Use Of Aprotinin Research Articles

The use of fibrinolysis inhibitors in cardiac surgery with cardiopulmonary bypass (literature review)

In cardiac surgery with cardiopulmonary bypass (CPB) is a common complication. The incidence of this complication in cardiac surgery patients is estimated at about 10%. For this reason, the introduction of a patient blood management (PBM) in cardiac surgery is extremely relevant. Antifibrinolytic therapy is a key pharmacological tool of a multimodal PBM in cardiac surgery with CPB. The use of antifibrinolytics (tranexamic acid (TXA) and epsilon aminocaproic acid (EACA)) is standard practice in complex cardiac surgery with CPB. However, there is currently ongoing discussion regarding the search for the optimal dose of EACA and TXA to achieve an effective concentration in blood plasma in order to inhibit fibrinolysis with the minimization of adverse events. The use of aprotinin has a number of potential advantages, but its use in routine clinical practice is significantly limited. This review presents modern approaches to antifibrinolytic therapy, examines the mechanisms of action of the main drugs, highlights the side effects associated with the use of antifibrinolytic agents.

Aprotinin (I): Understanding the Role of Host Proteases in COVID-19 and the Importance of Pharmacologically Regulating Their Function.

Proteases are produced and released in the mucosal cells of the respiratory tract and have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), takes advantage of host proteases in two ways: to change the spatial conformation of the spike (S) protein via endoproteolysis (e.g., transmembrane serine protease type 2 (TMPRSS2)) and as a target to anchor to epithelial cells (e.g., angiotensin-converting enzyme 2 (ACE2)). This infectious process leads to an imbalance in the mucosa between the release and action of proteases versus regulation by anti-proteases, which contributes to the exacerbation of the inflammatory and prothrombotic response in COVID-19. In this article, we describe the most important proteases that are affected in COVID-19, and how their overactivation affects the three main physiological systems in which they participate: the complement system and the kinin-kallikrein system (KKS), which both form part of the contact system of innate immunity, and the renin-angiotensin-aldosterone system (RAAS). We aim to elucidate the pathophysiological bases of COVID-19 in the context of the imbalance between the action of proteases and anti-proteases to understand the mechanism of aprotinin action (a panprotease inhibitor). In a second-part review, titled "Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions", we explain in depth the pharmacodynamics, pharmacokinetics, toxicity, and use of aprotinin as an antiviral drug.

Efficacy and utility of antifibrinolytics in pediatric spine surgery: a systematic review and network meta-analysis.

Antifibrinolytics have gained increasing attention in minimizing blood loss and mitigating the risks associated with massive transfusions, including infection and coagulopathy in pediatric patients undergoing spine surgery. Nevertheless, the selection of optimal agent is still a matter of debate. We aim to review the utility of these agents and compare the efficacy of antifibrinolytics in pediatric and adolescent spine surgeries. A comprehensive search was performed in Scopus, Web of Science, and MEDLINE databases for relevant works. Studies providing quantitative data on predefined outcomes were included. Primary outcome was perioperative bleeding between the groups. Secondary outcomes included transfusion volume, rate of complications, and operation time. Twenty-eight studies were included in the meta-analysis incorporating 2553 patients. The use of Tranexamic acid (RoM: 0.71, 95%CI: [0.62-0.81], p < 0.001, I2 = 88%), Aprotinin (RoM: 0.54, 95%CI: [0.46-0.64], p < 0.001, I2 = 0%), and Epsilon-aminocaproic acid (RoM: 0.71, 95%CI: [0.62-0.81], p < 0.001, I2 = 60%) led to a 29%, 46%, and 29% reduction in perioperative blood loss, respectively. Network meta-analysis revealed higher probability of efficacy with Tranexamic acid compared to Epsilon-aminocaproic acid (P score: 0.924 vs. 0.571). The rate of complications was not statistically different between each two antifibrinolytic agent or antifibrinolytics compared to placebo or standard of care. Our network meta-analysis suggests a superior efficacy of all antifibrinolytics compared to standard of care/placebo in reducing blood loss and transfusion rate. Further adequately-powered randomized clinical trials are recommended to reach definite conclusion on comparative performance of these agents and to also provide robust objective assessments and standardized outcome data and safety profile on antifibrinolytics in pediatric and adolescent pediatric surgeries.

Lack of efficacy of aprotinin over tranexamic acid in type A aortic dissection repair.

The role of aprotinin in modern cardiac surgery is not well defined. While licensed for use in isolated coronary artery bypass grafting it is more commonly used for cases deemed to be at an increased risk of bleeding. The relative efficacy, and safety profile, of aprotinin as compared to other antifibrinolytics in these high-risk cases is uncertain. A retrospective observational study with propensity matching to determine whether aprotinin versus tranexamic acid reduced bleeding or transfusion requirements in patients presenting for surgical repair of type A aortic dissection (TAD). Between 2016 and 2022, 250 patients presented for repair of TAD. A total of 231 patients were included in the final analysis. Bleeding and transfusion were similar between both groups in both propensity matched and unmatched cohorts. Compared to tranexamic acid, aprotinin use did not reduce transfusion requirements for any product. Rates of bleeding in the first 12 h, return to theater and return to intensive care unit with an open packed chest were similar between groups. There was no difference in rates of renal failure, stroke, or death. Aprotinin did not reduce the risk of bleeding or transfusion requirements in patients undergoing repair of type A aortic dissections. Efficacy of aprotinin may vary depending on the type of surgery performed and the underlying pathology.

In Nordic countries 30-day mortality rate is half that estimated with EuroSCORE II in high-risk adult patients given aprotinin and undergoing mainly complex cardiac procedures

Objectives. To describe current on- (isolated coronary arterty bypass grafting, iCABG) and off-label (non-iCABG) use of aprotinin and associated safety endpoints in adult patients undergoing high-risk cardiac surgery in Nordic countries. Design. Data come from 10 cardiac surgery centres in Finland, Norway and Sweden participating in the European Nordic aprotinin patient registry (NAPaR). Results. 486 patients were given aprotinin between 2016 and 2020. 59 patients (12.1%) underwent iCABG and 427 (87.9%) non-iCABG, including surgery for aortic dissection (16.7%) and endocarditis (36.0%). 89.9% were administered a full aprotinin dosage and 37.0% were re-sternotomies. Dual antiplatelet treatment affected 72.9% of iCABG and 7.0% of non-iCABG patients. 0.6% of patients had anaphylactic reactions associated with aprotinin. 6.4% (95 CI% 4.2%–8.6%) of patients were reoperated for bleeding. Rate of postoperative thromboembolic events, day 1 rise in creatinine >44μmol/L and new dialysis for any reason was 4.7% (95%CI 2.8%–6.6%), 16.7% (95%CI 13.4%–20.0%) and 14.0% (95%CI 10.9%–17.1%), respectively. In-hospital mortality and 30-day mortality was 4.9% (95%CI 2.8%–6.9%) and 6.3% (95%CI 3.7%–7.8%) in all patients versus mean EuroSCORE II 11.4% (95%CI 8.4%–14.0%, p < .01). 30-day mortality in patients undergoing surgery for aortic dissection and endocarditis was 6.2% (95%CI 0.9%–11.4%) and 6.3% (95%CI 2.7%–9.9%) versus mean EuroSCORE II 13.2% (95%CI 6.1%–21.0%, p = .11) and 14.5% (95%CI 12.1%–16.8%, p = .01), respectively. Conclusions. NAPaR data from Nordic countries suggest a favourable safety profile of aprotinin in adult cardiac surgery.

RETROSPECTIVE ANALYSIS ASSESSING ECONOMIC IMPACT OF APROTININ REINSTATEMENT IN 4 FRENCH CARDIAC SURGERY CENTRES

<h3>Objective</h3> Until 2008, aprotinin (APR) was used to reduce perioperative bleeding and transfusion needs in cardiac surgery but was suspended following the publication of the BART study,1 leaving only tranexamic acid (TXA) as available antifibrinolytic. In 2012, the European Medicine Agency revisited all APR data and restored APR to be given to adult patients at high risk of major blood loss undergoing isolated coronary artery bypass graft (CABG) surgery and requested the marketing authorization holder to gather more information on the profile of APR use through a registry (NAPaR). The economic impact of APR reintroduction on costs was compared to TXA. <h3>Design and Method</h3> This multicenter before-after study comparing APR with TXA was carried out in 4 French university centers. APR use followed ARCOTHOVA (French association of cardiothoracic and vascular anaesthetists) guidance in 2 indication classes: class 1, on-label (iCABG); class 2, off-label, patient with at least 3 risk factors (Trust score), 2 and/or exposed to high risk surgeries. APR data were retrieved from the NAPaR registry. TXA data were retrieved from each center's database, and were matched to APR data based on indication classes. Budget impact was evaluated using both direct costs associated with antifibrinolytics and transfusion products (within first 48h) and indirect costs such as surgery duration and ICU stay. <h3>Results</h3> Between December 2018 and November 2020, 236 patients were treated with APR and were matched to 223 matched patients treated with TXA between May 2016 and October 2019. The 459 patients were distributed as: 17% in class 1, 83% in class 2; 25 APR patients and 23 TXA patients died before ICU discharge and were excluded from the cost analysis. Mean costs per patient tended to be lower in APR group versus TXA group (21K€ vs 24K€), which resulted in an estimated gross saving > 660 K€ for the whole cohort in favour APR. The mean cost per patient differed with the indication class, 22K€ on-label vs 47K€ off-label. Differential costs between APR vs TXA were in the opposite direction for on-label (+4.7K€) and off-label (-5.3K€) use (Figure). Higher costs for TXA patients were related to longer ICU stay, mainly due to those patients who stayed more than 16 days in the ICU (stays exceeding the 90th percentile, p=0.002 versus APR patients). <h3>Conclusions</h3> Costs were driven by the ICU stay. The substantial savings observed with APR treatment were because fewer patients in the APR group stayed long at the ICU compared to TXA group. These unforeseen results raise the question of the role of the unspecific anti-protease action of APR, resulting in anti-inflammatory effect,3 in the observed improvement, and needs further investigation.

EUROPEAN NORDIC APROTININ PATIENT REGISTRY (NAPAR) DATA FROM NORDIC COUNTRIES INDICATE HALVED 30-DAY MORTALITY RATE COMPARED WITH EUROSCORE II IN HIGH-RISK HEART SURGERY

<h3>Objective</h3> According to European Medicines Agency (EMA) the on-label indication for aprotinin is for patients undergoing isolated coronary artery bypass graft surgery (iCABG), who are at high risk of major blood loss. The objective of the study was to describe current on- and off-label use of aprotinin and associated safety endpoints, including mortality, in adult patients undergoing high risk cardiac surgery in Nordic countries. <h3>Design and Method</h3> Data were analysed from cardiac surgery centres in Finland, Norway and Sweden that were participating in the European Nordic aprotinin patient registry (NAPaR), which is a non-interventional, post-authorization safety study (PASS) executed at EMA's request. Ethical approval was given by responsible authorities at each Hospital and all patients agreed to partake. The treating doctors determined if patients were to be given aprotinin. <h3>Results</h3> Altogether 489 patients were given aprotinin between 2016 to 2020 and of those 72.8% were male and 9.8% >75 years old. 59 patients (12.1%, on-label) underwent iCABG and 430 (87.9%, off-label) another procedure, including a surgery for aortic dissection (n=81, 18.8%) and endocarditis (n=175, 35.8%). 437 patients (89.4%) were given the full Hammersmith regimen and 37.2% had experienced at least one earlier heart procedure. 14.9% of all patients were on dual antiplatelet treatment, which affected 72.9% of iCABG and 7.4% of non-iCABG patients. Preoperative renal impairment (creatinine clearance < 85 mL/min) affected 50.7% of patients and 51.7% of the procedures were urgent, 17.0% emergent and 4.9% salvage. Mean/median bypass time was 159/148 min (range 25-637 min). 0.6% of patients had anaphylactic reactions associated with aprotinin. Within 24 and 48 hours postoperatively, 2.5% (CI95%:1.1%-3.8%) and 4.9% (3.0%-6.8%) of patients were reoperated for bleeding, respectively. Rate of postoperative thromboembolic events, day 1 rise in creatinine >44 μmol/L and new dialysis for any reason was 4.7% (CI95%: 2.8%-6.6%), 17.0% (CI95%: 13.6%-20.3%) and 14.3% (11.2%-17.4%), respectively. In-hospital mortality and 30-day mortality was 4.9% (CI95%: 2.8%-6.9%) and 6.3% (CI95%: 3.7%-7.8%) in all patients versus mean EuroSCORE II (estimates 30-day mortality) 11.4% (CI95%: 8.4%-14.0%, p<0.01). 30-day mortality in patients undergoing surgery for aortic dissection and endocarditis was 6.2% (CI95%: 0.9%-11.4%) and 6.3% (CI95%: 2.7%-9.9%) versus mean EuroSCORE II 13.4% (CI95%: 6.1%-21.0%, p=0.11) and 14.5% (CI95%: 12.1%-16.8%, p=0.01), respectively. <h3>Conclusions</h3> In patients given aprotinin at high risk of death and bleeding undergoing cardiac surgery, mainly complex procedures, 30-day mortality was significantly lower, with approximately halved mortality rates compared with estimations by EuroSCORE II. NAPaR data from Nordic countries suggest a favourable safety profile of aprotinin in adult cardiac surgery.

Therapeutic use of α2-antiplasmin as an antifibrinolytic and hemostatic agent in surgery and regenerative medicine

The biomaterial fibrin is widely used as a clinical tissue sealant in surgery. In preclinical research, fibrin is also extensively studied as a carrier material for growth factor delivery. In these applications, premature fibrin degradation leads to recurrent bleeding, tissue dehiscence and limited regenerative efficacy. Therefore, fibrinolysis inhibitors have been added to clinical fibrin formulations, for example the bovine-derived serine protease inhibitor aprotinin. Aprotinin is additionally used as a hemostatic agent to prevent excessive bleeding during surgery, in this case protecting endogenous fibrin clots. Nevertheless, aprotinin use has been associated with serious safety issues. Here, we explore the use the human physiological fibrinolysis inhibitor α2-antiplasmin (α2PI) as a substitute for aprotinin. We evaluate the efficacy of α2PI in the three main applications of aprotinin. We first showed that recombinant α2PI can successfully prolong the durability of fibrin biomaterials as compared to aprotinin in a model of subcutaneous implantation in mice mimicking application as a tissue sealant. We then used α2PI to enhance the delivery of engineered vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF)-BB in fibrin in promoting diabetic wound healing, which lead to improved wound closure, granulation tissue formation and angiogenesis. Lastly, we demonstrated that α2PI can be as effective as aprotinin as an intravenous hemostatic agent to prevent blood loss, using a tail-vein bleeding model in mice. Therefore, we believe that engineering fibrin biomaterials or endogenous fibrin with α2PI can have a strong impact in surgery and regenerative medicine by providing a competitive substitute to aprotinin that is of human origin.

Use and safety of aprotinin in routine clinical practice: A European postauthorisation safety study conducted in patients undergoing cardiac surgery.

BACKGROUNDAprotinin has been used to reduce blood loss and blood product transfusions in patients at high risk of major blood loss during cardiac surgery. Approval by the European Medicines Agency (EMA) for its current indication is limited to patients at high risk of major blood loss undergoing isolated coronary artery bypass graft surgery (iCABG).OBJECTIVETo report current real-world data on the use and certain endpoints related to the safety of aprotinin in adult patients.DESIGNThe Nordic aprotinin patient registry (NAPaR) received data from 83 European centres in a noninterventional, postauthorisation safety study (PASS) performed at the request of the EMA.SETTINGCardiac surgical centres committed to enrolling patients in the NAPaR.PATIENTSPatients receiving aprotinin agreeing to participate.INTERVENTIONThe decision to administer aprotinin was made by the treating physicians.MAIN OUTCOME MEASURESAprotinin safety endpoints were in-hospital death, thrombo-embolic events (TEEs), specifically stroke, renal impairment, re-exploration for bleeding/tamponade.RESULTSFrom 2016 to 2020, 5309 patients (male 71.5%; >75 years 18.9%) were treated with aprotinin; 1363 (25.7%) underwent iCABG and 3946 (74.3%) another procedure, including a surgical treatment for aortic dissection (n = 660, 16.7%); 54.5% of patients received the full-dose regimen. In-hospital mortality in iCABG patients was 1.3% (95% CI, 0.66 to 1.84%) vs. 8.3% (7.21 to 8.91%) in non-iCABG patients; incidence of TEEs and postoperative rise in creatinine level greater than 44 μmol l−1 2.3% (1.48 to 3.07%) and 2.7% (1.79 to 3.49%) vs. 7.2% (6.20 to 7.79%) and 15.5% (13.84 to 16.06%); patients undergoing re-exploration for bleeding 1.4% (0.71 to 1.93%) vs. 3.0% (2.39 to 3.44%). Twelve cases of hypersensitivity/anaphylactic reaction (0.2%) were reported as Adverse Drug Reactions.CONCLUSIONThe data in the NApaR indicated that in this patient population, at high risk of death or blood loss undergoing cardiac surgery, including complex cardiac surgeries other than iCABG, the incidence of adverse events is in line with data from current literature, where aprotinin was not used.TRIAL REGISTRATIONEU PAS register number: EUPAS11384.

A Narrative Review of 99mTc-Aprotinin in the Diagnosis of Cardiac Amyloidosis and a New Life for an Unfairly Abandoned Drug

Several studies investigated the use of 99mTc-labelled Aprotinin as an amyloid seeker some years ago. In vitro tests showed high binding affinity for several types of amyloid fibrils accompanied by an excellent specificity. Initial human studies demonstrated good accuracy in detecting cardiac involvement. Scintigraphy results were confirmed in a group of 28 endomyocardial biopsies. Unfortunately, clinical studies were halted because of a temporary suspension of the vector protein (Trasylol) and public health concerns over prion contamination of the bovine origin compound. To obviate these limitations, efforts have been made to label a recombinant Aprotinin with 99mTc, which exhibits the same affinity for h-insulin fibrils. With the aim of developing a PET tracer, the same recombinant protein was labeled with Gallium. The introduction of a bifunctional chelator did not affect fibril affinity. Finally, a synthetic peptidic fragment, the cyclic 30-51 SS, was synthetized. After direct technetium labeling, an impressive increase in affinity was demonstrated. This peptide appears to be a potential candidate for Gallium labeling through a bifunctional chelator for PET imaging.

APROTININ USE IN HIGH-RISK CARDIAC SURGERY: RECENT INSIGHTS FROM THE BELGIAN APROTININ PATIENT REGISTRY

Introduction In 2007, the use of aprotinin was temporarily suspended following several publications raising serious safety concerns.(1.2.3) However, Canadian and European Health Authorities concluded that these studies suffered from major flaws and lifted the suspension in 2013.(4,5) The reintroduction of aprotinin in 2016 was accompanied by a mandatory registry [Nordic Aprotinin Patient Registry (NAPaR)] in order to monitor the pattern of use, the effect of risk minimization measures, and overall safety. Objective of this study was to analyse the use of aprotinin in Belgium. Methods NAPaR is a non-interventional Post-Authorisation Safety Study (PASS), endorsed by the Pharmacovigilance Risk Assessment Committee of the European Medicine Agency. Results Between October 2018 and August 2020, six Belgian NAPaR centers included 694 patients [median age 70 (range 13-90y); 62% male; median EuroSCORE II 4.6 (range 0.5-93.4)]. 25% of the patients had an EuroSCOREII > 10. 57% of the patients were under an active antiplatelet therapy and 17% were treated with novel oral anti-coagulants. Preoperative renal impairment was present in 2/3 of patients. Only 4% of the patients received aprotinin on-label, i.e. for isolated coronary artery bypass grafting (CABG) on cardiopulmonary bypass (CPB). In 96% of the patients, aprotinin was used off-label, mainly for redo surgery (32%), CABG + valve surgery (29%), aortic surgery (20%) and multiple valve surgery (17%). One third of the procedures were urgent (23%) or emergent (9%). Median bypass time was 128min (range 13-600min). Median hospital stay was 11 days (range 3-151 days). Main reported indications for the use of aprotinin were active dual antiplatelet therapy (68% in iCABG), redo surgery (16%) and expected prolonged CPB time (55%). In 83% of the cases, aprotinin was administered at the Half Hammersmith dose (1 Mio KIU loading- and priming-dose + 250.000 KIU/h); most patients received the appropriate test dose (98%), none developed anaphylactic reactions. Median perioperative blood loss was 400ml (range 40 -10050 ml), 44% of the patients had RBC transfusion and 6% underwent reoperation for bleeding or tamponade. Overall mortality at discharge was 5%, i.e. within the range or lower than predicted by the EuroSCORE II. 2% of the patients had a postoperative stroke. Postoperative AKI as defined by a serum creatinine increase of 0,3mg/dL or more within 48 hours after surgery was present in 13% of cases. Most of these patients (76%) suffered from preoperative moderate or severe renal impairment including dialysis. Notably, in patients with postoperative AKI median CPB time was significantly higher than in patients without AKI: 172min (range 56-402) vs 125min (range 13-600min) (p Discussion In the Belgian centers, aprotinin was mainly used off-label and predominantly administered to older patients with significant comorbidities undergoing high-risk procedures. The observed safety outcomes are in line with published data within this high risk patient population. The data from the Belgian NAPaR suggest that aprotinin has an excellent safety profile in adult cardiac surgery.

APROTININ USE IN CARDIAC SURGERY IN A TERTIARY CENTRE IN IRELAND: CASE NUMBERS, INDICATIONS & COMPARISON TO TRANEXAMIC ACID

Introduction Aprotinin is a serine protease inhibitor which is used in cardiac surgery as an anti-fibrinolytic agent to minimise patient bleeding. It was withdrawn from the European market in 2008 due to potential increased mortality when compared to tranexamic acid. Aprotinin was subsequently re-introduced in 2012 with narrow licencing indications, specifically isolated coronary artery bypass graft surgery in high risk patients. Minimisation of intra-operative blood loss plays an important role in patient outcomes, especially in decreasing the need for transfusion which carries its own mortality risks(3,. Tranexamic acid is utilised in the majority of cardiac surgery cases throughout Europe. We looked to quantify and determine indications for aprotinin usage in an Irish tertiary cardiac centre and compare findings to tranexamic acid. Methods Retrospective study of aprotinin usage in cardiac surgery in an Irish tertiary centre over a 3 year period to determine number of cases and indications. Data collection involved operative notes, patient records, pharmacy dispensing accounts. Aprotinin dosage intra-operatively was per the full or half Hammersmith protocol. A cohort which had undergone comparable cardiac surgery procedures with tranexamic acid as the anti-fibrinolytic agent were also studied. Results From 2018-2021, 21 cardiac surgeries were carried out using aprotinin as the sole anti-fibrinolytic agent to minimise patient bleeding in a high risk cohort. For the same time period, to provide scale, 737 cardiac surgeries were carried out using tranexamic acid. Each of the cases which utilised aprotinin represents an emergent, life-threatening operation. The emergency cases comprised: repair of Stanford type A aortic dissection (8, 38%); aortic valve replacement (7, 33.3%); mitral valve replacement (3, 14.3%); tricuspid valve replacement (1, 4.8%); mediastinal revision for cardiac tamponade (1, 4.8%). Valve replacements were complicated by: acute infective endocarditis, aortic root abscess, haematoma, failure of pre-existing prosthetic valves. 1 case utilised aprotinin as per the licenced indication: isolated CABG in patient with high bleeding risk. An ST-elevated myocardial infarction necessitated the emergency CABG procedure in this case. Discussion In summation, 95% of aprotinin usage for cardiac surgery in an Irish tertiary centre falls outside the remit of the licenced indication. Given similar findings in a number of European institutes(5), is it time to re-assess the existing guidelines on aprotinin use, with view to expansion of the licenced indications?

Correction to: Aprotinin in adults at high risk of major blood loss during isolated CABG with cardiopulmonary bypass: a profile of its use in the EU

Prophylactic treatment with aprotinin, a haemostatic antifibrinolytic agent, is indicated to reduce blood loss and blood transfusion in adults with a high risk of major bleeding undergoing primary or repeat isolated coronary artery bypass graft (CABG) with cardiopulmonary bypass. Overall, aprotinin was consistently more effective than tranexamic acid, e-aminocaproic acid, desmopressin and placebo in reducing massive blood loss, the need for transfusions of blood products, and the need for reoperation due to diffuse bleeding in trials in this patient population, and was generally well-tolerated. The approval of aprotinin in the EU was reinstated by the European Medicines Agency (EMA) in 2012, following subsequent analysis of the clinical data that led to its suspension in 2007. The EMA analysis concluded that the reduction in massive bleeding provided by aprotinin in patients undergoing isolated CABG is clinically relevant, as it reduces complications, the need for blood product transfusions and the length of hospital stay, without increasing mortality. The relaunch of aprotinin was accompanied by a risk management to assess the pattern of use and safety of aprotinin in clinical practice. Data from centres enrolled in the Nordic Aprotinin Patient Registry are being collected and will be assessed in the final report.

Thrombotic risk in central venoarterial extracorporeal membrane oxygenation post cardiac surgery.

Post-cardiotomy cardiogenic shock is an accepted indication for venoarterial extracorporeal membrane oxygenation. The true incidence and risk factors for the development of thrombosis in this setting remain unclear. Patients supported with central venoarterial extracorporeal membrane oxygenation due to ventricular dysfunction precluding weaning from cardiopulmonary bypass were retrospectively identified. Electronic records from a single institution spanning a 4-year period from January 2015 to December 2018 were interrogated to assess the incidence of thrombosis. The relationship to exposures including intracardiac stasis and procoagulant usage was explored. Twenty-four patients met the inclusion criteria and six suffered major intracardiac thrombosis. All cases of thrombosis occurred early, and none survived to hospital discharge. The lack of left ventricular ejection conferred a 46% risk of developing thrombosis compared to 0% if ejection was maintained (p = 0.0093). Aprotinin use was also associated with thrombus formation (p = 0.035). There were no significant differences between numbers of patients receiving other procoagulants when grouped by thrombosis versus no thrombosis. Stasis is the predominant risk factor for intracardiac thrombosis. This occurs rapidly and the outcome is poor. As a result, we suggest early left ventricular decompression. Conventional management of post-bypass coagulopathy seems safe if the aortic valve is opening.

Aprotinin in adults at high risk of major blood loss during isolated CABG with cardiopulmonary bypass: a profile of its use in the EU

Prophylactic treatment with aprotinin, a haemostatic antifibrinolytic agent, is indicated to reduce blood loss and blood transfusion in adults with a high risk of major bleeding undergoing primary or repeat isolated coronary artery bypass graft (CABG) with cardiopulmonary bypass. Overall, aprotinin was consistently more effective than tranexamic acid, e-aminocaproic acid, desmopressin and placebo in reducing massive blood loss, the need for transfusions of blood products, and the need for reoperation due to diffuse bleeding in trials in this patient population, and was generally well-tolerated. The approval of aprotinin in the EU was reinstated by the European Medicines Agency (EMA) in 2012, following subsequent analysis of the clinical data that led to its suspension in 2007. The EMA analysis concluded that the reduction in massive bleeding provided by aprotinin in patients undergoing isolated CABG is clinically relevant, as it reduces complications, the need for blood product transfusions and the length of hospital stay, without increasing mortality. The relaunch of aprotinin was accompanied by a risk management to assess the pattern of use and safety of aprotinin in clinical practice. Data from centres enrolled in the Nordic Aprotinin Patient Registry are being collected and will be assessed in the final report.

Proteasuria-The impact of active urinary proteases on sodium retention in nephrotic syndrome.

Sodium retention and extracellular volume expansion are typical features of patients with nephrotic syndrome. In recent years, from in vitro data, endoluminal activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases has been proposed as an underlying mechanism. Recently, this concept was supported in vivo in nephrotic mice that were protected from proteolytic ENaC activation and sodium retention by the use of aprotinin for the pharmacological inhibition of urinary serine protease activity. These and other findings from studies in both rodents and humans highlight the impact of active proteases in the urine, or proteasuria, on ENaC-mediated sodium retention and edema formation in nephrotic syndrome. Targeting proteasuria could become a therapeutic approach to treat patients with nephrotic syndrome. However, pathophysiologically relevant proteases remain to be identified. In this review, we introduce the concept of proteasuria to explain tubular sodium avidity and conclude that proteasuria can be considered as a key mechanism of sodium retention in patients with nephrotic syndrome.

Calculation Algorithm Reduces Protamine Doses Without Increasing Blood Loss or the Transfusion Rate in Cardiac Surgery: Results of a Randomized Controlled Trial

The aim of the study was to investigate whether the HeProCalc algorithm affects heparin and protamine dosage, postoperative blood loss, and transfusion rate. Randomized controlled trial. University hospital. The study comprised 210 cardiac surgery patients undergoing cardiac surgery with cardiopulmonary bypass. Twenty patients were excluded because of re-exploration for localized surgical bleeding (n = 9), violation of protocol (n = 2), aprotinin use (n = 3 and nadir body temperature <32°C (n = 6). Study participants were randomly assigned to either traditional heparin and protamine dosage based on body weight only (control group) or dosage based on the HeProCalc algorithm (intervention group). The initial median heparin dose was 32,500 IU (interquartile range [IQR] 30,000-35,000) in the intervention group compared with 35,000 IU (IQR 30,000-37,500) (p = 0.025) in the control group. The total heparin dose in the intervention group was 40,000 IU (IQR 32,500-47,500) compared with 42,500 IU (IQR 35,000-50,000) in the control group (p = 0.685). The total protamine dose was 210 mg (IQR 190-240) in the intervention group compared with 350 mg (IQR 300-380) (p < 0.001) in the control group. The ratio of total protamine to initial dose of heparin in the intervention group was 0.62 compared with 1.0 (p < 0.001). The amount of chest tube bleeding after 12 postoperative hours was 320 mL (IQR 250-460) in the intervention group compared with 350 mL (IQR 250-450) (p = 0.754) in the control group. Neither the transfusion rate nor postoperative blood loss differed significantly between the 2 groups. Use of the HeProCalc algorithm reduced protamine dosage and the protamine/heparin ratio after cardiopulmonary bypass compared with conventional dosage based on weight without significant effect on postoperative blood loss or the transfusion rate.

Corticosteroids and Other Anti-Inflammatory Strategies in Pediatric Heart Surgery: A National Survey of Practice.

The role of steroids to mitigate the deleterious effects of pediatric cardiopulmonary bypass (CPB) remains a matter of debate; therefore, we aimed to assess preferences in administering corticosteroids (CSs) and the use of other anti-inflammatory strategies in pediatric cardiac surgery. A 19-question survey was distributed to consultants in pediatric cardiac anesthesia from 12 centers across the United Kingdom and Ireland. Of the 37 respondents (37/60, 62%), 24 (65%) use CSs, while 13 (35%) do not use steroids at all. We found variability within 5 (41%) of the 12 centers. Seven consultants (7/24, 29%) administer CSs in every case, while 17 administer CSs in selected cases only (17/24, 71%). There was variability in the dose of steroid administration. Almost all consultants (23/24, 96%) administer a single dose at induction, and one administers a two-dose regimen (1/24, 4%). There was variability in CS indications. Most consultants (24/37, 66%) use modified ultrafiltration at the conclusion of CPB. Fifteen consultants (15/32, 47%) report the use of aprotinin, while only 3 use heparin-coated circuits (3/24, 9%). We found wide variability in practice in the administration of CSs for pediatric cardiac surgery, both within and between units. While most anesthetists administer CSs in at least some cases, there is no consensus on the type of steroid, the dose, and at which patient groups this should be directed. Modified ultrafiltration is still used by most of the centers. Almost half of consultants use aprotinin, while heparin-coated circuits are infrequently used.

Short-term outcome of cardiac surgery under cardiopulmonary bypass in patients who refuse transfusion: a controlled study

Although bloodless cardiac surgery has been successfully performed for many years, studies with controls permitting transfusion are few and their results inconclusive. This study compares the outcome of cardiac surgery on Jehovah's Witnesses (JW) refusing transfusion, with that of controls permitting transfusion if required. Data from 172 operations in 162 JW were compared with 172 matched controls. Risk factors, preoperative, operative, 48 hour postoperative variables, outcome data and transfusions were recorded. Preoperative and operative variables were similar in both groups except for more previous cardiac operations, and more frequent use of cell saver and aprotinin in JW, who bled less and had higher hemoglobin concentrations at all periods. Thirty-day mortality was higher in JW (9.9% vs. 3.5%; P=0.03) (Risk difference 6.4%; CI95%: 2.7-10.1). Nevertheless operative mortality was similar in both groups (9.9% vs. 7.6%; P=0.44). Mortality in low-risk subjects was higher in JW (8.9% vs. 1.0%; P=0.02) (Risk difference 7.9%; CI95%: 2.7-13.2). Moreover, death associated with hemorrhage and anemia tended to be more frequent in JW. Mortality of transfused controls (14.1%) and their matched JW (13.0%) was similar. In contrast, mortality of non-transfused controls was zero versus 6.3% in their matched JW (P=0.059). Low-risk JW had significantly higher mortality than controls. Bleeding related deaths tended to be more frequent in JW. Blood-sparing maneuvers should be intensively implemented in both JW and patients permitting transfusion in order to reduce bleeding and the need for transfusion with its harmful effects.

Safety of Perioperative Aprotinin Administration During Isolated Coronary Artery Bypass Graft Surgery: Insights From the ART (ArterialRevascularization Trial).

BackgroundThere is still uncertainty about the safety of aprotinin for coronary artery bypass graft surgery. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral versus single internal thoracic artery grafting. Many of the ART patients (≈30%) received perioperative aprotinin. We investigated the association between perioperative aprotinin administration and short‐term (in‐hospital) and long‐term outcomes by performing a post hoc analysis of the ART.Methods and ResultsAmong patients enrolled in the ART (n=3102) from 2004 to 2007, we excluded those who did not undergo surgery (n=18) and those with no information about use of perioperative aprotinin (n=9). Finally, 836 of 3076 patients (27%) received aprotinin. Propensity matching was used to select 536 pairs for final comparison. Aprotinin was also associated with an increased risk of hospital mortality (9 [1.7%] versus 1 [0.2%]; odds ratio, 9.12; 95% confidence interval [CI], 1.15–72.2; P=0.03), intra‐aortic balloon pump insertion (37 [6.9%] versus 17 [3.2%]; odds ratio, 2.26; 95% CI, 1.26–4.07; P=0.006), and acute kidney injury (102 [19.0%] versus 76 [14.2%]; odds ratio, 1.42; 95% CI, 1.03–1.97; P=0.03). Aprotinin was not associated with a lower incidence of transfusion (37 [6.9%] versus 28 [5.2%]; odds ratio, 1.34; 95% CI, 0.81–2.23; P=0.25) and reexploration (26 [4.9%] versus 19 [3.5%]; hazard ratio, 1.39; 95% CI, 0.76–2.53; P=0.28). At 5 years, all‐cause mortality was significantly increased in the aprotinin group (56 [10.6%] versus 38 [7.3%]; hazard ratio, 1.51; 95% CI, 1.0–2.28; P=0.045).ConclusionsIn the present post hoc ART analysis, aprotinin was associated with a significantly increased risk of early and late mortality.Clinical Trial Registration URL: http://www.isrctn.com. Unique identifier: ISRCTN46552265.