Clinical guideline on reversal of direct oral anticoagulants in patients with life threatening bleeding.

BACKGROUND: Anticoagulation is essential for the treatment and prevention of thromboembolic events. Current guidelines recommend direct oral anticoagulants (DOACs) over vitamin K antagonists in DOAC-eligible patients. The major complication of anticoagulation is serious or life-threatening haemorrhage, which may necessitate prompt haemostatic intervention. Reversal of DOACs may also be required for patients in need of urgent invasive procedures. This guideline from the European Society of Anaesthesiology and Intensive Care (ESAIC) aims to provide evidence-based recommendations and suggestions on how to manage patients on DOACs undergoing urgent or emergency procedures including the treatment of DOAC-induced bleeding. DESIGN: A systematic literature search was performed, examining four drug comparators (dabigatran, rivaroxaban, apixaban, edoxaban) and clinical scenarios ranging from planned to emergency surgery with the outcomes of mortality, haematoma growth and thromboembolic complications. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to assess the methodological quality of the included studies. Consensus on the wording of the recommendations was achieved by a Delphi process. RESULTS: So far, no results from prospective randomised trials comparing two active comparators (e.g. a direct reversal agent and an unspecific haemostatic agent such as prothrombin complex concentrate: PCC) have been published yet and the majority of publications were uncontrolled and observational studies. Thus, the certainty of evidence was assessed to be either low or very low (GRADE C). Thirty-five recommendations and clinical practice statements were developed. During the Delphi process, strong consensus (>90% agreement) was achieved in 97.1% of recommendations and consensus (75 to 90% agreement) in 2.9%. DISCUSSION: DOAC-specific coagulation monitoring may help in patients at risk for elevated DOAC levels, whereas global coagulation tests are not recommended to exclude clinically relevant DOAC levels. In urgent clinical situations, haemostatic treatment using either the direct reversal or nonspecific haemostatic agents should be started without waiting for DOAC level monitoring. DOAC levels above 50 ng ml-1 may be considered clinically relevant necessitating haemostatic treatment before urgent or emergency procedures. Before cardiac surgery under activated factor Xa (FXa) inhibitors, the use of andexanet alfa is not recommended because of inhibition of unfractionated heparin, which is needed for extracorporeal circulation. In the situation of DOAC overdose without bleeding, no haemostatic intervention is suggested, instead measures to eliminate the DOACs should be taken. Due to the lack of published results from comparative prospective, randomised studies, the superiority of reversal treatment strategy vs. a nonspecific haemostatic treatment is unclear for most urgent and emergency procedures and bleeding. Due to the paucity of clinical data, no recommendations for the use of recombinant activated factor VII as a nonspecific haemostatic agent can be given. CONCLUSION: In the clinical scenarios of DOAC intake before urgent procedures and DOAC-induced bleeding, practitioners should evaluate the risk of bleeding of the procedure and the severity of the DOAC-induced bleeding before initiating treatment. Optimal reversal strategy remains to be determined in future trials for most clinical settings.

Perioperative hemostatic management of patients with type A aortic dissection.

Coagulopathy is common in patients undergoing thoracic aortic repair for Stanford type A aortic dissection. Non-critical administration of blood products may adversely affect the outcome. It is therefore important to be familiar with the pathologic conditions that lead to coagulopathy in complex cardiac surgery. Adequate care of these patients includes the collection of the medical history regarding the use of antithrombotic and anticoagulant drugs, and a sophisticated diagnosis of the coagulopathy with viscoelastic testing and subsequently adapted coagulation therapy with labile and stable blood products. In addition to the above-mentioned measures, intraoperative blood conservation measures as well as good interdisciplinary coordination and communication contribute to a successful hemostatic management strategy.

A Narrative Review of Clinical Decision Support Systems for Perioperative Bleeding Management in Cardiac Surgery.

Bleeding complications in patients undergoing cardiac surgery are common. The clinician must assimilate multiple sources of monitoring information, make rational decisions on the etiology of the bleeding, and then formulate a treatment strategy. Clinical decision support systems that acquire this information and present the data in an easily usable format may be useful tools to guide the physician in optimizing treatment strategies through adherence to evidence-based best practice guidelines. The authors present a narrative review of the literature and discuss how clinical decision support systems may be useful to the clinician.

Management of severe peri-operative bleeding: Guidelines from the European Society of Anaesthesiology and Intensive Care: Second update 2022.

BACKGROUND: Management of peri-operative bleeding is complex and involves multiple assessment tools and strategies to ensure optimal patient care with the goal of reducing morbidity and mortality. These updated guidelines from the European Society of Anaesthesiology and Intensive Care (ESAIC) aim to provide an evidence-based set of recommendations for healthcare professionals to help ensure improved clinical management. DESIGN: A systematic literature search from 2015 to 2021 of several electronic databases was performed without language restrictions. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used to assess the methodological quality of the included studies and to formulate recommendations. A Delphi methodology was used to prepare a clinical practice guideline. RESULTS: These searches identified 137 999 articles. All articles were assessed, and the existing 2017 guidelines were revised to incorporate new evidence. Sixteen recommendations derived from the systematic literature search, and four clinical guidances retained from previous ESAIC guidelines were formulated. Using the Delphi process on 253 sentences of guidance, strong consensus (>90% agreement) was achieved in 97% and consensus (75 to 90% agreement) in 3%. DISCUSSION: Peri-operative bleeding management encompasses the patient's journey from the pre-operative state through the postoperative period. Along this journey, many features of the patient's pre-operative coagulation status, underlying comorbidities, general health and the procedures that they are undergoing need to be taken into account. Due to the many important aspects in peri-operative nontrauma bleeding management, guidance as to how best approach and treat each individual patient are key. Understanding which therapeutic approaches are most valuable at each timepoint can only enhance patient care, ensuring the best outcomes by reducing blood loss and, therefore, overall morbidity and mortality. CONCLUSION: All healthcare professionals involved in the management of patients at risk for surgical bleeding should be aware of the current therapeutic options and approaches that are available to them. These guidelines aim to provide specific guidance for bleeding management in a variety of clinical situations.

Mid-term outcomes of an alternative remodelling technique for aortic root replacement without coronary ostial mobilisation or reimplantation.

BACKGROUND: We compare the early and late outcomes of a modified aortic root remodelling (ARR) technique for aortic root replacement without mobilisation or reimplantation of the coronary ostia, with those of the modified Bentall-de Bono procedure. METHODS: A retrospective observational study was performed comprising 181 consecutive patients who underwent aortic root replacement with a modified Bentall-de Bono procedure (104 patients) or ARR (77 patients) between January 2013 and December 2019. Primary endpoints included hospital mortality and late survival. Secondary endpoints included incidence of post-operative complications and freedom from late re-operation. RESULTS: ARR procedures were performed with shorter cross-clamp times and comparable cardiopulmonary bypass times to modified Bentall-de Bono procedures. The incidence of early post-complications was comparable between groups. 30-day mortality was numerically lower with ARR than the modified Bentall-de Bono procedure. Over 7-year follow-up, 4 patients (3.8%) required repeat aortic surgery after a modified Bentall-de Bono procedure, and none after ARR. Long-term mortality after ARR and after modified Bentall-de Bono procedures was 17.1% and 22.7%, respectively. The cumulative incidence of reintervention on the aortic root/valve was 3.2% after a modified Bentall-de Bono procedure and 0% after ARR. When adjusted for other independent risk factors, late mortality was not influenced by the procedure performed, although competing risk adjusted for age showed that the modified Bentall-de Bono procedure was associated with an increased risk of aortic root/aortic valve re-operation. CONCLUSIONS: The modified ARR technique is associated with reduced myocardial ischaemia time, lower post-operative mortality and aortic re-intervention rates compared to a modified Bentall-de Bono procedure. It may be considered a safe and feasible procedure for aortic root/ascending aortic replacement offering good long-term outcomes.

Left ventricular free-wall rupture: An unusual presentation of non-bacterial thrombotic endocarditis.

Non-bacterial thrombotic endocarditis (NBTE) is a rare, often asymptomatic, condition. A 55-year-old woman presented with hemiparesis, facial palsy and chest pain. After urgent investigation, she was referred as a case of type A aortic dissection complicated by tamponade, myocardial infarction and stroke. Review of her imaging identified haemopericardium but no dissection, and emergency surgery proceeded considering her unstable condition. She underwent an emergency repair of left-ventricular free-wall rupture and excision of an aortic valve vegetation. Postoperative investigations confirmed a diagnosis of NBTE in the setting of a plexiform neurofibroma, and she was discharged 9 weeks later with residual neurological symptoms. This case poses a previously unreported acute presentation of NBTE and highlights the complexities in its diagnosis and management.

Single-Stage Off-Pump Hybrid Repair of Kommerell's Diverticulum with Right-Sided Aortic Arch Using a Surgeon-Customized Vascular Prosthesis.

We report the successful single-stage hybrid management of Kommerell's diverticulum associated with a right-sided aortic arch in a 63-year-old woman. She underwent total aortic arch debranching utilizing a surgeon-customized vascular prosthesis, without cardiopulmonary bypass or deep hypothermic circulatory arrest, and concomitant zone-0 endovascular stent-graft deployment.

Perioperative Anemia Management as Part of PBM in Cardiac Surgery - A Narrative Updated Review.

Anemia is common in patients with cardiac disease. Iron deficiency is the cause of anemia in about 80% of all cases. Preoperative anemia is associated with an increased morbidity and mortality in patients undergoing cardiac surgery. The risk of receiving red blood cell transfusions, which are potentially associated with severe side effects, is very high in these patients. Patient Blood Management (PBM) is a multidisciplinary approach to manage anemia, minimize unnecessary blood loss, and optimize transfusion therapy. PBM comprises 3 pillars: (1) detection and treatment of preoperative anemia, (2) reduction of perioperative blood loss, and (3) optimization of allogeneic blood therapy. The World Health Organization has urged all Member States to implement PBM. This narrative review focuses on pre-, intra-, and postoperative strategies to detect, prevent, and treat anemia as part of PBM in cardiac surgery.

Prothrombin Complex Concentrate in Cardiac Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Prothrombin complex concentrate (PCC) has recently emerged as an effective alternative to fresh frozen plasma (FFP) in treating excessive perioperative bleeding. This systematic review and meta-analysis evaluated the safety and efficacy of PCC administration as first-line treatment for coagulopathy after adult cardiac surgery. METHODS: PubMed/MEDLINE, EMBASE, and the Cochrane Library were searched from inception to the end of March 2018 to identify eligible articles. Adult patients undergoing cardiac surgery and receiving perioperative PCC were compared with patients receiving FFP. RESULTS: A total of 861 adult patients from four studies were retrieved. No randomized studies were identified. Pooled odds ratios (ORs) showed that the PCC cohort was associated with a significant reduction in the risk of RBC transfusion (OR, 2.22; 95% confidence interval [CI], 1.45 to 3.40) and units of RBC received (OR, 1.34; 95% CI, 0.78 to 1.90). No differences were observed between the groups for reexploration for bleeding (OR, 1.09; 95% CI, 0.66 to 1.82), chest drain output at 24 hours (OR, 66.36; 95% CI, -82.40 to 216.11), hospital mortality (OR, 0.94; 95% CI, 0.59 to 1.49), stroke (OR, 0.80; 95% CI, 0.41 to 1.56), and occurrence of acute kidney injury (OR, 0.80; 95% CI, 0.58 to 1.12). A trend toward increased risk of renal replacement therapy was observed in the PCC group (OR, 0.41; 95% CI, 0.16 to 1.02). CONCLUSIONS: In patients with significant bleeding after cardiac surgery, PCC administration seems to be more effective than FFP in reducing perioperative blood transfusions. No additional risks of thromboembolic events or other adverse reactions were observed. Randomized controlled trials are needed to establish the safety of PCC in cardiac surgery definitively.

Aortic centres should represent the standard of care for acute aortic syndrome.

Background Existing evidence suggests that patients affected by acute aortic syndromes (AAS) may benefit from treatment at dedicated specialized aortic centres. The purpose of the present study was to perform a meta-analysis to evaluate the impact aortic service configuration has in clinical outcomes in AAS patients. Methods The design was a quantitative and qualitative review of observational studies. We searched PubMed/ MEDLINE, EMBASE, and Cochrane Library from inception to the end of December 2017 to identify eligible articles. Areas of interest included hospital and surgeon volume activity, presence of a multidisciplinary thoracic aortic surgery program, and a dedicated on-call aortic team. Participants were patients undergoing repair for AAS, and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were adopted for synthesizing hospital/30-day mortality. Results A total of 79,131 adult patients from a total of 30 studies were obtained. No randomized studies were identified. Pooled unadjusted ORs showed that patients treated in high-volume centres or by high-volume surgeons were associated with lower mortality rates (OR 0.51; 95% CI 0.46-0.56, and OR 0.41, 95% CI 0.25-0.66, respectively). Pooled adjusted estimates for both high-volume centres and surgeons confirmed these survival benefits (adjusted OR, 0.56; 95% CI 0.45-0.70, respectively). Patients treated in centres that introduced a specific multidisciplinary aortic program and a dedicated on-call aortic team also showed a significant reduction in mortality (OR 0.31; 95% CI 0.19-0.5, and OR 0.37; 95% CI 0.15-0.87, respectively). Conclusions We found that specialist aortic care improves outcomes and decreases mortality in patients affected by AAS.

Early Outcome of Bilateral Versus Single Internal Mammary Artery Grafting in the Elderly.

BACKGROUND: Bilateral internal mammary artery (BIMA) grafting is increasingly used in elderly patients without evidence of its risks or benefits compared with single internal mammary artery (SIMA) grafting. METHODS: In all, 2,899 patients aged 70 years or older (855 [29.5%] underwent BIMA grafting) operated on from January 2015 to December 2016 and included in the prospective multicenter Outcome After Coronary Artery Bypass Grafting (E-CABG) study were considered in this analysis. RESULTS: One-to-one propensity matching resulted in 804 pairs with similar preoperative risk profile. Propensity score matched analysis showed that BIMA grafting was associated with a nonstatistically significant increased risk of inhospital death (2.7% versus 1.6%, p = 0.117). The BIMA grafting cohort had a significantly increased risk of any sternal wound infection (7.7% versus 5.1%, p = 0.031) as well as higher risk of deep sternal wound infection/mediastinitis (4.0% versus 2.2%, p = 0.048). The BIMA grafting cohort required more frequently extracorporeal membrane oxygenation (1.0% versus 0.1%, p = 0.02), and the intensive care unit stay (mean 3.6 versus 2.6 days, p < 0.001) and inhospital stay (mean 11.3 versus 10.0 days, p < 0.001) were significantly longer compared with the SIMA grafting cohort. Test for interaction showed that urgent operation in patients undergoing BIMA grafting was associated with higher risk of inhospital death (5.6% versus 1.3%, p = 0.009). CONCLUSIONS: Bilateral internal mammary artery grafting in elderly patients seems to be associated with a worse early outcome compared with SIMA grafting, particularly in patients undergoing urgent operation. Until more conclusive results are gathered, BIMA grafting should be reserved only for elderly patients with stable coronary artery disease, without significant baseline comorbidities and with long life expectancy.

European guidelines on perioperative venous thromboembolism prophylaxis: Cardiovascular and thoracic surgery.

: None of the predictive models for venous thromboembolism (VTE) prophylaxis have been designed for and validated in patients undergoing cardiothoracic and vascular surgery. The presence of one or more risk factors [age over 70 years old, transfusion of more than 4 U of red blood cells/fresh frozen plasma/cryoprecipitate, mechanical ventilation lasting more than 24 h, postoperative complication (e.g. acute kidney injury, infection/sepsis, neurological complication)] should place the cardiac population at high risk for VTE. In this context, we suggest the use of pharmacological prophylaxis as soon as satisfactory haemostasis has been achieved, in addition to intermittent pneumatic compression (IPC) (Grade 2C). In patients undergoing abdominal aortic aneurysm repair, particularly when an open surgical approach is used, the risk for VTE is high and the bleeding risk is high. In this context, we suggest the use of pharmacological prophylaxis as soon as satisfactory haemostasis is achieved (Grade 2C). Patients undergoing thoracic surgery in the absence of cancer could be considered at low risk for VTE. Patients undergoing thoracic surgery with a diagnosis of primary or metastatic cancer should be considered at high risk for VTE. In low-risk patients, we suggest the use of mechanical prophylaxis using IPC (Grade 2C). In high-risk patients, we suggest the use of pharmacological prophylaxis in addition to IPC (Grade 2B).

European guidelines on perioperative venous thromboembolism prophylaxis: Patients with preexisting coagulation disorders and after severe perioperative bleeding.

: In patients with inherited bleeding disorders undergoing surgery, we recommend assessment of individual risk for venous thromboembolism, taking into account the nature of the surgery and anaesthetic, type and severity of bleeding disorder, age, BMI, history of thrombosis, the presence of malignancy and other high-risk comorbidities. Venous thromboembolism risk should be balanced against the increased bleeding risk associated with anticoagulant use in patients with known bleeding disorders (Grade 1C). In these patients undergoing major surgery, we recommend against routine postoperative use of pharmacological thromboprophylaxis, especially for patients with haemophilia A and B (Grade 1B). Glomerular filtration rate should be assessed before initiation of each direct oral anticoagulant, and also at least once a year or more frequently as needed, such as postoperatively before the resumption of therapeutic direct oral anticoagulant administration, when it is suspected that renal function could decline or deteriorate (Grade 1C). Reduced dosages of low molecular weight heparins may be used relatively safely during transient severe (<50 × 10 l) thrombocytopaenia (Grade 2C). Monitoring of anti-Xa levels may be used to adjust the doses of low molecular weight heparin in patients with moderate or severe thrombocytopaenia (Grade 2C). The delay between major gastrointestinal bleeding and resuming warfarin should be at least 7 days (Grade 2C). For patients at a high risk of thromboembolism and with a high bleeding risk after surgery, we consider that administering a reduced dose of direct oral anticoagulant on the evening after surgery and on the following day (first postoperative day) after surgery is a good practice (Grade 2B).

Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: First update 2016.

: The management of perioperative bleeding involves multiple assessments and strategies to ensure appropriate patient care. Initially, it is important to identify those patients with an increased risk of perioperative bleeding. Next, strategies should be employed to correct preoperative anaemia and to stabilise macrocirculation and microcirculation to optimise the patient's tolerance to bleeding. Finally, targeted interventions should be used to reduce intraoperative and postoperative bleeding, and so prevent subsequent morbidity and mortality. The objective of these updated guidelines is to provide healthcare professionals with an overview of the most recent evidence to help ensure improved clinical management of patients. For this update, electronic databases were searched without language restrictions from 2011 or 2012 (depending on the search) until 2015. These searches produced 18 334 articles. All articles were assessed and the existing 2013 guidelines were revised to take account of new evidence. This update includes revisions to existing recommendations with respect to the wording, or changes in the grade of recommendation, and also the addition of new recommendations. The final draft guideline was posted on the European Society of Anaesthesiology website for four weeks for review. All comments were collated and the guidelines were amended as appropriate. This publication reflects the output of this work.

Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery.

BACKGROUND: Bleeding after cardiac surgery requiring surgical reexploration and blood component transfusion is associated with increased morbidity and mortality. Although prothrombin complex concentrate (PCC) has been used satisfactorily in bleeding disorders, studies on its efficacy and safety after cardiopulmonary bypass are limited. METHODS: Between January 2005 and December 2013, 3454 consecutive cardiac surgery patients were included in an observational study aimed at investigating the efficacy and safety of PCC as first-line coagulopathy treatment as a replacement for fresh frozen plasma (FFP). Starting in January 2012, PCC was introduced as solely first-line treatment for bleeding following cardiac surgery. RESULTS: After one-to-one propensity score-matched analysis, 225 pairs of patients receiving PCC (median dose 1500 IU) and FFP (median dose 2 U) were included. The use of PCC was associated with significantly decreased 24-h post-operative blood loss (836 ± 1226 vs. 935 ± 583 ml, p < 0.0001). Propensity score-adjusted multivariate analysis showed that PCC was associated with significantly lower risk of red blood cell (RBC) transfusions (odds ratio [OR] 0.50; 95% confidence interval [CI] 0.31-0.80), decreased amount of RBC units (ß unstandardised coefficient -1.42, 95% CI -2.06 to -0.77) and decreased risk of transfusion of more than 2 RBC units (OR 0.53, 95% CI 0.38-0.73). Patients receiving PCC had an increased risk of post-operative acute kidney injury (AKI) (OR 1.44, 95% CI 1.02-2.05) and renal replacement therapy (OR 3.35, 95% CI 1.13-9.90). Hospital mortality was unaffected by PCC (OR 1.51, 95% CI 0.84-2.72). CONCLUSIONS: In the cardiac surgery setting, the use of PCC compared with FFP was associated with decreased post-operative blood loss and RBC transfusion requirements. However, PCC administration may be associated with a higher risk of post-operative AKI.

Validation of the European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG) Bleeding Severity Definition.

BACKGROUND: This study evaluated the prognostic significance of a novel bleeding severity classification in adult patients undergoing cardiac operations. METHODS: The European multicenter study on Coronary Artery Bypass Grafting (E-CABG) bleeding severity classification proposes 4 grades of postoperative bleeding: grade 0, no need of blood products with the exception of 1 unit of red blood cells (RBCs); grade 1, transfusion of platelets, plasma, or 2 to 4 units of RBCs, or both; grade 2, transfusion of 5 to 10 units of RBCs or reoperation for bleeding, or both; grade 3, transfusion of more than 10 units of RBCs. This classification was tested in a cohort of 7,491 patients undergoing CABG or valve operations, or combined procedures. RESULTS: The E-CABG bleeding severity grading method was an independent predictor of in-hospital death, stroke, acute kidney injury, renal replacement therapy, deep sternal wound infection, atrial fibrillation, intensive care unit stay of 5 days or more, and composite adverse events of death, stroke, renal replacement therapy, and intensive care unit stay of 5 days or more. The area under the receiver operating characteristic curve of the E-CABG bleeding severity grading method for predicting in-hospital death was 0.858 (95% confidence interval, 0.827 to 0.889). E-CABG bleeding severity grades 0 to 3 were associated with in-hospital mortality rates of 0.2%, 1.1%, 7.9%, and 29.0%, respectively (p <0.001), and with composite adverse events of 2.7%, 9.6%, 29.7%, and 75.8%, respectively (p <0.001). CONCLUSIONS: The E-CABG bleeding severity classification seems to be a valuable tool in the assessment of the severity and prognostic effect of perioperative bleeding in cardiac operations.

Bioadhesive microdevices with multiple reservoirs: a new platform for oral drug delivery.

A variety of delivery systems have been devised, in recent years, to improve the oral bioavailability of drugs including enterically coated tablets, capsules, particles, and liposomes. Microfabrication technology may offer some potential advantages over conventional drug delivery technologies. This technology, combined with appropriate surface chemistry, may permit the highly localized and unidirectional release of drugs, permeation enhancers, and/or promoters. In this study, we demonstrate the fabrication of prototype reservoir-containing microdevices and a surface chemistry protocol that can be used to bind lectin via avidin-biotin interactions to these micromachined drug delivery vehicles. The use of microfabrication allows one to tailor the size, shape, reservoir volume, and surface characteristics of the drug delivery vehicle. In vitro studies show enhanced bioadhesion of these lectin conjugated silicon microdevices. This approach may be used to improve the absorption of pharmacologically active biopolymers such as peptides, proteins and oligonucleotides into circulation at targeted sites in the GI system via the creation of a robust hybrid organic/inorganic delivery system. This paper describes one of the first applications of microfabrication to oral drug delivery.