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Journal of Clinical Anesthesia Jun 2022The concept of patient blood management (PBM) was introduced by the World Health Organization in 2011 and is defined as a "patient-focused, evidence-based and systematic... (Review)
Review
The concept of patient blood management (PBM) was introduced by the World Health Organization in 2011 and is defined as a "patient-focused, evidence-based and systematic approach for optimizing the management of patients and transfusion of blood products to ensure high quality and effective patient care". Patient blood management is a multimodal approach based on three pillars: optimization of blood mass, minimization of blood loss and optimization of patient tolerance to anaemia. Antifibrinolytics play a major role in cardiac surgery, where the risk of perioperative bleeding is high and affects a majority of patients, by effectively reducing bleeding, transfusions, re-operations, as well as their associated morbidity and mortality. They represent an essential part of the pharmacological arsenal of patient blood management. However, despite the trend towards high-level PBM practices, currently very few European countries have national PBM guidelines and these guidelines, taken as a whole, are heterogeneous in form and content. In particular, the use of antifibrinolytics in cardiac surgery is often not discussed in detail beyond general prophylactic use and any recommendations lack detail including choice of drug, dosing, and mode of administration. Thus, the implementation of PBM programs in Europe is still challenging. In 2021, the WHO published a new document highlighting the urgent need to close the gap in PBM awareness and implementation and announced their upcoming initiative to develop specific PBM implementation guidelines. This review aims first, to summarize the role played by fibrinolysis in haemostatic disorders; second, to give an overview of the current available guidelines in Europe detailing PBM implementation in cardiac surgery; and third, to analyse the place and use of antifibrinolytics in these guidelines.
Topics: Anemia; Antifibrinolytic Agents; Blood Loss, Surgical; Blood Transfusion; Cardiac Surgical Procedures; Hemorrhage; Humans
PubMed: 35065393
DOI: 10.1016/j.jclinane.2022.110654 -
International Journal of Molecular... Jul 2023Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical "magic shotgun". Until 2007, APR was widely used as an antithrombotic and... (Review)
Review
Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical "magic shotgun". Until 2007, APR was widely used as an antithrombotic and anti-inflammatory drug in cardiac and noncardiac surgeries for reduction of bleeding and thus limiting the need for blood transfusion. The ability of APR to inhibit proteolytic activation of some viruses leads to its use as an antiviral drug for the prevention and treatment of acute respiratory virus infections. However, due to incompetent interpretation of several clinical trials followed by incredible controversy in the literature, the usage of APR was nearly stopped for a decade worldwide. In 2015-2020, after re-analysis of these clinical trials' data the restrictions in APR usage were lifted worldwide. This review discusses antiviral mechanisms of APR action and summarizes current knowledge and prospective regarding the use of APR treatment for diseases caused by RNA-containing viruses, including influenza and SARS-CoV-2 viruses, or as a part of combination antiviral treatment.
Topics: Humans; Aprotinin; SARS-CoV-2; Prospective Studies; COVID-19; Antiviral Agents; Respiration Disorders
PubMed: 37446350
DOI: 10.3390/ijms241311173 -
The Physician and Sportsmedicine May 2020Patellar tendinopathy, or jumper's knee is a common musculoskeletal condition characterized by progressive activity-related pain on the anterior aspect of the knee and... (Review)
Review
Patellar tendinopathy, or jumper's knee is a common musculoskeletal condition characterized by progressive activity-related pain on the anterior aspect of the knee and tenderness on the patellar tendon. A conservative method is often the first choice of treatment, which can include anti-inflammatory medication, injection therapies, physiotherapy, eccentric exercises, extra corporeal shock wave therapy, orthosis, etc. Although there are several treatment options available, the management of patellar tendinopathy is still controversial. The literature reveals many different injection methods are being used by clinicians for the treatment of patellar tendinopathy. Platelet rich plasma, corticosteroids, autologous blood, and aprotinin are the most commonly used injection treatments. Injection therapies give promising results in the management of Patellar tendinopathy. However, due to low quality research and variation in the protocol and population it is difficult to provide a firm conclusion on its effectiveness. More high-quality clinical studies are recommended to determine the effectiveness of injections and at which stage of Patellar tendinopathy they are the most effective. This review can provide insight to clinicians involved in the management of this condition.
Topics: Adrenal Cortex Hormones; Aprotinin; Blood; Humans; Hyaluronic Acid; Injections; Male; Patellar Ligament; Platelet-Rich Plasma; Prolotherapy; Sclerosing Solutions; Serine Proteinase Inhibitors; Tendinopathy; Viscosupplements
PubMed: 31539489
DOI: 10.1080/00913847.2019.1671143 -
Expert Review of Cardiovascular Therapy Nov 2022Cardiopulmonary bypass (CPB) is an integral component of cardiac surgery; however, one of its most critical complications is acute lung injury induced by multiple... (Review)
Review
INTRODUCTION
Cardiopulmonary bypass (CPB) is an integral component of cardiac surgery; however, one of its most critical complications is acute lung injury induced by multiple factors including systemic inflammatory response.
AREAS COVERED
The objective of this review is to investigate the multiple factors that can lead to CPB-induced lung injury. These include contact of blood components with the artificial surface of the CPB circuit, local and systemic inflammatory response syndrome (SIRS), lung ischemia/re-perfusion injury, arrest of ventilation, and circulating endotoxins. We also focus on possible interventions to curtail the negative impact of CPB, such as off-pump surgery, impregnation of the circuit with less biologically active substances, leukocyte depletion filters and ultrafiltration, and pharmacological agents such as steroids and aprotinin.
EXPERT OPINION
Although many aspects of CPB are proposed to contribute to lung injury, its overall role is still not clear. Multiple interventions have been introduced to reduce the risk of pulmonary dysfunction, with many of these interventions having shown promising results, significantly attenuating inflammatory mediators and improving post-operative outcome. However, since lung injury is multifactorial and affected by inextricably linked components, multiple interventions tackling each of them is required.
Topics: Humans; Cardiopulmonary Bypass; Lung Injury; Lung; Cardiac Surgical Procedures; Inflammation Mediators
PubMed: 36408601
DOI: 10.1080/14779072.2022.2149492 -
Cells Oct 2020Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is the cause of the current coronavirus disease 19 (COVID-19) pandemic. Protease inhibitors are under...
Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is the cause of the current coronavirus disease 19 (COVID-19) pandemic. Protease inhibitors are under consideration as virus entry inhibitors that prevent the cleavage of the coronavirus spike (S) protein by cellular proteases. Herein, we showed that the protease inhibitor aprotinin (but not the protease inhibitor SERPINA1/alpha-1 antitrypsin) inhibited SARS-CoV-2 replication in therapeutically achievable concentrations. An analysis of proteomics and translatome data indicated that SARS-CoV-2 replication is associated with a downregulation of host cell protease inhibitors. Hence, aprotinin may compensate for downregulated host cell proteases during later virus replication cycles. Aprotinin displayed anti-SARS-CoV-2 activity in different cell types (Caco2, Calu-3, and primary bronchial epithelial cell air-liquid interface cultures) and against four virus isolates. In conclusion, therapeutic aprotinin concentrations exert anti-SARS-CoV-2 activity. An approved aprotinin aerosol may have potential for the early local control of SARS-CoV-2 replication and the prevention of COVID-19 progression to a severe, systemic disease.
Topics: Animals; Antiviral Agents; Aprotinin; COVID-19; Caco-2 Cells; Chlorocebus aethiops; Epithelial Cells; Humans; Pandemics; SARS-CoV-2; Serine Proteinase Inhibitors; Vero Cells; Virus Replication; COVID-19 Drug Treatment
PubMed: 33143316
DOI: 10.3390/cells9112377 -
European Journal of Anaesthesiology Apr 2022The relicensing of aprotinin in Europe and Canada has stimulated discussions on its usefulness in paediatric cardiac surgery. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The relicensing of aprotinin in Europe and Canada has stimulated discussions on its usefulness in paediatric cardiac surgery.
OBJECTIVE
To systematically evaluate the available evidence on the efficacy and safety of aprotinin in paediatric cardiac surgery.
DESIGN
Systematic review of all randomised and observational studies comparing aprotinin with tranexamic acid, epsilon aminocaproic acid, placebo or no drug in paediatric cardiac surgery. Meta-analyses were performed on efficacy and safety outcomes.
DATA SOURCES
PubMed, Cochrane Central Register of Controlled Trials, Web of Science and Embase were searched from January 2000 to March 2021.
ELIGIBILITY CRITERIA
Studies that enrolled children under 18 years undergoing cardiac surgery with cardiopulmonary bypass.
RESULTS
Thirty-two studies enrolling a total of 63 894 paediatric cardiac procedures were included. Aprotinin significantly reduced total blood loss [mean difference -4.70 ml kg-1, 95% confidence interval (CI), -7.88 to -1.53; P = 0.004], postoperative transfusion requirements and the incidence of surgical re-exploration for bleeding [odds ratio (OR) 0.74, 95% CI, 0.56 to 0.97; P = 0.03]. Aprotinin had no effects on 30-day mortality (OR 1.02, 95% CI, 0.93 to 1.11; P = 0.73) and on other safety outcomes, except for the incidence of renal replacement therapy (RRT), which was significantly increased in patients given aprotinin (OR 1.29, 95% CI, 1.08 to 1.54; P = 0.006). Findings from observational and randomised controlled trials did not largely differ. A sub-group analysis in neonates showed that aprotinin significantly reduced packed red blood cell transfusions and the incidence of postoperative surgical re-exploration for bleeding and/or tamponade. When compared with lysine analogues, aprotinin was more effective at reducing bleeding and transfusion without increasing the risk of side effects.
CONCLUSION
This meta-analysis suggests that aprotinin is effective and well tolerated in paediatric cardiac surgery. Given the large heterogeneity of the results and the risk of selection bias in observational studies, large randomised controlled trials are warranted.
Topics: Adolescent; Antifibrinolytic Agents; Aprotinin; Blood Loss, Surgical; Cardiac Surgical Procedures; Child; Humans; Tranexamic Acid
PubMed: 34783684
DOI: 10.1097/EJA.0000000000001632 -
Current Opinion in Nephrology and... Mar 2020Proteinuria in nephrotic syndrome is associated with sodium retention and edema. Recent studies from mice, rats and humans have shown that the sodium retention depends... (Review)
Review
PURPOSE OF REVIEW
Proteinuria in nephrotic syndrome is associated with sodium retention and edema. Recent studies from mice, rats and humans have shown that the sodium retention depends on urinary serine proteases and that it can be mitigated by blockers (amiloride, triamterene) of the epithelial sodium channel ENaC. The present review outlines the mechanisms of protease-stimulated sodium retention during proteinuric diseases.
RECENT FINDINGS
Inhibition of protease activity in nephrotic mice using aprotinin alleviates sodium retention. From both human and mice studies, an increased proteolytic cleavage of the γENaC subunit plays a role in ENaC activation. In animal models, urokinase-plasmin contributes but not as sole mediators of sodium retention. Across experimental models, human case reports and small intervention trials, amiloride alleviates nephrotic sodium retention and low-renin hypertension with high efficacy.
SUMMARY
Although the exact mechanisms for proteolytic ENaC activation are not resolved, multiple, redundant proteases are involved. Experimental and clinical evidence indicate that aberrant proteolytic ENaC activation is a primary driver of sodium retention in nephrotic syndrome and contributes to hypertension in conditions with low-grade proteinuria. Thus, we foresee increased and personalized use of amiloride treatment of nephrotic and other proteinuric disease patients with associated sodium retention and hypertension.
Topics: Animals; Epithelial Sodium Channels; Humans; Hypertension; Nephrotic Syndrome; Sodium
PubMed: 31789848
DOI: 10.1097/MNH.0000000000000578 -
The Journal of Surgical Research Jul 2021Acute mesenteric ischemia arises through sudden interruption of mesenteric blood flow, mostly due to an occlusion of the superior mesenteric artery and is associated...
BACKGROUND
Acute mesenteric ischemia arises through sudden interruption of mesenteric blood flow, mostly due to an occlusion of the superior mesenteric artery and is associated with a high mortality of approximately 50% to 90%. In previous studies, the single application of β-alanine or aprotinin caused an ameliorated intestinal damage but without any systemic effects.
METHODS
To analyze the combined effect of β-alanine and aprotinin on acute ischemia and reperfusion of the small intestine, a model with anesthetized rats was used. Ischemia and reperfusion were initiated by occluding and reopening the superior mesenteric artery. After 120 min of ischemia and 180 min of reperfusion, the intestine was analyzed for tissue damage, the activity of the saccharase, and accumulation of granulocytes. In addition, systemic and metabolic as well as inflammatory parameters were measured in blood at certain points in time.
RESULTS
The combination of β-alanine and aprotinin resulted in a clearly stabilized mean arterial blood pressure and blood glucose level during the reperfusion period. Furthermore, the combined administration resulted in significantly reduced tissue damage parameters, cytokine and cell-free hemoglobin concentrations in blood plasma. In addition, the damage to the small intestine was significantly attenuated, so that the animals ultimately survived the entire test period because of the administration of both substances.
CONCLUSIONS
Overall, the simultaneous application of both substances leads to a synergistic protection without the occurrence of undesirable side effects. The combined usage of β-alanine and aprotinin can be seen as a promising approach to inhibit the onset of acute mesenteric ischemia.
Topics: Animals; Aprotinin; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Humans; Injections, Intralesional; Intestinal Mucosa; Male; Mesenteric Artery, Superior; Mesenteric Ischemia; Rats; Reperfusion Injury; beta-Alanine
PubMed: 33639373
DOI: 10.1016/j.jss.2021.01.026 -
Current Drug Targets 2021Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic... (Review)
Review
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic management remains the standard of care. Repurposing of many existing drugs, including several anti-viral drugs, is being attempted to tackle the COVID-19 pandemic. However, most of them have failed to show significant benefit in clinical trials. An attractive approach may be to target host proteases involved in SARS-CoV-2 pathogenesis. The priming of the spike (S) protein of the virus by proteolytic cleavage by the transmembrane serine protease-2 (TMPRSS2) is necessary for the fusion of the virus to the host cell after it binds to its receptor angiotensin converting enzyme-2 (ACE2). There are other proteases with varying spatiotemporal locations that may be important for viral entry and subsequent replication inside the cells, and these include trypsin, furin and cathepsins. In this report, we have discussed the tentative therapeutic role of inhibitors of TMPRSS2, cathepsin, trypsin, furin, plasmin, factor X and elastase in infection caused by SARS-CoV-2. Both available evidence, as well as hypotheses, are discussed, with emphasis on drugs which are approved for other indications such as bromhexine, ammonium chloride, nafamostat, camostat, tranexamic acid, epsilon amino-caproic acid, chloroquine, ulinastatin, aprotinin and anticoagulant drugs. Simultaneously, novel compounds being tested and problems with using these agents are also discussed.
Topics: Angiotensin-Converting Enzyme 2; Antiviral Agents; COVID-19; Clinical Trials as Topic; Drug Repositioning; Humans; SARS-CoV-2; Serine Endopeptidases; Serine Proteinase Inhibitors; Spike Glycoprotein, Coronavirus; Virus Internalization
PubMed: 32972339
DOI: 10.2174/1389450121666200924113243 -
Journal of Neurosurgery. Pediatrics May 2022Craniosynostosis surgery is associated with considerable blood loss and need for transfusion. Considering the lower estimated blood volume (EBV) of children compared to... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of aprotinin versus tranexamic acid for reducing absolute blood loss and transfusion in pediatric patients undergoing craniosynostosis surgery: a randomized, double-blind, three-arm controlled trial.
OBJECTIVE
Craniosynostosis surgery is associated with considerable blood loss and need for transfusion. Considering the lower estimated blood volume (EBV) of children compared to adults, excessive blood loss may quickly lead to hypovolemic shock. Therefore, reducing blood loss is important in craniosynostosis surgery. This study was conducted to evaluate the efficacy of aprotinin or tranexamic acid (TXA) in blood loss reduction in these patients.
METHODS
In the current randomized controlled trial, 90 eligible pediatric patients with craniosynostosis were randomly divided into three groups to receive either aprotinin, TXA, or no intervention. The absolute blood loss and transfusion amount were assessed for all patients both intraoperatively and 2 and 8 hours postoperatively.
RESULTS
Although crude values of estimated blood loss were not significantly different between groups (p = 0.162), when adjusted to the patient's weight or EBV, the values reached the significance level (p = 0.018), particularly when the aprotinin group was compared to the control group (p = 0.0154). The EBV losses 2 hours and 8 hours postoperatively significantly dropped in the TXA and aprotinin groups compared to the control group (p = 0.001 and p < 0.001, respectively). Rates of postoperative blood transfusion were significantly higher in the control group (p = 0.024). Hemoglobin and hematocrit 8 hours postoperatively were lower in the control group than in the TXA or aprotinin treatment groups (p < 0.002 and p < 0.001, respectively). There were no serious adverse events associated with the interventions in this study.
CONCLUSIONS
Aprotinin and TXA can reduce blood loss and blood transfusion without serious complications and adverse events in pediatric patients undergoing craniosynostosis surgery.
Topics: Adult; Child; Humans; Tranexamic Acid; Aprotinin; Antifibrinolytic Agents; Blood Loss, Surgical; Blood Transfusion; Craniosynostoses; Double-Blind Method
PubMed: 35148511
DOI: 10.3171/2021.12.PEDS21532