfusion with SSI. Odds ratio (OR) of SSI was calculated relative to a normal BMI (18.5-24.9 kg/m 2 ) after adjustment of potential confounding factors. RESULTS: Perioperative transfusion decreased significantly over time for both TKA and THA; however, SSI rates remained steady at just under 1% for TKA and 3% for THA. In TKA, a higher OR for SSI was associated only with a BMI of 40+ (OR, 1.86; 95% confidence interval [CI], 1.60-2.18) compared to a referent BMI. In THA, increased ORs of SSI were seen for all BMI levels above normal and were highest for a BMI 40+ (OR, 3.08; 95% CI, 2.47-3.83). In TKA, ORs of transfusion decreased with increasing BMI and were lowest for a BMI 40+ (OR, 0.51; 95% CI, 0.47-0.54). In THA, ORs of transfusion began to increase slightly in overweight patients, reaching an OR of 1.36 (95% CI, 1.21-1.54) for a BMI 40+. CONCLUSIONS: SSI incidence remained unchanged despite continuous reductions in blood transfusion in TKA and THA patients over 8 years. In TKA, ORs for SSI increased, but ORs for transfusion decreased with increasing BMI above normal. Conversely, in THA, ORs for SSI and transfusion both increased for a BMI 40+, but only OR for transfusion increased in underweight patients. These findings suggest the importance of controlling obesity in reducing SSI following TKA and THA.