Bivalirudin anticoagulation for cardiopulmonary bypass during cardiac surgery.

INTRODUCTION: Heparin is the primary anticoagulant for cardiopulmonary bypass (CPB) support during cardiac surgery. While widely used, ∼2% of cardiac surgery patients develop heparin-induced thrombocytopenia (HIT) and 4-26% develop heparin resistance. Bivalirudin is an alternative anticoagulant mainly used for percutaneous coronary interventions. Given the challenges associated with heparin anticoagulation, we conducted a review to explore the use of bivalirudin for CPB surgery. METHODS: PubMed and Embase scoping review included 2 randomized controlled trials, a retrospective comparison study, 3 pilot studies, and 30 case reports. To provide a contemporary series, we searched for articles published from 2010 to 2023. Our review included studies from both adult and pediatric populations. RESULTS: While data is limited, bivalirudin seems to supply similar effectiveness and safety as heparin for CPB anticoagulation. Across the three comparative studies, the heparin cohorts had a 0-9% mortality rate and 0-27% rate of major bleeding/reoperation compared to a 0-3% mortality and 0-6% major bleeding/reoperation rate for the bivalirudin cohorts. Bivalirudin was successfully used as an anticoagulant in a wide range of CPB surgeries (e.g., heart transplants, ventricular assisted device placements, and valve repairs). Successful patient outcomes were reported with bivalirudin infusion of ∼2 mg/kg/hour, activated clotting time monitoring (target >400 s or 2.5× baseline), use of cardiotomy suctions, minimization of stagnant blood, and post-bypass modified ultrafiltration. CONCLUSION: Bivalirudin is a safe and effective anticoagulant for CPB, especially for patients with HIT or heparin resistance. Further comparative research is called for to optimize bivalirudin utilization for CPB during cardiac surgery.

Factor XI Inhibition With Heparin Reduces Clot Formation in Simulated Pediatric Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) supplies circulatory support and gas exchange to critically ill patients. Despite the use of systemic anticoagulation, blood exposure to ECMO surfaces causes thromboembolism complications. Inhibition of biomaterial surface-mediated activation of coagulation factor XI (FXI) may prevent device-associated thrombosis. Blood was collected from healthy volunteers (n = 13) following the U.S. Army Institute of Surgical Research standard operating procedure for testing in an ex vivo ECMO circuit. A roller-pump circuit circulated either 0.5 U/ml of unfractionated heparin alone or in combination with the anti-FXI immunoglobulin G (IgG) (AB023) for 6 hours or until clot formation caused device failure. Coagulation factor activity, platelet counts, time to thrombin generation, peak thrombin, and endogenous thrombin potential were quantified. AB023 in addition to heparin sustained circuit patency in all tested circuits (5/5) after 6 hours, while 60% of circuits treated with heparin alone occluded (3/8), log-rank p < 0.03. AB023 significantly prolonged the time to clot formation as compared to heparin alone (15.5 vs . 3.3 minutes; p < 0.01) at the 3-hour time point. AB023 plus heparin significantly reduced peak thrombin compared to heparin alone (123 vs . 217 nM; p < 0.01). Inhibition of contact pathway activation of FXI may be an effective adjunct to anticoagulation in extracorporeal life support.

A cohort study on blood coagulation in childhood cancer survivors.

Cancer survivors are at an increased risk of thromboembolism compared to the general pediatric population. Anticoagulant therapy decreases the risk of thromboembolism in cancer patients. We hypothesized that pediatric cancer survivors are in a chronically hypercoagulable state compared to healthy controls. Children who survived for more than five years from cancer diagnosis at the UT Health Science Center at San Antonio Cancer Survivorship Clinic were compared to healthy controls. The exclusion criteria were recent NSAID use or a history of coagulopathy. Coagulation analysis included platelet count, thrombin-antithrombin complexes (TAT), plasminogen activator inhibitor (PAI), routine coagulation assays, and thrombin generation with and without thrombomodulin. We enrolled 47 pediatric cancer survivors and 37 healthy controls. Platelet count was significantly lower in cancer survivors at a mean of 254 × 109/L (95%CI: 234-273 × 109/L) compared at 307 × 109/L (283-331 × 109/L) in healthy controls (p < 0.001), although not outside the normal range. Routine coagulation assays showed no differences, except for a significantly lower prothrombin time (PT) in cancer survivors (p < 0.004). Cancer survivors has significantly elevated biomarkers of the procoagulant state, such as TAT and PAI, compared to healthy controls (p < 0.001). A multiple logistic regression model controlling for age, BMI, gender, and race/ethnicity documented that a low platelet count, short prothrombin clot time, and higher procoagulant biomarkers (TAT and PAI) were significantly associated with past cancer therapy. Survivors of childhood cancer have a persistent procoagulant imbalance for more than five years after diagnosis. Further studies are needed to establish whether procoagulant imbalance increases the risk of thromboembolism in childhood cancer survivors.

A Narrative Review of Postoperative Anticoagulation Therapy for Congenital Cardiac Disease.

Congenital heart disease encompasses a range of cardiac birth defects. Some defects require early and complex surgical intervention and post-operative thromboprophylaxis primarily for valve, conduit, and shunt patency. Antiplatelet and anticoagulant management strategies vary considerably and may or may not align with recognized consensus practice guidelines. In addition, newer anticoagulant agents are being increasingly used in children, but these medications are not addressed in most consensus statements. This narrative review evaluated the literature from 2011 through 2021 on the topic of postoperative thromboprophylaxis after congenital heart disease operations. The search was focused on the descriptions and results of pediatric studies for replacement and/or repair of heart valves, shunts, conduits, and other congenital heart disease operations. Wide variability in practice exists and, as was true a decade ago, few randomized controlled trials have been conducted. Aspirin, warfarin, and perioperative heparin remain the most commonly used agents with varying dosing, duration, and monitoring strategies, making comparisons difficult. Only recently have data on direct oral anticoagulants been published in children, suggesting evolving paradigms of care. Our findings highlight the need for more research to strengthen the evidence for standardized thromboprophylaxis strategies.

Regional blood acidification inhibits coagulation during extracorporeal carbon dioxide removal (ECCO2 R).

BACKGROUND: Consumption of platelets and coagulation factors during extracorporeal carbon dioxide removal (ECCO2 R) increases bleeding complications and associated mortality. Regional infusion of lactic acid enhances ECCO2 R by shifting the chemical equilibrium from bicarbonate to carbon dioxide. Our goal was to test if regional blood acidification during ECCO2 R inhibits platelet function and coagulation. METHODS: An ECCO2 R system containing a hemofilter circulated blood at 0.25 L/min in eight healthy ewes (Ovis aries) for 36 h. Three of the sheep received ECCO2 R with no recirculation compared to five sheep that received ECCO2 R plus 12 h of regional blood acidification via the hemofilter, placed upstream from the oxygenator, into which 4.4 M lactic acid was infused. Blood gases, platelet count and function, thromboelastography, coagulation-factor activity, and von Willebrand factor activity (vWF:Ag) were measured at baseline, at start of lactic acid infusion, and after 36 h of extracorporeal circulation. RESULTS: Twelve hours of regional acid infusion significantly inhibited platelet aggregation response to adenosine diphosphate; vWF; and platelet expression of P-selectin compared to control. It also significantly reduced consumption of fibrinogen and of coagulation factors V, VII, IX, compared to control. CONCLUSIONS: Regional acidification reduces platelet activation and vitamin-K-dependent coagulation-factor consumption during ECCO2 R. This is the first report of a simple method that may enhance effective anticoagulation for ECCO2 R.

Post-tonsillectomy hemorrhage control with nebulized tranexamic acid: A retrospective cohort study.

OBJECTIVE: Evaluate nebulized tranexamic acid (TXA) as a treatment to reduce the need for an operation to control a post-tonsillectomy hemorrhage (PTH). METHODS: Based on a successful case report of a child treated with nebulized TXA for PTH in 2018, our institution began to treat PTH patients with three doses of nebulized TXA. To evaluate the outcomes of this non-invasive management, we conducted a three-year retrospective cohort study of children presenting with PTH from 2016 to 2019. Demographics, insurance, and laboratory information were collected from all pediatric tonsillectomies with and without adenoidectomy performed during the study period. Tonsillar fossae observations of bleeding and clot were documented before and after receiving TXA. RESULTS: The incidence of pediatric PTH at our institution during the study period was 5.4%. Fourteen out of 58 PTH patients received nebulized TXA. Receiving nebulized TXA had no adverse events and over 60% showed resolution of bleeding on exam. Receiving nebulized TXA compared to routine care decreased the need for an operation to restore hemostasis by 44%, p < 0.005. There was no significant difference in age, gender, body mass index, hemoglobin, platelet count, trainee presence, or Medicaid status between the children that received TXA and those that did not. CONCLUSION: Treatment of PTH with nebulized TXA may be a safe first-line therapy to decrease the need for operative control of bleeding. This data suggests that a large clinical trial is needed to determine the efficacy of nebulized TXA to mitigate this common and potentially fatal post-operative complication. LEVEL OF EVIDENCE: 4.

Thrombosis and Bleeding in Extracorporeal Membrane Oxygenation (ECMO) Without Anticoagulation: A Systematic Review.

Extracorporeal membrane oxygenation (ECMO) causes both thrombosis and bleeding. Major society guidelines recommend continuous, systemic anticoagulation to prevent thrombosis of the ECMO circuit, though this may be undesirable in those with active, or high risk of, bleeding. We aimed to systematically review thrombosis and bleeding outcomes in published cases of adults treated with ECMO without continuous systemic anticoagulation. Ovid MEDLINE, Cochrane CENTRAL and CDSR, and hand search via SCOPUS were queried. Eligible studies were independently reviewed by two blinded authors if they reported adults (≥18 years) treated with either VV- or VA-ECMO without continuous systemic anticoagulation for ≥24 hours. Patient demographics, clinical data, and specifics of ECMO technology and treatment parameters were collected. Primary outcomes of interest included incidence of bleeding, thrombosis of the ECMO circuit requiring equipment exchange, patient venous or arterial thrombosis, ability to wean off of ECMO, and mortality. Of the 443 total publications identified, 34 describing 201 patients met our inclusion criteria. Most patients were treated for either acute respiratory distress syndrome or cardiogenic shock. The median duration of anticoagulant-free ECMO was 4.75 days. ECMO circuity thrombosis and patient thrombosis occurred in 27 (13.4%) and 19 (9.5%) patients, respectively. Any bleeding and major or "severe" bleeding was reported in 66 (32.8%) and 56 (27.9%) patients, respectively. Forty patients (19%) died. While limited by primarily retrospective data and inconsistent reporting of outcomes, our systematic review of anticoagulant-free ECMO reveals an incidence of circuity and patient thrombosis comparable to patients receiving continuous systemic anticoagulation while on ECMO.

Electromagnetic Versus Blind Guidance of a Postpyloric Feeding Tube in Critically Ill Children.

BACKGROUND AND OBJECTIVES: Postpyloric feeding tube placement is a time-consuming procedure associated with multiple attempts and radiation exposure. Our objective with this study is to compare the time, attempts, and radiation exposure using the electromagnetic versus blind method to place a postpyloric feeding tube in critically ill children. Our hypothesis is that using electromagnetic guidance decreases the procedure time, number of x-rays, and number of attempts, compared to the blind method. METHODS: Eleven pediatric nurses participated in a randomized controlled intention-to-treat study at an academic pediatric medical, surgical, and congenital cardiac ICU. University of Texas Health Epidemiology and Biostatistics generated a randomization sequence with sealed envelopes. A standard (2-sided) F-test of association between the electromagnetic and blind method yielded 40 subjects with 86% power. Data were analyzed with Fisher's exact test for categorical variables and the Wilcoxon rank test for continuous variables, with data documented as median (interquartile range [IQR]). RESULTS: We randomly assigned 52 patients to either the electromagnetic (n = 28) or blind method (n = 24). The number of attempts and radiographs was at a median of 2 (IQR: 1-2.25) using the blind method, compared to the electromagnetic method at a median of 1 (IQR: 1.0-1.0; P = .001). Successful guidance was 96.4% with the electromagnetic method, compared to only 66.7% with the blind technique (P = .008). The total time required was 2.5 minutes (IQR: 2.0-7.25) with the electromagnetic method, compared to 19 minutes (IQR: 9.25-27.0) for the blind method (P = .001). CONCLUSIONS: Electromagnetic guidance is a superior, faster, and overall safer method to place a postpyloric feeding tube in critically ill children.

Effect of blood flow on platelets, leukocytes, and extracellular vesicles in thrombosis of simulated neonatal extracorporeal circulation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has frequent and sometimes lethal thrombotic complications. The role that activated platelets, leukocytes, and small (0.3-micron to 1-micron) extracellular vesicles (EVs) play in ECMO thrombosis is not well understood. OBJECTIVES: To test the effect of blood flow rate on the generation of activated platelets, leukocytes, and EVs in a simulated neonatal ECMO circuit using heparinized human whole blood. METHODS: Simulated neonatal roller pump circuits circulated whole blood at low, nominal, and high flow rates (0.3, 0.5, and 0.7 L/min) for 6 h. Coagulopathy was defined by thromboelastography (TEG), STA® -procoagulant phospholipid clot time (STA®- Procoag-PPL), and calibrated automated thrombogram. High-resolution flow cytometry measured the cellular expression of prothrombotic phospholipids and proteins on platelets, leukocytes, and EV. RESULTS: Despite heparinization, occlusive thrombosis halted flow in two of five circuits at 0.3 L/min and three of five circuits at 0.7 L/min. None of the five circuits at 0.5 L/min exhibited occlusive thrombosis. Phosphatidylserine (PS)-positive platelets and EVs increased at all flow rates more than blood under static conditions (P < .0002). Tissue factor (TF)-positive leukocytes and EVs increased only in low-flow and high-flow circuits (P < .0001). Tissue factor pathway inhibitor (TFPI), at 50 times more than the concentration in healthy adults, failed to suppress thrombin initiation in low-flow and high-flow circuits. CONCLUSIONS: This in vitro study informs ECMO specialists to avoid low and high blood flow that increases TF expression on leukocytes and EVs, which likely initiate clot formation. Interventions to decrease TF generated by ECMO may be an effective approach to decrease thrombosis.

Extracorporeal membrane oxygenation support in individuals with thoracic insufficiency.

INTRODUCTION: Respiratory failure is the leading cause of mortality in individuals with congenital spine and rib deformities. We present a case report of a child with Jeune syndrome surviving respiratory failure using extracorporeal membrane oxygenation (ECMO). We also summarize thoracic insufficiency syndrome cases reported in the Extracorporeal Life Support Organization (ELSO) registry. CASE REPORT: A two-year-old male with a chest circumference less than a third percentile for age was admitted with influenza pneumonia developing a peak oxygenation index of 103.5. The child survived to baseline pulmonary function after nine days of venous-arterial ECMO support. DISCUSSION: The ELSO registry contained 27 individuals with a surrogate diagnosis of thoracic insufficiency (0.05%). There was no significant difference in survival to discharge for thoracic insufficiency patients (52%) compared to a previously healthy population supported with ECMO. CONCLUSION: ECMO is safe and may be effective in supporting individuals with thoracic insufficiency.

Rotational thromboelastometry significantly optimizes transfusion practices for damage control resuscitation in combat casualties.

BACKGROUND: Up to 40% of combat casualties with a truncal injury die of massive hemorrhage before reaching a surgeon. This hemorrhage can be prevented with damage control resuscitation (DCR) methods, which are focused on replacing shed whole blood by empirically transfusing blood components in a 1:1:1:1 ratio of platelets:fresh frozen plasma:erythrocytes:cryoprecipitate (PLT:FFP:RBC:CRYO). Measurement of hemostatic function with rotational thromboelastometry (ROTEM) may allow optimization of the type and quantity of blood products transfused. Our hypothesis was that incorporating ROTEM measurements into DCR methods at the US Role 3 hospital at Bagram Airfield, Afghanistan would change the standard transfusion ratios of 1:1:1:1 to a product mix tailored specifically for the combat causality. METHODS: This retrospective study collected data from the Department of Defense Trauma Registry to compare transfusion practices and outcomes before and after ROTEM deployment to Bagram Airfield. Over the course of six months, 134 trauma patients received a transfusion (pre-ROTEM) and 85 received a transfusion and underwent ROTEM testing (post-ROTEM). Trauma teams received instruction on ROTEM use and interpretation, with no provision of a specific transfusion protocol, to supplement their clinical judgment and practice. RESULTS: The pre and post groups were not significantly different in terms of mortality, massive transfusion protocol activation, mean injury severity score, or coagulation measurements. Despite the difference in size, each group received an equal total number of transfusions. However, the post-ROTEM group received a significant increase in PLT and CRYO transfusions ratios, 4× and 2×, respectively. CONCLUSION: The introduction of ROTEM significantly improved adherence to DCR practices. The transfusion differences suggest that aggressive DCR without thromboelastometry data may result in reduced hemostatic support and underestimate the need for PLT and CRYO. Thus, future controlled trials should include ROTEM-guided coagulation management in trauma resuscitation. LEVEL OF EVIDENCE: Therapeutic, level IV.

Low-Dose Heparin Anticoagulation During Extracorporeal Life Support for Acute Respiratory Distress Syndrome in Conscious Sheep.

BACKGROUND: Over 32% of burned battlefield causalities develop trauma-induced hypoxic respiratory failure, also known as acute respiratory distress syndrome (ARDS). Recently, 9 out of 10 US combat soldiers' survived life-threatening trauma-induced ARDS supported with extracorporeal membrane oxygenation (ECMO), a portable form of cardiopulmonary bypass. Unfortunately, the size, incidence of coagulation complications, and the need for systematic anticoagulation for traditional ECMO devices have prevented widespread use of this lifesaving technology. Therefore, a compact, mobile, ECMO system using minimal anticoagulation may be the solution to reduce ARDS in critically ill military and civilian patients. METHODS: We conducted a prospective cohort laboratory investigation to evaluate the coagulation function in an ovine model of oleic acid induced ARDS supported with veno-venous ECMO. The experimental design approximated the time needed to transport from a battlefield setting to an advanced facility and compared bolus versus standard heparin anticoagulation therapy. RESULTS: Comprehensive coagulation and hemostasis assays did not show any difference because of ECMO support over 10 h between the two groups but did show changes because of injury. Platelet count and function did decrease with support on ECMO, but there was no significant bleeding or clot formation during the entire experiment. CONCLUSIONS: A bolus heparin injection is sufficient to maintain ECMO support for up to 10 h in an ovine model of ARDS. With a reduced need for systematic anticoagulation, ECMO use for battlefield trauma could reduce significant morbidity and mortality from ventilator-induced lung injury and ARDS. Future studies will investigate the mechanisms and therapies to support patients for longer periods on ECMO without coagulation complications. LEVEL OF EVIDENCE: V--therapeutic animal experiment.

Platelet-derived microparticles generated by neonatal extracorporeal membrane oxygenation systems.

Current anticoagulation strategies do not eliminate thromboembolic stroke or limb loss during neonatal extracorporeal membrane oxygenation (ECMO), a form of cardiopulmonary bypass (CPB). In adults, CPB surgery generates prothrombotic platelet-derived microparticles (PMPs), submicron membrane vesicles released from activated platelets. However, information on PMP generation in neonatal ECMO systems is lacking. The objective of this study was to compare PMP generation in five different neonatal ECMO systems, using a simulated circuit with swine blood at 300 ml/min for 4 hours. Systems were composed of both newer components (centrifugal pump and hollow-fiber oxygenator) and traditional components (roller-head pump and silicone membrane oxygenator). Free plasma hemoglobin levels were measured as an indicator of hemolysis and flow cytometry-measured PMP. Hemolysis generated in all ECMO systems was similar to that observed in noncirculated static blood (p = 0.48). There was no difference in net PMP levels between different oxygenators with a given pump. In contrast, net PMP generation in ECMO systems with a centrifugal pump was at least 2.5 times greater than in roller-head pump systems. This was significant when using either a hollow-fiber (p < 0.005) or a silicone membrane (p < 0.05) oxygenator. Future studies are needed to define the relationship between pump-generated PMP and thrombosis.

Hemolytic and thrombocytopathic characteristics of extracorporeal membrane oxygenation systems at simulated flow rate for neonates.

OBJECTIVE: A state-of-the-art centrifugal pump combined with hollow-fiber oxygenator for extracorporeal membrane oxygenation has potential advantages such as smaller priming volumes and decreased potential to cause tubing rupture as compared with the traditional roller head/silicone membrane systems. Adoption of these state-of-the-art systems has been slow in neonates as a result of past evidence of severe hemolysis that may lead to renal failure and increased mortality. Extracorporeal systems have also been linked to platelet dysfunction, a contributing factor toward intracranial hemorrhage, a leading cause of infant morbidity. Little data exist comparing the centrifugal systems with the roller systems in terms of hemolysis and platelet aggregation at low flow rates commonly used in neonatal extracorporeal membrane oxygenation. DESIGN: Prospective, comparative laboratory study. SETTING: University research laboratory. SUBJECTS: Centrifugal pump, roller pump, hollow-fiber oxygenator, and silicone membrane oxygenator. INTERVENTIONS: Comparative study using two pumps, the centrifugal Jostra Rotaflow (Maquet, Wayne, NJ) and the roller-head (Jostra, Maquet, Wayne, NJ), and two oxygenators, polymethlypentene Quadrox-D (Maquet) and silicone membrane (Medtronic, Minneapolis, MN). Five test runs of four circuit combinations were examined for hemolysis and platelet aggregation during 6 hrs of continuous use in a simulated in vitro extracorporeal membrane oxygenation circuit circulating whole swine blood at 300 mL/min. MEASUREMENTS AND MAIN RESULTS: Hemolysis was assessed by spectrophometric measurement of plasma-free hemoglobin. Platelet aggregation was evaluated using monoclonal CD61 antibody fluorescent flow cytometry profiles. All of the extracorporeal membrane oxygenation systems created plasma-free hemoglobin at a similar rate compared with static blood control. There was no difference in the mean normalized index of hemolysis of the centrifugal/hollow-fiber oxygenator system as compared with the roller-head/silicone membrane systems (0.0032 g/100 L vs. 0.0058 g/100 L, p ≥ .7). None of the extracorporeal membrane oxygenation systems had a significant increase in platelet aggregation above baseline. CONCLUSIONS: In a low-flow neonatal environment, a state-of-the-art centrifugal pump combined with new fiber-type oxygenators appear to be safe in regard to hemolysis and platelet aggregation.