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.

The Year in Coagulation and Transfusion: Selected Highlights from 2022.

This is an annual review to cover highlights in transfusion and coagulation in patients undergoing cardiovascular surgery. The goal of this article is to provide readers with a focused summary of the most important transfusion and coagulation topics published in 2022. This includes a discussion covering the management of anemia and red blood cell transfusion, the management of factor Xa inhibitors, updates in coagulation testing, updates in the use of factor concentrates, advances in platelet therapy, advances in anticoagulation management of patients on extracorporeal membrane oxygenation and other forms of mechanical circulatory support, and advances in the diagnosis and management of heparin-induced thrombocytopenia.

Perioperative Doppler ultrasound assessment of portal vein flow pulsatility in high-risk cardiac surgery patients: a multicentre prospective cohort study.

BACKGROUND: Portal vein Doppler ultrasound pulsatility measured by transoesophageal echocardiography is a marker of the haemodynamic impact of venous congestion in cardiac surgery. We investigated whether the presence of abnormal portal vein flow pulsatility is associated with a longer duration of invasive life support and postoperative complications in high-risk patients. METHODS: In this multicentre cohort study, pulsed-wave Doppler ultrasound assessments of portal vein flow were performed during anaesthesia before initiation of cardiopulmonary bypass (before CPB) and after separation of cardiopulmonary bypass (after CPB). Abnormal pulsatility was defined as portal pulsatility fraction (PPF) ≥50% (PPF50). The primary outcome was the cumulative time in perioperative organ dysfunction (TPOD) requiring invasive life support during 28 days. Secondary outcomes included major postoperative complications. RESULTS: 373 patients, 71 (22.0%) had PPF50 before CPB and 77 (24.9%) after CPB. PPF50 was associated with longer duration of TPOD (median [inter-quartile range]; before CPB: 27 h [11-72] vs 19 h [8.5-42], P=0.02; after CPB: 27 h [11-61] vs 20 h [8-42], P=0.006). After adjusting for confounders, PPF50 before CPB showed significant association with TPOD. PPF50 after CPB was associated with a higher rate of major postoperative complications (36.4% vs 20.3%, P=0.006). CONCLUSIONS: Abnormal portal vein flow pulsatility before cardiopulmonary bypass was associated with longer duration of life support therapy after cardiac surgery in high-risk patients. Abnormal portal vein flow pulsatility after cardiopulmonary bypass separation was associated with a higher risk of major postoperative complications although this association was not independent of other factors. CLINICAL TRIAL REGISTRATION: NCT03656263.

The FIBTEM paradox: Do coronary artery bypass grafting patients with high baseline FIBTEM clot firmness need more allogeneic blood transfusion?

BACKGROUND: Fibrinogen thromboelastometry (FIBTEM) test is clinically used for rotational thromboelastometry as a surrogate measure of fibrinogen. Elevated fibrinogen might confer protection against bleeding after major surgery. This single-center study was conducted to assess any relationship between baseline FIBTEM value and exposure to allogeneic transfusion in patients undergoing coronary artery bypass grafting (CABG). STUDY DESIGN AND METHODS: Data were obtained retrospectively from local FIBTEM data and the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database between 2016 and 2019. Preoperative FIBTEM 10-min amplitude (A10) was categorized as low (≤ 18 mm), intermediate (19-23 mm), or high (≥24 mm). The primary outcome was any transfusion during the hospitalization, including red blood cells (RBCs), platelets, plasma, and cryoprecipitate. A multivariable regression model was used to adjust for confounders and calculate an odds ratio (OR) for any transfusion. RESULTS: The high FIBTEM group included more female and African-American patients, as well as urgent surgery. The STS predicted risks of morbidity and mortality were greater, and anemia was most prevalent with high FIBTEM. Unadjusted blood transfusion rates were increased with high FIBTEM due to RBC transfusion, but non-RBC transfusion was highest with low FIBTEM. After adjustments, a lower OR for transfusion was associated with high FIBTEM (0.426; 95% confidence interval, 0.199-0.914) compared to low FIBTEM. CONCLUSION: The high FIBTEM group frequently presented with anemia and comorbidities, and received more RBCs but not non-RBC products. Postoperative blood loss was less with high FIBTEM, and after adjustments, it conferred protection against any transfusion.

Coagulation and Transfusion Updates From 2021.

2021 and the COVID 19 pandemic have brought unprecedented blood shortages worldwide. These deficits have propelled national efforts to reduce blood usage, including limiting elective services and accelerating Patient Blood Management (PBM) initiatives. A host of research dedicated to blood usage and management within cardiac surgery has continued to emerge. The intent of this review is to highlight this past year's research pertaining to PBM and COVID-19-related coagulation changes.

Intraoperative echocardiographic assessment of mitral valve translocation.

OBJECTIVES: The aim of this study was to present a rigorous method to analyse the intraoperative echocardiographic images from the novel mitral translocation procedure, which assesses the changes in mitral structure and function and compares this data to a control group of patients who have no mitral regurgitation (MR). METHODS: Transoesophageal echocardiography was post-processed using dedicated 3D software. Ten patients with normal mitral valves (MV) undergoing non-mitral cardiac surgery served as controls. Mitral coaptation area, mid-leaflet coaptation length and mitral annular circumference were measured in 3D. RESULTS: Twenty-three consecutive patients with severe secondary MR underwent MV translocation. All patients had none/trace MR post-translocation. The mean coaptation surface area increased from 63 to 427 mm2 (P < 0.001) and coaptation length increased from 1.0 to 10.5 mm (P < 0.001). The control group coaptation surface area (136 mm2) and length (2.5 mm) were greater than pre-translocation (P = 0.019; P < 0.001) and less than post-translocation (P < 0.001; P < 0.001). 3D mitral annular circumference in the translocation group decreased 15% (130-110 mm) (P < 0.001). Post-translocation, the mean gradient was 2(2-3) mmHg with the diastolic mitral orifice area of 3.4 ± 0.3 cm2 by planimetry and 3.5 ± 0.3 cm2 by pressure half-time. The coaptation to septum distance remained unchanged (P = 0.305) without systolic anterior leaflet motion. CONCLUSIONS: This echocardiographic analysis method demonstrates that MV translocation abolishes secondary MR, increases coaptation area and length and produces acceptable diastolic function. This method of analysis should allow precise structural and quantitative assessment of the durability of the repair in future long-term follow-up.

A Pharmacokinetic and Plasmin-Generation Pharmacodynamic Assessment of a Tranexamic Acid Regimen Designed for Cardiac Surgery With Cardiopulmonary Bypass.

OBJECTIVES: To examine the pharmacokinetics (PK) and pharmacodynamics of a tranexamic (TXA) regimen designed for cardiac surgery with cardiopulmonary bypass (CPB). DESIGN: A pilot study quantifying TXA concentrations, fibrinolysis markers, and a plasmin- generation (PG) assay. For comparison, PG assay was performed on pooled normal plasma (PNP) with varying TXA concentrations. SETTING: A single-center, tertiary, academic medical center. PARTICIPANTS: Twenty patients undergoing cardiac surgery with CPB for valve surgery and/or coronary artery bypass grafting. INTERVENTION: TXA 100 mg/h infusion for 5 hours starting before incision; 1 g TXA in CPB prime and 1 g TXA at CPB end prior to heparin reversal. MEASUREMENTS AND MAIN RESULTS: The PK fit a 2-compartment disposition model. TXA concentrations were above 15 mg/L in all patients during CPB through 2 hours post-TXA infusion. During and after CPB, the TXA regimen decreased the median peak PG by 60% (95% confidence interval [CI], 56%-62%). Lowest median peak PG occurred 15 minutes postprotamine. Peak median D-dimer level of 1.24 (0.95-1.71; 95% CI) mg/L occurred at 15 minutes postprotamine and baseline-adjusted ΔD dimer correlated with increased CPB time (p = 0.004) and lower TXA level (p = 0.001). The median 24-hour chest tube output was 447 (330-664; 95% CI) mL. PG assay on PNP revealed a plateau inhibition at 5 mM TXA (786 mg/L). CONCLUSIONS: This regimen, with total perioperative dose of 2.5 grams, provided TXA concentrations above 15 mg/L for all patients from CPB initiation through 2 hours post-TXA. PG was significantly inhibited (p < 0.0001) during and after CPB, with maximum inhibition measured at 15 minutes after protamine administration.

In vitro effects of emicizumab on activated clotting time in blood samples from cardiac surgical patients.

BACKGROUND: Heparin management in hemophilia A (HA) patients with a factor VIII (FVIII) inhibitor can be challenging due to severe activated clotting time (ACT) prolongations. It is important to better understand the impact of emicizumab, a FVIII mimetic on ACT, and tissue factor (TF)-based coagulation assays. METHODS: Whole blood from 18 patients undergoing cardiopulmonary bypass (CPB) were mixed in vitro with pooled normal plasma, FVIII-deficient or FVIII-inhibitor plasma to affect functional FVIII levels. ACTs and heparin concentration by protamine titration were measured in whole blood mixture with/without emicizumab (50-100 µg/ml). Thrombin generation and plasmin generation were measured in the patient's plasma mixed with normal plasma or FVIII-inhibitor plasma to assess the impact of emicizumab under low TF activation. RESULTS: FVIII inhibitors prolonged ACTs by 2.2-fold compared to those in normal plasma mixture at baseline. During CPB, ACTs in normal plasma mixture, and FVIII-deficient mixture were in 400s, but ACTs reached 900s in FVIII-inhibitor mixture. Emicizumab shortened ACTs by up to 100s in normal plasma mixture, and FVIII-deficient mixtures. ACTs remained over 600s in FVIII-inhibitor mixture, despite adding emicizumab at 100 µg/ml. Heparin concentration measured by TF-based protamine titration was unaffected. Emicizumab enhanced thrombin peak in the presence of FVIII inhibitors, whereas plasmin generation was mainly affected by thrombin generation, and systemic use of ɛ-aminocaproic acid. CONCLUSIONS: FVIII inhibitors extensively prolong ACTs in heparinized whole blood, and clinical levels of emicizumab partially reverse ACT values. Protamine titration should be considered for optimal heparin monitoring in emicizumab-treated patients with FVIII inhibitors.

In Vitro Comparison of Recombinant and Plasma-Derived von Willebrand Factor Concentrate for Treatment of Acquired von Willebrand Syndrome in Adult Extracorporeal Membrane Oxygenation Patients.

BACKGROUND: Coagulopathic bleeding is common during adult extracorporeal membrane oxygenation (ECMO), and acquired von Willebrand syndrome is a contributing factor. We compared ECMO patient blood samples that were treated in vitro with recombinant von Willebrand Factor concentrate and plasma-derived von Willebrand Factor concentrate. Our hypothesis was that recombinant von Willebrand Factor (vWF) would have greater efficacy in increasing vWF function. Secondarily, we hypothesized that recombinant vWF would have less impact on thrombin generation. METHODS: Thirty ECMO patients and 10 cardiac surgical controls were enrolled in the study. ECMO patient blood samples were treated in vitro with low- and high-dose recombinant vWFs and low- and high-dose plasma-derived vWFs. Whole blood ristocetin-induced platelet aggregation (RIPA), plasma ristocetin cofactor activity (RCo), and thrombin generation were compared between ECMO patient blood samples and control blood samples and between vWF-treated ECMO patient blood samples and nontreated samples. RESULTS: ECMO patient blood samples had severely reduced median RIPA compared to control samples 2 ohms (1-12 [25th-75th percentile]) vs 20 ohms (11-42) (P < .001). Treatment of ECMO patient blood samples with high-dose recombinant vWF significantly increased median RIPA to 10 ohms (2-15) (P < .001), while low-dose recombinant vWF and low- and high-dose plasma-derived vWFs did not significantly increase RIPA; 6 ohms (3-14), 4 ohms (1-13), and 6 ohms (2-10), respectively (P = .25, >.99, and >.99). Treatment with high-dose recombinant vWF and low- and high-dose plasma-derived vWFs significantly increased median plasma RCo to 4.7 international units (IU)/mL (3.7-5.9), 3.3 IU/mL (2.7-4.8), and 3.9 IU/mL (3.4-5.3), respectively, compared to controls 1.8 IU/mL (1.5-2.3) (all P < .001). Treatment with low- and high-dose plasma-derived vWFs significantly increased mean endogenous thrombin potential (6270.2 ± 2038.7 and 6313.1 ± 1913.3) compared to nontreated samples (5856.7 ± 1924.6) (P = .04 and .006), whereas treatment with low- and high-dose recombinant vWFs had no significant effect on mean endogenous thrombin potential (5776.1 ± 2087.3 and 5856.2 ± 1946.4) (P > .99 for both comparisons). CONCLUSIONS: In vitro treatment of ECMO patient blood samples with high-dose recombinant vWF was superior to low-dose recombinant vWF and plasma-derived vWF in terms of improving RIPA. In addition, recombinant vWF treatment did not increase endogenous thrombin potential, which may reduce overall thrombotic risk if it used to treat acquired von Willebrand syndrome in ECMO patients.

Mitral Valve Translocation: A Novel Operation for the Treatment of Secondary Mitral Regurgitation.

BACKGROUND: Conventional annuloplasty repair of secondary (functional) ischemic mitral regurgitation (IMR) is associated with a 60% recurrence of moderate or greater mitral regurgitation at 2 years. We developed a novel repair technique for IMR that addresses the underlying geometric alterations of the mitral valve apparatus and compared outcomes with those of conventional repair in a swine model. METHODS: Chronic IMR was induced by percutaneous embolization of the circumflex artery. Swine with severe IMR (median 9 weeks after infarction) underwent undersized rigid annuloplasty (n = 5) or translocation repair (n = 6). Translocation repair consisted of detaching the mitral valve en bloc at the annulus, creating a 1 cm wide frustum-shaped pericardial patch, and suturing the outer circumference of the patch to the annulus and inner circumference to the mitral valve. RESULTS: Operative survival was 92% (11 of 12). All animals had none/trace residual central mitral regurgitation, and mean inflow gradients were similar (1 mm Hg [interquartile range, 1 to 2] vs 2 mm Hg [interquartile range, 1 to 2]; P = .75) in the annuloplasty and translocation groups, respectively. Median coaptation length marginally improved in conventional swine (3 to 4 mm, P = .05), but dramatically improved in translocation swine (3 to 8 mm, P = .003). Posterior leaflet angle increased from 39 to 80 degrees (P = .05) in annuloplasty swine but decreased from 50 to 31 degrees (P = .03) in translocation swine. The posterior leaflet was immobile after annuloplasty but had preserved motion after translocation (excursion, 1 degree vs 24 degrees; P = .045). CONCLUSIONS: Mitral valve translocation effectively treats mitral regurgitation by relieving leaflet tethering. Compared with annuloplasty, mitral valve translocation creates a larger surface of coaptation and preserves leaflet mobility without compromising diastolic function.

The Year in Coagulation: Selected Highlights from 2020.

This is the second annual review in the Journal of Cardiothoracic and Vascular Anesthesia to cover highlights in coagulation for cardiac surgery. The goal of this article is to provide readers with a focused summary from the literature of the prior year's most important coagulation topics. In 2020, this included a discussion covering allogeneic transfusion, antiplatelet and anticoagulant therapy, factor concentrates, coagulation testing, mechanical circulatory support, and the effects of coronavirus disease 2019.

Tissue Factor Pathway Inhibitor Levels During Veno-Arterial Extracorporeal Membrane Oxygenation in Adults.

Tissue factor pathway inhibitor (TFPI) has multiple anticoagulant properties. To our knowledge, no studies have measured TFPI levels in adult veno-arterial (VA) extracorporeal membrane oxygenation patients. We hypothesized that adult VA ECMO patients would have increased TFPI levels and slowed tissue factor triggered thrombin generation. Twenty VA ECMO patients had TFPI levels and thrombin generation lag time measured on ECMO day 1 or 2, day 3, and day 5. TFPI levels and thrombin generation lag time were compared against healthy control plasma samples. Mean TFPI levels were significantly higher in ECMO patients on ECMO day 1 or 2 = 81,877 ± 19,481 pg/mL, day 3 = 73,907 ± 26,690 pg/mL, and day 5 = 77,812 ± 23,484 pg/mL compared with control plasma = 38,958 ± 9,225 pg/mL (P < 0.001 for all comparisons). Median thrombin generation lag time was significantly longer in ECMO patients on ECMO day 1 or 2 = 10.0 minutes [7.5, 13.8], day 3 = 9.0 minutes [6.8, 12.1], and day 5 = 10.7 minutes [8.3, 15.2] compared with control plasma = 3.6 minutes [2.9, 4.2] (P < 0.001 for all comparisons). TFPI is increased in VA ECMO patients and tissue factor triggered thrombin generation is slowed. Increased TFPI levels could contribute to the multifactorial coagulopathy that occurs during ECMO.

Hematologic evaluation of intraoperative autologous blood collection and allogeneic transfusion in cardiac surgery.

BACKGROUND: Acute normovolemic hemodilution is recommended as a technique to reduce allogeneic red blood cell (RBC) transfusions in cardiac surgery, but its efficacy to reduce non-RBC transfusion has not been consistently demonstrated. We hypothesized that intraoperative large-volume autologous whole blood (AWB) collection and reinfusion improves viscoelastic coagulation parameters. STUDY DESIGN AND METHODS: Prospective observational study of cardiac surgery patients at the University of Maryland Medical Center between December 2017 and August 2019. Rotational thromboelastometry parameters were compared between AWB and control groups (n = 25 in each group) at three time points: T1, baseline; T2, on cardiopulmonary bypass (CPB) after the cross-clamp removal; and T3, 30-60 minutes after protamine administration. The study's primary outcomes were whole blood viscoelastic coagulation parameters that included EXTEM clotting time (CT), FIBTEM amplitude at 10 minutes, and EXTEM amplitude at 10 minutes (EXTEM-A10 ). Chest tube drainage and allogeneic transfusion were secondary outcomes. RESULTS: Reinfusion of AWB after CPB resulted in a significantly shorter EXTEM CT; mean difference, -11.4 seconds (-21.4 to -1.4; P = .03). It also resulted in a greater percentage increase in EXTEM A10 from T2 to T3; mean difference, 7.8% (95% CI, 1.1%-14.5%; P = .02). Statistical significance was not found in 24-hour chest tube drainage. CONCLUSION: Large-volume AWB collection and reinfusion are feasible in selected cardiac surgical patients, and may be associated with prohemostatic effects according to thromboelastometry, warranting further investigation with a prospective randomized study.

Evolution of viscoelastic coagulation testing.

INTRODUCTION: The methods of viscoelastic coagulation testing (VCT) have evolved since the original invention of thrombelastography over 60 years ago, and new generations of devices are clinically used to guide hemostatic interventions at bedside. The utility of VCTs has been demonstrated in several clinical trials, but diagnostic performance of VCT may vary between devices, various transfusion algorithms, and patient populations. AREAS COVERED: Working principles and currently available data on the evolving VCTs for coagulation monitoring in acute care settings are reviewed. The PubMed database was used to search pertinent retrospective, prospective, and meta-analysis data on VCTs. EXPERT OPINION: Point-of-care VCTs provide clinically useful information on platelet count, fibrin polymerization, and other procoagulant factor activities in acute bleeding due to trauma or major surgery, and antithrombotic therapy. The addition of fibrin-specific VCT channel has brought renewed attention to early correction of fibrinogen deficiency using fibrinogen-rich component therapy, and stabilization of fibrin with antifibrinolytic agents. Normal reference ranges vary between devices, and diagnostic and treatment algorithms should be specifically established for each device and indication. There is interest in utilizing VCTs in complex coagulation management relating to hemophilia with inhibitors, but the standardized protocol has not been established.

Reversal of Vasodilatory Shock: Current Perspectives on Conventional, Rescue, and Emerging Vasoactive Agents for the Treatment of Shock.

Understanding the different mechanisms of vasoconstrictors is crucial to their optimal application to clinically diverse shock states. We present a comprehensive review of conventional, rescue, and novel vasoactive agents including their pharmacology and evidence supporting their use in vasodilatory shock. The role of each drug in relation to the Surviving Sepsis Guidelines is discussed to provide a context of how each one fits into the algorithm for treating vasodilatory shock. Rescue agents can be utilized when conventional medications fail, although there are varying levels of evidence on their clinical effectiveness. In addition, novel agents for the treatment of vasodilatory shock have recently emerged such as ascorbic acid and angiotensin II. Ascorbic acid has been used with some success in vasoplegia and is currently undergoing a more rigorous evaluation of its utility. Angiotensin II (Ang-2) is the newest available vasopressor for the treatment of vasodilatory shock. In addition to its catecholamine-sparing properties, it has been shown to hold promising mortality benefits in certain subsets of critically ill patients.

Impact of intraoperative high-volume autologous blood collection on allogeneic transfusion during and after cardiac surgery: a propensity score matched analysis.

BACKGROUND: Perioperative use of allogeneic blood products is associated with higher morbidity, mortality, and hospital costs after cardiac surgery. Blood conservation techniques such as acute normovolemic hemodilution (ANH) report variable success. We hypothesized that large-volume ANH with limited hemodilution would reduce allogeneic blood transfusion compared to the standard practice. STUDY DESIGN AND METHODS: Retrospective observational study of cardiac surgery patients at the University of Maryland Medical Center between January 2014 and September 2017. Using the institutional Society of Thoracic Surgeons database 91 autologous and 981 control patients who underwent coronary artery bypass grafting, aortic valve replacement, or both were identified. After propensity matching of 13 preoperative characteristics, 84 autologous and 84 control patients were evaluated. Our primary endpoint was avoidance of blood transfusion during index hospitalization, and secondary endpoints were postoperative bleeding and major adverse outcomes. RESULTS: The median harvest volumes in the ANH and control groups were 1100 mL and 400 mL, respectively. Of the ANH group, 25% received any transfusion versus 45.2% of the control group after propensity score matching (p < 0.006). When controlling for preoperative platelet count, the transfusion rate ratios for ANH were 0.58 (95% confidence interval, 0.39-0.88) for RBCs and 0.63 (0.44-0.89) for non-RBC components, which were both found to be statistically significant. There was no difference found in major adverse events. CONCLUSION: These results suggest that large-volume ANH is beneficial in reducing both RBC and non-RBC component usage in cardiac surgery. A further prospective validation is warranted.