Assessing the impact of different heparin dosing regimens for cardiopulmonary bypass on anticoagulation: the HepDOSE pilot study.

PURPOSE: It has been suggested that a larger heparin dose during cardiopulmonary bypass (CPB) is associated with reduced perioperative coagulopathy and thromboembolic complications. We investigated the effect of different heparin doses during routine elective cardiac surgery. Our primary outcomes include blood loss and transfusion and secondary outcomes investigate the effects on coagulation biomarkers. METHODS: In this prospective pilot trial, we allocated 60 patients undergoing cardiac surgery on CPB in a single tertiary cardiac centre into three groups to receive an initial dose of 300, 400, or 500 units (U) per kilogram of intravenous heparin prior to the commencement of CPB. Blood was sampled after induction of anesthesia, at 30 and 60 min of CPB, and three minutes after heparin reversal with protamine. Samples were analyzed for fibrinopeptide A (FPA), fibrinopeptide B (FPB), D-dimer, and thrombin-antithrombin (TAT) complexes. Postoperative blood loss and transfusion was measured for the first 24-hr period after surgery. RESULTS: The total mean (95% CI) administered heparin dose in the 300 U·kg-1, 400 U·kg-1, and 500 U·kg-1 groups were 39,975 (36,528 to 43,421) U, 43,195 (36,940 to 49,449) U and 47,900 (44,807 to 50,992) U, respectively. There were no statistically significant differences in FPA, FPB or D-dimer levels at the measured time intervals. There was a trend towards lower TAT levels while on CPB with greater heparin dosing, which was statistically significant after the administration of protamine. The clinical significance appears to be negligible, as there is no difference in overall blood loss and amount of packed red blood cell transfusion or other blood product transfusion. CONCLUSION: This pilot study indicates that, while larger heparin dosing for routine cardiac surgery results in subtle biochemical changes in coagulation, there is no demonstrable benefit in postoperative blood loss or transfusion requirements.

RéSUMé: OBJECTIF: Il a été suggéré qu'une dose plus élevée d'héparine pendant la circulation extracorporelle (CEC) serait associée à une réduction de la coagulopathie périopératoire et des complications thromboemboliques. Nous avons étudié l'effet de différentes doses d'héparine au cours d'une chirurgie cardiaque non urgente de routine. Nos critères d'évaluation principaux comprenaient la perte de sang et la transfusion, et les critères d'évaluation secondaires exploraient les effets sur les biomarqueurs de la coagulation. MéTHODE: Dans cette étude pilote prospective, nous avons réparti 60 patient·es bénéficiant d'une chirurgie cardiaque sous CEC dans un seul centre cardiaque tertiaire en trois groupes à recevoir une dose initiale de 300, 400 ou 500 unités (U) par kilogramme d'héparine intraveineuse avant le début de la CEC. Le sang a été prélevé après l'induction de l'anesthésie, à 30 et 60 minutes de CEC, et trois minutes après la neutralisation de l'héparine avec la protamine. Les échantillons ont été analysés pour les complexes fibrinopeptide A (FPA), fibrinopeptide B (FPB), D-dimère et thrombine-antithrombine (TAT). La perte de sang postopératoire et la transfusion ont été mesurées pendant la première période de 24 heures après la chirurgie. RéSULTATS: La dose moyenne totale (IC 95 %) d'héparine administrée dans les 300 U·kg−1, 400 U·kg−1, et 500 U·kg−1 était de 39 975 (36 528 à 43 421) U, 43 195 (36 940 à 49 449) U et 47 900 (44 807 à 50 992) U, respectivement. Il n'y avait aucune différence statistiquement significative dans les taux de FPA, FPB ou D-dimères aux intervalles de temps mesurés. Une tendance à des niveaux de TAT plus bas pendant la CEC a été observée avec une dose d'héparine plus élevée, ce qui était statistiquement significatif après l'administration de protamine. La signification clinique semble négligeable, car il n'y a pas de différence dans la perte de sang globale et la quantité de transfusion de concentrés globulaires ou d'autres produits sanguins. CONCLUSION: Cette étude pilote indique que, bien qu'une dose plus importante d'héparine pour la chirurgie cardiaque de routine entraîne des changements biochimiques subtils dans la coagulation, il n'y a aucun avantage démontrable en matière de saignement postopératoire ou de besoins transfusionnels.

Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial.

BACKGROUND: The dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio. METHODS AND FINDINGS: We undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: NCT03532594). Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78-1.14] vs. 0.75 [IQR 0.57-0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75-245] vs. 135 [IQR 94-222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160-210] vs. 280 [IQR 250-300] mg; p < 0.001). Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C). CONCLUSIONS: Using a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov Unique identifier NCT03532594.

Evaluation of Increase in Intraoperative Lactate Level as a Predictor of Outcome in Adults After Cardiac Surgery.

OBJECTIVES: Early onset hyperlactatemia develops intraoperatively or within the first 6 hours of admission to the intensive care unit (ICU) and is associated with a poor prognosis. The aim of the present study was to determine the utility of an increase in the intraoperative lactate level, independent of the absolute lactate value at baseline after induction, as a dynamic parameter for morbidity (ICU length of stay, postoperative renal failure, and inotrope use) and mortality in adults post-cardiac surgery. DESIGN: Retrospective observational study. SETTING: Single-center study in an academic hospital. PARTICIPANTS: The study comprised 779 patients who underwent elective cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were classified into the following 5 groups based on the increase in the intraoperative lactate level: (1) group 1-negative, (2) group 2-1- to 1.59-fold increase, (3) group 3-1.6- to 1.99-fold increase, (4) group 4-2- to 3-fold increase, and (5) group 5->3-fold increase. Logistic regression analyses were performed. Group 5 had a 4 times greater mortality (7.7%), the longest ICU length of stay (89.02 ± 78.73 h), and the greatest incidence of postoperative renal failure (n = 5 [19.2%]) compared with group 1. The increase in the intraoperative lactate level was a statistically significant predictor of mortality (p = 0.001) and ICU length of hospital stay (p = 0.0006) and was highly predictive for postoperative renal failure requiring renal replacement therapy (p = 0.001). CONCLUSIONS: An increase in intraoperative lactate, independent of the level on induction, is a useful dynamic parameter to identify patients at risk of postoperative morbidity and mortality and might provide an early trigger for introducing measures to avoid poor outcomes.

Post-infarction biventricular free wall rupture with extracardiac shunt presenting as ventricular septal rupture.

Ventricular free wall rupture is a rare, usually fatal complication of acute myocardial infarction. Subacute free wall rupture with pseudoaneurysm formation is even rarer, but may be associated with a chance of survival if surgery is performed expeditiously. Although rupture of the left ventricle is more common, right-sided rupture has also been reported. We report an unusual case of post-infarct biventricular rupture masquerading as a ventricular septal defect, due to an extracardiac shunt within the pseudoaneurysm. Our patient underwent urgent surgery, made an excellent recovery and was discharged home in a fully functional condition within a week post-surgery.

High-dose tranexamic Acid is associated with nonischemic clinical seizures in cardiac surgical patients.

BACKGROUND: In 2 separate centers, we observed a notable increase in the incidence of postoperative convulsive seizures from 1.3% to 3.8% in patients having undergone major cardiac surgical procedures. These events were temporally coincident with the initial use of high-dose tranexamic acid (TXA) therapy after withdrawal of aprotinin from general clinical usage. The purpose of this review was to perform a retrospective analysis to examine whether there was a relation between TXA usage and seizures after cardiac surgery. METHODS: An in-depth chart review was undertaken in all 24 patients who developed perioperative seizures. Electroencephalographic activity was recorded in 11 of these patients, and all patients had a formal neurological evaluation and brain imaging studies. RESULTS: Twenty-one of the 24 patients did not have evidence of new cerebral ischemic injury, but seizures were likely due to ischemic brain injury in 3 patients. All patients with seizures did not have permanent neurological abnormalities. All 24 patients with seizures received high doses of TXA intraoperatively ranging from 61 to 259 mg/kg, had a mean age of 69.9 years, and 21 of 24 had undergone open chamber rather than coronary bypass procedures. All but one patient were managed using cardiopulmonary bypass. No evidence of brain ischemic, metabolic, or hyperthermia-induced causes for their seizures was apparent. CONCLUSION: Our results suggest that use of high-dose TXA in older patients in conjunction with cardiopulmonary bypass and open-chamber cardiac surgery is associated with clinical seizures in susceptible patients.

Pulmonary arterial hypertension.

The last 10 years have seen significant advances in the understanding of the pathophysiology and treatment of pulmonary arterial hypertension (PAH). This has included new insights into the genetics, cell-signalling pathways and pathological changes seen in the small pulmonary arteries as well as the introduction of new treatments which have improved prognosis. The classification of pulmonary hypertension (PH) has also been changed several times, most recently in 2003. It now divides forms of PH into 5 broad groups according to their pathophysiology and response to treatment. This review focuses primarily on the advances that have been made in the comprehension and treatment of Group 1 (PAH); however reference is also made to other groups within the classification. Pharmacologic treatment now includes calcium-channel blockers, endothelin antagonists, prostanoids, phosphodiesterase type 5 inhibitors, anticoagulants and diuretics. There are 2 recent sets of guidelines directing treatment, one published by the American College of Chest Physicians in 2007 and the most recent published by the National Pulmonary Hypertension Centres of the UK and Ireland in 2008. The recent advances in understanding of the underlying cellular mechanisms have also opened the doorway to new potential therapies such as stem cell transplantation and the targeting of platelet-derived factors and apoptosis.