Topical Versus Intravenous Tranexamic Acid in Patients Undergoing Cardiac Surgery: The DEPOSITION Randomized Controlled Trial.

BACKGROUND: Although intravenous tranexamic acid is used in cardiac surgery to reduce bleeding and transfusion, topical tranexamic acid results in lower plasma concentrations compared to intravenous tranexamic acid, which may lower the risk of seizures. We aimed to determine whether topical tranexamic acid reduces the risk of in-hospital seizure without increasing the risk of transfusion among cardiac surgery patients. METHODS: We conducted a multicenter, double dummy, blinded, randomized controlled trial of patients recruited by convenience sampling in academic hospitals undergoing cardiac surgery with cardiopulmonary bypass. Between September 17, 2019, and November 28, 2023, a total of 3242 patients from 16 hospitals in 6 countries were randomly assigned (1:1 ratio) to receive either intravenous tranexamic acid (control) through surgery or topical tranexamic acid (treatment) at the end of surgery. The primary outcome was seizure, and the secondary outcome was red blood cell transfusion. After the last planned interim analysis-when 75% of anticipated participants had completed follow up-the Data and Safety Monitoring Board recommended to terminate the trial, and upon unblinding, the Operations Committee stopped the trial for safety. RESULTS: Among 3242 randomized patients (mean age, 66.0 years; 77.7% male), in-hospital seizure occurred in 4 of 1624 patients (0.2%) in the topical group and in 11 of 1628 patients (0.7%) in the intravenous group (absolute risk difference, -0.5%; 95% CI, -0.9 to 0.03; P = .07). Red blood cell transfusion occurred in 570 patients (35.1%) in the topical group and in 433 (26.8%) in the intravenous group (absolute risk difference, 8.3%; 95% CI, 5.2 to 11.5; P = .007). The absolute risk difference in transfusion of ≥4 units of red blood cells in the topical group compared to the intravenous group was 8.2% (95% CI, 3.4 to 12.9). CONCLUSIONS: Among patients having cardiac surgery, topical administration of tranexamic acid resulted in an 8.3% absolute increase in transfusion without reducing the incidence of seizure, compared to intravenous tranexamic acid.

Effects of RBT-1 on preconditioning response biomarkers in patients undergoing coronary artery bypass graft or heart valve surgery: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

Background: RBT-1 is a combination drug of stannic protoporfin (SnPP) and iron sucrose (FeS) that elicits a preconditioning response through activation of antioxidant, anti-inflammatory, and iron-scavenging pathways, as measured by heme oxygenase-1 (HO-1), interleukin-10 (IL-10), and ferritin, respectively. Our primary aim was to determine whether RBT-1 administered before surgery would safely and effectively elicit a preconditioning response in patients undergoing cardiac surgery. Methods: This phase 2, double-blind, randomised, placebo-controlled, parallel-group, adaptive trial, conducted in 19 centres across the USA, Canada, and Australia, enrolled patients scheduled to undergo non-emergent coronary artery bypass graft (CABG) and/or heart valve surgery with cardiopulmonary bypass. Patients were randomised (1:1:1) to receive either a single intravenous infusion of high-dose RBT-1 (90 mg SnPP/240 mg FeS), low-dose RBT-1 (45 mg SnPP/240 mg FeS), or placebo within 24-48 h before surgery. The primary outcome was a preoperative preconditioning response, measured by a composite of plasma HO-1, IL-10, and ferritin. Safety was assessed by adverse events and laboratory parameters. Prespecified adaptive criteria permitted early stopping and enrichment. This trial is registered with ClinicalTrials.gov, NCT04564833. Findings: Between Aug 4, 2021, and Nov 9, 2022, of 135 patients who were enrolled and randomly allocated to a study group (46 high-dose, 45 low-dose, 44 placebo), 132 (98%) were included in the primary analysis (46 high-dose, 42 low-dose, 44 placebo). At interim, the trial proceeded to full enrollment without enrichment. RBT-1 led to a greater preconditioning response than did placebo at high-dose (geometric least squares mean [GLSM] ratio, 3.58; 95% CI, 2.91-4.41; p < 0.0001) and low-dose (GLSM ratio, 2.62; 95% CI, 2.11-3.24; p < 0.0001). RBT-1 was generally well tolerated by patients. The primary drug-related adverse event was dose-dependent photosensitivity, observed in 12 (26%) of 46 patients treated with high-dose RBT-1 and in six (13%) of 45 patients treated with low-dose RBT-1 (safety population). Interpretation: RBT-1 demonstrated a statistically significant cytoprotective preconditioning response and a manageable safety profile. Further research is needed. A phase 3 trial is planned. Funding: Renibus Therapeutics, Inc.

Conduit selection and early graft failure in coronary artery bypass surgery: A post hoc analysis of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) coronary artery bypass grafting study.

OBJECTIVES: Relative rates of early graft failure and conduit selection in coronary artery bypass grafting (CABG) surgery remain controversial. Therefore, we sought to determine the incidence and determinants of graft failure of the left internal mammary artery (LIMA), radial artery, saphenous vein, and right internal mammary artery (RIMA) 1 year after CABG surgery. METHODS: A post hoc analysis of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) CABG study, involving patients from 83 centers in 22 countries. We completed an analysis of 3480 grafts from 1068 patients who underwent CABG surgery with complete computed tomography angiography data. The primary outcome was graft failure as diagnosed by computed tomography angiography 1 year after surgery. RESULTS: Graft failure occurred in 6.4% (68/1068) for LIMA, 9.9% (9/91) for radial artery, 10.4% (232/2239) for saphenous vein, and 26.8% (22/82) for RIMA grafts. The RIMA had a greater rate of graft failure (26.8%) than radial artery (9.9%) and veins (10.4%) (adjusted odds ratio, 2.69; 95% confidence interval, 1.30-5.57; P = .008 and adjusted odds ratio, 2.07; 95% confidence interval, 1.33-3.21; P = .001, respectively). CONCLUSIONS: In this international trial dataset, LIMA and radial artery performed as expected, whereas vein grafts performed better. However, high rates of RIMA failure are worrisome and highlight the need for a thorough evaluation of the patency and safety of the RIMA in CABG surgery.

Skeletonized vs Pedicled Internal Mammary Artery Graft Harvesting in Coronary Artery Bypass Surgery: A Post Hoc Analysis From the COMPASS Trial.

Importance: The relative safety and patency of skeletonized vs pedicled internal mammary artery grafts in patients undergoing coronary artery bypass graft (CABG) surgery are unknown. Objective: To investigate the association of skeletonized vs pedicled harvesting with internal mammary artery graft patency and clinical outcomes 1 year after CABG surgery. Design, Setting, and Participants: This study was a post hoc analysis of the multicenter, randomized, double-blind, placebo-controlled Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) clinical trial, which enrolled 27 395 patients from 602 centers in 33 countries from March 2013 through May 2016. Eligibility criteria for the trial included CABG surgery for coronary artery disease with at least 2 grafts implanted and an estimated glomerular filtration rate of at least 30 mL/min. A total of 1002 of 1448 patients were randomized to the CABG arm of the COMPASS trial and underwent skeletonized (282 [28.1%]) or pedicled (720 [71.9%]) internal mammary artery harvesting. The patients had evaluable angiography results 1 year after surgery. Data were analyzed from October 11, 2019, to May 14, 2020. Interventions: Patients underwent graft harvesting with either the pedicled technique or skeletonized technique. Main Outcomes and Measures: The primary outcome was graft occlusion 1 year after CABG surgery, as assessed by computed tomography angiography. Results: A total of 1002 patients underwent skeletonized (282 [28.1%]; mean [SD] age, 65.9 [8.1] years; 229 men [81.2%]; 194 White patients [68.8%]) or pedicled (720 [71.9%]; mean [SD] age, 64.8 [7.6] years; 603 men [83.8%]; 455 White patients [63.2%]) internal mammary artery harvesting. Rates of internal mammary artery graft occlusion 1 year after CABG surgery were higher in the skeletonized group than in the pedicled group (33 of 344 [9.6%] vs 30 of 764 [3.9%]; graft-level adjusted odds ratio, 2.41; 95% CI, 1.39-4.20; P = .002), including the left internal mammary artery to left anterior descending artery (21 of 289 [7.3%] vs 25 of 725 [3.4%]; graft-level adjusted odds ratio, 2.10; 95% CI, 1.14-3.88, P = .02). After a mean follow-up of 23 months, skeletonized graft harvesting was also associated with a higher rate of major adverse cardiovascular events (20 [7.1%] vs 15 [2.1%]; adjusted hazard ratio, 3.19; 95% CI, 1.53-6.67; P = .002) and repeated revascularization (14 [5.0%] vs 10 [1.4%]; adjusted hazard ratio, 2.75; 95% CI, 1.10-6.88; P = .03). Conclusions and Relevance: This post hoc analysis of the COMPASS randomized clinical trial found that harvesting of the internal mammary artery during CABG surgery using a skeletonized technique was associated with a higher rate of graft occlusion and worse clinical outcomes than the traditional pedicled technique. Future randomized clinical trials are needed to establish the safety and patency of the skeletonized technique. Trial Registration: ClinicalTrials.gov Identifier: NCT01776424.

Feasibility of studying the association between intraoperative regional cerebral oxygen saturation and postoperative functional decline (ReFUNCTION): a pilot sub-study of NeuroVISION-Cardiac Surgery.

PURPOSE: Function describes an individual's ability to perform everyday activities. In the context of cardiac surgery, functional changes quantify the effect of surgery on one's day-to-day life. Decreases in regional cerebral oxygen saturation (rScO2) measured using near-infrared spectroscopy (NIRS) has been associated with postoperative cognitive decline but its relationship with function has not been studied. We sought to determine the feasibility of conducting a large observational study examining the relationship between decreases in rScO2 during cardiac surgery and postoperative functional decline. METHODS: We undertook a single-centre, pilot sub-study of the NeuroVISION-Cardiac Surgery pilot study, which included adults undergoing isolated coronary artery bypass grafting on cardiopulmonary bypass; all patients enrolled in NeuroVISION-Cardiac Surgery were included. Function was evaluated at baseline, 30 days, and three months using the Standardized Assessment of Global activities in the Elderly (SAGE) scale. Blinded NIRS monitors were affixed for the duration of surgery. Our feasibility outcomes were to recruit one patient per week, obtain complete NIRS data in ≥ 90%, obtain SAGE at all time-points in ≥ 90%, and determine the time required for NIRS data to be transcribed into case report forms. RESULTS: 49/50 patients enrolled in NeuroVISION-Cardiac Surgery were recruited over 48 weeks (1.02 patients/week). Of the 49 included patients, 49 (100%) had complete NIRS data and 44 (90%) had complete SAGE data. The time required for NIRS data collection was a mean (standard deviation) of 5.5 (1.8) min per patient. CONCLUSION: This pilot study shows the feasibility of conducting a large observational study examining the relationship between decreases in cerebral saturation during cardiac surgery and postoperative functional decline. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT04241289); registered 27 January 2020.

RéSUMé: OBJECTIF : La capacité fonctionnelle constitue la capacité d'une personne à accomplir des activités quotidiennes. Dans le contexte d'une chirurgie cardiaque, les changements fonctionnels permettent de quantifier l'effet de la chirurgie sur le quotidien des individus. Les baisses de la saturation en oxygène cérébral régional (rScO2) mesurées à l'aide de la spectroscopie proche infrarouge (NIRS) ont été associées à un déclin cognitif postopératoire, mais leur relation par rapport à la capacité fonctionnelle n'a pas été étudiée. Nous avons tenté de déterminer s'il était possible de réaliser une vaste étude observationnelle examinant la relation entre les baisses de rScO2 pendant une chirurgie cardiaque et le déclin fonctionnel postopératoire. MéTHODE : Nous avons entrepris une sous-étude pilote monocentrique de l'étude pilote NeuroVISION-Cardiac Surgery, qui incluait des adultes subissant une chirurgie de pontage aortocoronarien sous circulation extracorporelle; tous les patients recrutés dans l'étude NeuroVISION-Cardiac Surgery ont été inclus dans ce volet. La capacité fonctionnelle a été évaluée avant l'opération, puis à 30 jours et trois mois à l'aide de l'échelle SAGE (Standardized Assessment of Global activities in the Elderly, soit Évaluation standardisée de la fonction globale chez la personne âgée). Des moniteurs de NIRS étaient installés pour toute la durée de la chirurgie sans que les valeurs ne soient connues de l'équipe traitante. Nos critères de faisabilité consistaient à recruter un patient par semaine, obtenir des données de NIRS complètes pour ≥ 90 % des patients, obtenir des données de SAGE pour tous les points dans le temps pour ≥ 90 % des patients, et déterminer le temps nécessaire à retranscrire les données de NIRS dans les formulaires d'étude de cas. RéSULTATS : Au total, 49/50 patients recrutés dans l'étude NeuroVISION-Cardiac Surgery ont été recrutés sur une période de 48 semaines (1,02 patients/semaine). Parmi les 49 patients inclus, les données de NIRS ont été obtenues pour 49 (100 %) patients et les données de SAGE pour 44 (90 %) patients. Le temps nécessaire à la collecte de données de NIRS était en moyenne (écart type) de 5,5 (1,8) min par patient. CONCLUSION : L'étude pilote a démontré la faisabilité d'une vaste étude observationnelle examinant la relation entre les baisses de la saturation cérébrale pendant la chirurgie cardiaque et le déclin fonctionnel postopératoire. ENREGISTREMENT DE L'éTUDE : www.clinicaltrials.gov (NCT04241289); enregistrée le 27 janvier 2020.

Perioperative covert stroke in patients undergoing coronary artery bypass graft surgery.

Objectives: Covert stroke is a complication of coronary artery bypass graft surgery that is increasingly recognized as a serious problem. In noncardiac surgery settings, covert stroke is associated with the development of delirium, long-term cognitive decline, and future clinical stroke. Therefore, we sought to determine the feasibility of conducting a large, prospective cohort study of the influence of covert stroke on neurocognitive outcomes in patients undergoing coronary artery bypass graft surgery. Methods: NeuroVISION Cardiac pilot was a prospective cohort study enrolling patients aged ≥21 years undergoing isolated coronary artery bypass graft surgery to receive diffusion-weighted magnetic resonance imaging of the brain after surgery to identify patients with covert stroke. Patients were screened for postoperative delirium in-hospital and were administered questionnaires of cognitive and global function (once before and twice after surgery). Regional cerebral oxygen saturation was recorded during surgery using near-infrared spectroscopy. Results: Between March 27, 2017, and February 11, 2018, 50 of 66 patients enrolled (76%) completed the brain magnetic resonance imaging (1 patient per week). Among the 49 patients included in the analysis, 19 (39%; 95% confidence interval, 26%-53%) experienced perioperative covert stroke and 3 (6%) had a clinical stroke within 30 days of surgery. Postoperative delirium occurred in 5 (26%) patients with covert stroke and in 3 (10%) patients who did not experience covert stroke. Conclusions: The NeuroVISION Cardiac pilot study established the feasibility of conducting a large, prospective cohort study of the determinants and consequences of covert stroke in patients undergoing coronary artery bypass graft surgery.

Mechanisms of calcium sequestration by isolated Malpighian tubules of the house cricket Acheta domesticus.

Hemolymph calcium homeostasis in insects is achieved by the Malpighian tubules, primarily by sequestering excess Ca2+ within internal calcium stores (Ca-rich granules) most often located within type I (principal) tubule cells. Using both the scanning ion-selective electrode technique and the Ramsay secretion assay this study provides the first measurements of basolateral and transepithelial Ca2+ fluxes across the Malpighian tubules of an Orthopteran insect, the house cricket Acheta domesticus. Ca2+ transport was specific to midtubule segments, where 97% of the Ca2+ entering the tubule is sequestered within intracellular calcium stores and the remaining 3% is secreted into the lumen. Antagonists of voltage-gated (L-type) calcium channels decreased Ca2+ influx ≥fivefold in adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated tubules, suggesting basolateral Ca2+ influx is facilitated by voltage-gated Ca2+ channels. Increasing fluid secretion through manipulation of intracellular levels of cAMP or Ca2+ had opposite effects on tubule Ca2+ transport. The adenylyl cyclase-cAMP-PKA pathway promotes Ca2+ sequestration whereas both 5-hydroxytryptamine and thapsigargin inhibited sequestration. Our results suggest that the midtubules of Acheta domesticus are dynamic calcium stores, which maintain hemolymph calcium concentration by manipulating rates of Ca2+ sequestration through stimulatory (cAMP) and inhibitory (Ca2+ ) regulatory pathways.

Segment-specific Ca(2+) transport by isolated Malpighian tubules of Drosophila melanogaster: A comparison of larval and adult stages.

Haemolymph calcium homeostasis in insects is achieved through the regulation of calcium excretion by Malpighian tubules in two ways: (1) sequestration of calcium within biomineralized granules and (2) secretion of calcium in soluble form within the primary urine. Using the scanning ion-selective electrode technique (SIET), basolateral Ca(2+) transport was measured at the distal, transitional, main and proximal tubular segments of anterior tubules isolated from both 3rd instar larvae and adults of the fruit fly Drosophila melanogaster. Basolateral Ca(2+) transport exceeded transepithelial secretion by 800-fold and 11-fold in anterior tubules of larvae and adults, respectively. The magnitude of Ca(2+) fluxes across the distal tubule of larvae and adults were larger than fluxes across the downstream segments by 10 and 40 times, respectively, indicating a dominant role for the distal segment in whole animal Ca(2+) regulation. Basolateral Ca(2+) transport across distal tubules of Drosophila varied throughout the life cycle; Ca(2+) was released by distal tubules of larvae, taken up by distal tubules of young adults and was released once again by tubules of adults ⩾ 168 h post-eclosion. In adults and larvae, SIET measurements revealed sites of both Ca(2+) uptake and Ca(2+) release across the basolateral surface of the distal segment of the same tubule, indicating that Ca(2+) transport is bidirectional. Ca(2+) uptake across the distal segment of tubules of young adults and Ca(2+) release across the distal segment of tubules of older adults was also suggestive of reversible Ca(2+) storage. Our results suggest that the distal tubules of D. melanogaster are dynamic calcium stores which allow efficient haemolymph calcium regulation through active Ca(2+) sequestration during periods of high dietary calcium intake and passive Ca(2+) release during periods of calcium deficiency.

Ammonium secretion by Malpighian tubules of Drosophila melanogaster: application of a novel ammonium-selective microelectrode.

Ammonia is a toxic nitrogenous waste product of amino acid metabolism that may accumulate to high levels in the medium ingested by larvae of the fruit fly Drosophila melanogaster. Here we report measurements of haemolymph NH4(+) concentration and the secretion of NH4(+) by the Malpighian (renal) tubules. Measurement of NH4(+) concentrations in secreted droplets is complicated either by the requirement for large sample volumes for enzymatic assays or by the inadequate selectivity of NH4(+)-selective microelectrodes based on nonactin. We have developed a novel liquid membrane NH4(+)-selective microelectrode based on a 19-membered crown compound (TD19C6), which has been used previously in ammonium-selective macroelectrodes. In conjunction with an improved technique for correcting for interference of potassium, NH4(+)-selective microelectrodes based on TD19C6 permit accurate measurement of ammonium concentration in haemolymph samples and nanolitre droplets of fluid secreted by the Malpighian tubules of D. melanogaster. The results indicate that active secretion of ammonium into the Malpighian tubule lumen is sufficient to maintain concentrations of ~1 mmol l(-1) ammonium in the haemolymph of larvae reared on diets containing 100 mmol l(-1) ammonium chloride.