Intravenous Dabigatran Provides Adequate Anticoagulation for Cardiopulmonary Bypass Using a Rabbit Model.

BACKGROUND: Heparin anticoagulation has been used successfully for cardiopulmonary bypass (CPB). However, an alternative anticoagulant approach is desirable due to the cases of heparin-induced thrombocytopenia. Dabigatran provides anticoagulation for an in vitro model of simulated CPB. The current analysis tests the hypothesis that dabigatran provides sufficient anticoagulation for CPB in intact rabbits. METHODS: Nonlinear mixed effects models were used to estimate dabigatran parameters for a two-compartment pharmacokinetic model in 10 New Zealand White rabbits. A dabigatran infusion designed to maintain a plasma concentration of 90 µg/ml was run throughout CPB based on the pharmacokinetics. Animals were subjected to sternotomy and anticoagulated with IV dabigatran (six animals) or heparin (four animals). Rabbits were cannulated centrally using the right atrium and ascending aorta and CPB was maintained for 120 min. Measurement of activated clotting time, thromboelastometric reaction time, and blood gases were performed during CPB. Then, the animals were euthanized, and the brain and one kidney were removed for histology. Sections of the arterial filters were inspected using electron microscopy. RESULTS: The observed dabigatran concentrations during CPB were greater than the target concentration, ranging from 137 ± 40 µg/ml at 5 min of CPB to 428 ± 150 µg/ml at 60 min, and 295 ± 35 µg/ml at 120 min. All rabbits completed 2 h of CPB without visible thrombosis. In the two groups, reaction time values were elevated, reaching 10,262 ± 4,198 s (dabigatran group) and 354 ± 141 s (heparin group) at 120 min of CPB. Brains and kidneys showed no evidence of thrombosis or ultrastructural damage. Sections of the arterial line filter showed minimal or no fibrin. There was no significant difference in outcomes between dabigatran- and heparin-treated animals. CONCLUSIONS: In this first-use, proof-of-concept study, the authors have shown that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis using a rabbit CPB model.

Rivaroxaban Reduces the Dabigatran Dose Required for Anticoagulation During Simulated Cardiopulmonary Bypass.

BACKGROUND: Heparin is the standard anticoagulant for cardiopulmonary bypass (CPB); however, there are problems with its use that make the development of suitable alternatives desirable. Currently, no ideal alternative exists. We have previously reported that the direct thrombin inhibitor dabigatran can prevent coagulation in simulated CPB at high concentrations. These high concentrations may cause difficulties in achieving the reversal of dabigatran with idarucizumab, given the markedly different pharmacokinetics of the 2 drugs. Herein, we test the hypothesis that the addition of the anti-Xa drug rivaroxaban would provide suitable anticoagulation at a lower concentration of dabigatran given likely synergy between the 2 classes of drugs. The primary goal of the study was to investigate whether the addition of rivaroxaban reduces the concentration of dabigatran necessary to allow 2 hours of simulated CPB. METHODS: The study was performed in sequential steps. Blood collected from consenting healthy donors was used throughout. First, we added graded concentrations of dabigatran and rivaroxaban alone and in combination and assessed inhibition of anticoagulation using thromboelastometry. Using results from this step, combinations of dabigatran and rivaroxaban were tested in both Chandler loop and simulated CPB circuits. Dabigatran and rivaroxaban were added before recalcification, and the circuits were run for 120 minutes. In both models of CPB, 120 minutes of circulation without visible thrombus was considered successful. In the Chandler loop system, idarucizumab was added to reverse anticoagulant effects. In the CPB circuits, the arterial line filters were examined using scanning electron microscope (SEM) to qualitatively assess for fibrin deposition. RESULTS: In vitro analysis of blood samples treated with dabigatran and rivaroxaban showed that dabigatran and rivaroxaban individually prolonged clotting time (CT) in a dose-dependent manner. However, when combined, the drugs behaved synergistically. In the Chandler loop system, dabigatran 2400 and 4800 ng/mL plus rivaroxaban (150 ng/mL) effectively prevented clot formation and reduced the dynamics of clot propagation for 120 minutes. Idarucizumab (250-1000 µg/mL) effectively reversed anticoagulation. In the CPB circuits, dabigatran (2500 ng/mL) and rivaroxaban (200 ng/mL) were successful in allowing 120 minutes of simulated CPB and prevented fibrin deposition. Biomarkers of coagulation activation did not increase during simulated CPB. Heparin controls performed similarly to dabigatran and rivaroxaban. CONCLUSIONS: The dual administration of oral anticoagulant drugs (dabigatran and Rivaroxaban) with different pharmacologic mechanisms of action produced synergistic inhibition of coagulation in vitro and successfully prevented clotting during simulated CPB.

American Society of ExtraCorporeal Technology: Development of Standards and Guidelines for Pediatric and Congenital Perfusion Practice (2019).

The development of standards and guidelines by professional societies offers clinicians guidance toward providing evidence-based care. The ultimate goals of standards and guidelines are to standardize care and improve patient safety and outcomes while also minimizing risk. The American Society of ExtraCorporeal Technology (AmSECT) currently offers perfusionists several clinical resources, primarily the Standards and Guidelines for Perfusion Practice; however, no document exists specific to pediatric perfusion. Historically, the development of a pediatric-specific document has been limited by available scientific evidence due to smaller patient populations, sample sizes, and variable techniques among congenital perfusionists. In the current setting of evolving clinical practices and increasingly complex cardiac operations, a subcommittee of pediatric perfusionists developed the Standards and Guidelines for Pediatric and Congenital Perfusion Practice. The development process included a comprehensive literature review for supporting evidence to justify new recommendations or updates to the existing AmSECT Adult Standards and Guidelines document. Multiple revisions incorporating feedback from the community led to a finalized document accepted by the AmSECT membership and made available electronically in May 2019. The Standards and Guidelines for Pediatric and Congenital Perfusion Practice is an essential tool for pediatric perfusionists and serves as the backbone for institutionally based protocols, promotes improved decision-making, and identifies opportunities for future research and collaboration with other disciplines. The purpose of this manuscript is to summarize the process of development, the content, and recommended utilization of AmSECT's Standards and Guidelines for Pediatric and Congenital Perfusion Practice.

High-Dose Dabigatran Is an Effective Anticoagulant for Simulated Cardiopulmonary Bypass Using Human Blood.

BACKGROUND: Currently no ideal alternative exists for heparin for cardiopulmonary bypass (CPB). Dabigatran is a direct thrombin inhibitor for which a reversal agent exists. The primary end point of the study was to explore whether Dabigatran was an effective anticoagulant for 120 minutes of simulated CPB. METHODS: The study was designed in 2 sequential steps. Throughout, human blood from healthy donors was used for each experimental step. Initially, increasing concentrations of Dabigatran were added to aliquots of fresh whole blood, and the anticoagulant effect measured using kaolin/tissue factor-activated thromboelastography (rapidTEG). The dynamics of all thromboelastography (TEG) measurements were studied with repeated measures analysis of variance (ANOVA). Based on these data, aliquots of blood were treated with high-concentration Dabigatran and placed in a Chandler loop as a simple ex vivo bypass model to assess whether Dabigatran had sufficient anticoagulant effects to maintain blood fluidity for 2 hours of continuous contact with the artificial surface of the PVC tubing. Idarucizumab, humanized monoclonal antibody fragment, was used to verify the reversibility of Dabigatran effects. Finally, 3 doses of Dabigatran were tested in a simulated CPB setup using a heart-lung machine and a commercially available bypass circuit with an arteriovenous (A-V) loop. The primary outcome was the successful completion of 120 minutes of simulated CPB with dabigatran anticoagulation, defined as lack of visible thrombus. Thromboelastographic reaction (R) time was measured repeatedly in each bypass simulation, and the circuits were continuously observed for clot. Scanning Electron Microscopy (SEM) was used to visualize fibrin formation in the filters meshes during CPB. RESULTS: In in vitro blood samples, Dabigatran prolonged R time and reduced the dynamics of clot propagation (as measured by speed of clot formation [Angle], maximum rate of thrombus generation [MRTG], and time to maximum rate of thrombus generation [TMRTG]) in a dose-dependent manner. In the Chandler Loop, high doses of Dabigatran prevented clot formation for 120 minutes, but only at doses higher than expected. Idarucizumab decreased R time and reversed anticoagulation in both in vitro and Chandler Loops settings. In the A-V loop bypass simulation, Dabigatran prevented gross thrombus generation for 120 minutes of simulated CPB. CONCLUSIONS: Using sequential experimental approaches, we showed that direct thrombin inhibitor Dabigatran in high doses maintained anticoagulation of blood for simulated CPB. Idarucizumab reduced time for clot formation reversing the anticoagulation action of Dabigatran.

American Society of ExtraCorporeal Technology: Development of Standards and Guidelines for Pediatric and Congenital Perfusion Practice (2019).

The development of standards and guidelines by professional societies offers clinicians guidance toward providing evidence-based care. The ultimate goals of standards and guidelines are to standardize care and improve patient safety and outcomes while also minimizing risk. The American Society of ExtraCorporeal Technology (AmSECT) currently offers perfusionists several clinical resources, primarily the Standards and Guidelines for Perfusion Practice; however, no document exists specific to pediatric perfusion. Historically, the development of a pediatric-specific document has been limited by available scientific evidence because of smaller patient populations, sample sizes, and variable techniques among congenital perfusionists. In the current setting of evolving clinical practices and increasingly complex cardiac operations, a subcommittee of pediatric perfusionists developed the Standards and Guidelines for Pediatric and Congenital Perfusion Practice. The development process included a comprehensive literature review for supporting evidence to justify new recommendations or updates to the existing AmSECT Adult Standards and Guidelines document. Multiple revisions incorporating feedback from the community led to a finalized document accepted by the AmSECT member and made available electronically in May 2019. The Standards and Guidelines for Pediatric and Congenital Perfusion Practice is an essential tool for pediatric perfusionists, serves as the backbone for institutionally based protocols, promotes improved decision-making, and identifies opportunities for future research and collaboration with other disciplines. The purpose of this article is to summarize the process of development, the content, and recommended utilization of AmSECT's Standards and Guidelines for Pediatric and Congenital Perfusion Practice. AmSECT recommends adoption of the Standards and Guidelines for Pediatric and Congenital Perfusion Practice to reduce practice variation and enhance clinical safety.

Pharmacokinetics of ε-Aminocaproic Acid in Neonates Undergoing Cardiac Surgery with Cardiopulmonary Bypass.

BACKGROUND: Antifibrinolytic medications such as ε-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. The authors sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. METHODS: Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70-kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/l). RESULTS: Pharmacokinetics were described using a two-compartment model plus an additional compartment for the cardiopulmonary bypass pump. First-order elimination was described with a clearance of 5.07 l/h × (WT/70). Simulation showed a dosing regimen with a loading dose of 40 mg/kg and an infusion of 30 mg · kg · h, with a pump prime concentration of 100 mg/l maintained plasma concentrations above 50 mg/l in 90% of neonates during cardiopulmonary bypass surgery. CONCLUSIONS: EACA clearance, expressed using allometry, is reduced in neonates compared with older children and adults. Loading dose and infusion dose are approximately half those required in children and adults.

Cardiopulmonary bypass simulation at the Boot Camp.

OBJECTIVE: At Boot Camp, we evaluated a modular approach to skills mastery related to cardiopulmonary bypass and crisis scenarios. METHODS: With 32 first-year cardiothoracic surgery residents divided into 4 groups, 4 consecutive hours were devoted to cardiopulmonary bypass skills by using a perfused nonbeating heart model, computer-controlled CPB simulator, and perfused beating heart simulator. Based on the cardiopulmonary bypass simulator, each resident was assessed by using a checklist rating score on cardiopulmonary bypass management and 1 crisis scenario. An overall cardiopulmonary bypass score was determined. Economy of time and thought was assessed (1 = unnecessary/disorganized to 5 = maximum economy). At the end of the session, residents completed a written examination. Residents rated the sessions on cannulation skills, cardiopulmonary bypass knowledge, and cardiopulmonary bypass emergency and crisis scenarios on a 5-point scale (5 = very helpful to 1 = not helpful). RESULTS: Thirty residents completed cardiopulmonary bypass simulator exercises. For initiation and termination of cardiopulmonary bypass, most residents performed the tasks and sequence correctly. Some elements were not performed correctly. For instance, 3 residents did not verify the activated clotting time before cardiopulmonary bypass initiation. Four residents demonstrated inadequate communication with the perfusionist, including lack of assertiveness and unclear commands. In crisis scenarios management of massive air embolism (n = 8) was challenging and resulted in the most errors; poor venous drainage and high arterial line pressure scenarios were managed with fewer errors. For the protamine reaction scenario, all residents (n = 7) identified the problem, but in 3 cases heparin was not redosed before resuming cardiopulmonary bypass for right ventricular failure. The score for economy of time and thought was 3.83 ± 0.6 (range, 3-5). The score of the written examination was 90.0 ± 11.3 (range, 60-100), which did not correlate with the overall cardiopulmonary bypass score of 91.4 ± 7.1 (range, 80-100; r = 0.07). The session on acquiring aortic cannulation skills was rated 4.92, that for cardiopulmonary bypass knowledge was rated 4.96, and that for cardiopulmonary bypass crisis scenarios was rated 4.96. CONCLUSIONS: This Boot Camp session introduced residents early in their training to aortic cannulation, principles and management of cardiopulmonary bypass, and crisis management. Based on a modular approach, technical skills and knowledge of cardiopulmonary bypass can be acquired and assessed by using simulations, but further work with more comprehensive educational modules and practice will accelerate the path to mastery of these critical skills.