Use Of Aprotinin Research Articles

Effectiveness and Safety of Aprotinin Use in Thoracic Aortic Surgery

To determine the effectiveness and safety of aprotinin use in adult patients undergoing thoracic aortic surgery. Single-center, retrospective study. All cases performed at a single university hospital. Between January 2004 and December 2014, 846 adult patients underwent thoracic aortic surgery. Due to missing or duplicated data on primary outcomes, 314 patients were excluded. The final sample of 532 patients underwent surgery on the thoracic aorta. The patients were divided in the following 2 groups: 107 patients (20.1%) received aprotinin during the surgery, which represented the study group, whereas the remaining 425 patients (79.9%) underwent surgery without the use of aprotinin. To adjust for patient selection and preoperative characteristics, a propensity score-matched analysis was conducted. Mean total blood loss at 12 hours after surgery was similar between the 2 groups. The blood product transfusion rates did not differ in the 2 groups, except for the rate of fresh frozen plasma transfusion being significantly higher in the aprotinin group. Re-exploration for bleeding and the incidence of a major postoperative bleeding event were similar between the groups. Rates of in-hospital mortality, renal failure, and cerebrovascular accidents did not show any statistically significant difference. Aprotinin did not represent a risk factor for mortality over the long term (hazard ratio 1.14, 95% confidence interval 0.62-2.08, p = 0.66). The use of aprotinin demonstrated a limited effect in reducing postoperative bleeding and prevention of major bleeding events. Aprotinin did not adversely affect early outcomes and long-term survival.

Перспективи застосування апротиніну в щелепно-лицевій хірургії та стоматології (огляд літератури)

The article adduces the current experience of using of the aprotinin (inhibitor of proteolisis and kininogenesis) in the clinical medicine. We also highlighted the mechanism of its influence on the organizm and described the indications for it use with therapeutic purposes after surgical pain syndrome. We confirmed the effectivness of drugs based on aprotinin for the treatment in various pathological conditions, because of its anti-inflammatory, antifibrinolitic, antishock action. Nowadays, the drugs which contain the main active substance as aprotinin are used for the prevention and treatment of pancreatitis, pancreonecrosis, hyperfibrinolitic bleeding, complications after thrombolytic therapy and in cardiac surgery. Injection of aprotinin before surgery helps to prevent the development of diffuse bleeding during operation. The anti-inflammatory mechanism of aprotinin has multivalent character. The ability of aprotinin to reduce the production of proinflammatory interleukines and at the same time stimulates the appearance of anti-inflammatory interleukins that allows to use it for reducing of surgery trauma and postoperative pain syndrome. In addition, we presented the results of local application of products containing aprotinin ("Gordoх", "Contrical", "Tachokomb", "Aerus"), used by the physiotherapy. In this article we analyzed recent literature data on the use of aprotinin in clinical dental practice and maxillofacial surgery (treatment of the maxillofacial area soft tissue inflammation, complications of bone fractures, impacted lower third molars surgery). The ability of the aprotinin to reduce the symptoms of inflammation, improve microcirculation, heal postoperative wounds and its positive impact on haemodynamics makes it an alternative to dexamethasone while dealing with the pain and swelling. All above mentioned serves as a base for more widespread application of aprotinin in practical of dentistry and maxillofacial surgery.

Open heart surgery: Management of nonsurgical bleeding in the peri-operative period; 31/2-years institutional experience

BACKGROUND:Excessive perioperative bleeding remains a major complication following open heart surgery, resulting in increased morbidity and mortality of some patients in our institution.A study of the principal causes of excessive nonsurgical haemostatic perioperative bleeding,clinical evaluation,treatment and preventive strategies is justified.OBJECTIVE/AIM: To identify the causes of bleeding in patients with haemorrhage that did not require reexploration and assess the impact on the patient outcomes from different causes of nonsurgical bleeding perioperatively.MATERIALS AND METHOD: For a period of 31/2 years (March 2013 – February 2016), the National Cardiothoracic Center of Excellence,UNTH,Ituku/Ozalla,Enugu,Nigeria, partnered with different foreign cardiac missions (USA,UK and India) for the performance of open heart surgery.The case files of the patients managed in the envisaged period were retrieved and analyzed using SPSS, version 2.0(Chicago). The data analyzed were patients' demographics, the total number of open heart surgery cases, the number that had perioperative nonsurgical bleeding,clinical detection strategies,treatment and preventive modalities as well as the outcome.RESULTS: During the period,a total number of 78 cases of open heart surgery (OHS) were done.There were 43 males and 35 females, with a ratio of approximately 1.3:1.The youngest age was 5 months and the oldest was 74 years, with a mean of 11.1 +/-SD 0.05. Out of these 78 cases, a total of 7 patients had perioperative nonsurgical bleeding, giving a percentage of 9%.3 patients were noticed intraoperatively in the operating room (OR) while 4 were noticed postoperatively in the intensive care unit (ICU). Treatment included the use of tranexemic acid or aprotinin, fresh frozen plasma (FFP) or fresh whole blood, platelet concentrate and additional doses of protamine, when incomplete reversal of heparin was the cause.CONCLUSION: Detection of the cause(s) of nonsurgical bleeding without thromboelastography or platelet function analyzer can be quite challenging in our environment.Applying appropriate pharmacologic agents among other interventions can reduce allogenic blood requirements with their attendant complications.KEY WORDS:Perioperative,Open heart surgery (OHS),thromboelastography,platelet function analyzer.

Adult cardiac surgery blood/blood product utilization in the post aprotinin era: an 855 patient, community hospital, retrospective experience

Prior to 2008, when it was withdrawn, aprotinin use in cardiac surgery patients was associated with reduced bleeding and blood utilization, but studies linked its administration to increased patient mortality. We investigated (a) blood/blood product utilization between 2008 and 2013 at our community hospital heart center according to the type of surgery performed following the withdrawal of aprotinin and (b) clinical variables associated with increased patient blood utilization. Seven hundred nine patients were retrospectively investigated for blood/blood product utilization. Variables examined were patient age, body surface area (BSA), gender, preoperative creatinine level, hematocrit level, total cell saved blood (CSB) administered, cardiopulmonary bypass (CPB) time, type of surgical procedure performed, and preoperative clopidogrel usage. Variables (categorical and continuous) were placed into a forward stepwise regression model for the continuous outcome, packed red blood cell (PRBC) utilization. The stepwise function utilized a P value threshold of 0.25 for entering the model and 0.1 for leaving the model. For coronary artery bypass graft (CABG) surgery, use of PRBC was 29.26 % (0.75/1.44), of platelets was 14.18 % (0.24/0.72), of fresh frozen plasma (FFP) was 7.34 % (0.19/0.78), and of cryoprecipitate was 10.63 % (0.23/0.97) among our patient sample. [Data expressed as percent patient utilization, mean/S.D. in units transfused]. Increased age, smaller BSA, higher preoperative creatinine level, lower preoperative hematocrit level, longer CPB time, and increased CSB administration was associated with increased PRBC administration (P < 0.0001). At our community heart surgery center, with a multidisciplinary blood conservation program in place, expected increase in blood/blood product utilization following aprotinin withdrawal was not experienced.

Impact of Aprotinin - A Proteolytic Enzyme on Postsurgical Symptoms in Patients Undergoing Third Molar Surgeries.

Dealing with postoperative pain and inflammation remains an arena for never ending research. Different agents have been the subject of many studies to prevent the occurrence of unpleasant postoperative sequel. Extraction of third molars is often associated with significant deterioration in oral health related quality of life (physical, social and psychological) in immediate postoperative period. The complaints of pain, swelling and limitation of mouth opening, which ensue as a result of acute inflammatory response, are frequent consequences of postsurgical procedures involving extraction of impacted 3(rd) molars. Aprotinin, a naturally occurring protease inhibitor was assessed for its effectiveness in plummeting postsurgical pain and swelling, after surgical removal of impacted 3(rd) molars. Thirty randomly selected adult patients age ranging from 16-35 years, who required simultaneous surgical removal of bilateral impacted mandibular third molars were recruited. Before the surgical procedure, randomly selected side of the patient was injected with 1 m of 10,000 Kallikrein Inactivator Units (KIU) of aprotinin sub-mucosally around the surgical site and the contra lateral side with 1ml of isotonic saline as a control following which adequate local anaesthesia was obtained. The surgical removal of impacted 3(rd) molars was conducted in a similar manner on both test and control sides on all patients. Postoperatively, the patients were evaluated for pain and swelling for one week i.e., 1(st), 2(nd) and 7(th) day. It was observed that there was marked clinical reduction in postoperative pain and swelling. There were no adverse affects observed after using aprotinin. Since, the current pharmacologic agents being used have adverse effects and associated morbidity which still pose a problem, aprotinin a naturally occurring agent could be efficiently used after surgical extraction of 3(rd) molars in management of postsurgical symptoms and improve patient comfort and quality of life. In future, further studies with use of aprotinin in a large number of patients and comparative studies with other drugs are required.

Antifibrinolytic Use and Blood Transfusions in Pediatric Scoliosis Surgeries Performed at US Children’s Hospitals

Retrospective cohort study using the Pediatric Health Information Systems database. To determine the association between antifibrinolytic use and red cell transfusions in spinal fusion operations performed at 37 US Children's Hospitals. Evidence from randomized clinical trials and systematic reviews suggests that antifibrinolytic therapy can significantly reduce blood loss in children undergoing scoliosis surgery; however, the effectiveness of these agents as used in surgeries performed at US children's has not been studied. We included children aged 0-18 years with diagnoses indicating adolescent idiopathic scoliosis (AIS) or neuromuscular scoliosis (NMS) for whom a spinal fusion procedure was performed between January 1, 2006 and September 30, 2009. Patients with malignancy, trauma, coagulation disorders, or for whom a cell salvage device was employed were excluded. Multilevel logistic regression was used to determine associations between ε-aminocaproic acid (EACA), tranexamic acid (TXA), and aprotinin (APR) use and blood transfusions, controlling for patient and surgery characteristics. Cohorts consisted of 2722 AIS and 1547 NMS procedures. Antifibrinolytic use varied across hospitals (AIS 3.3%, interquartile range, 0%-42%; NMS 12 interquartile range, 0%-46%), and was significantly associated with NMS, posterior fusion, number of vertebrae fused. Overall, 15% of children received EACA, 7% TXA, and 2% APR. The median hospital-specific rate of red cell transfusions was 24% for AIS and 43% for NMS. In AIS operations, EACA use, but not TXA use, was associated with significantly lower odds of transfusion (odds ratio, 0.42; P<0.001 vs. odds ratio, 1.0; P=0.8). In NMS operations, neither EACA nor TXA use was associated with a decrease in odds of red cell transfusions. The effectiveness of antifibrinolytics as used outside of clinical trials is unclear and should continue to be explored. Future prospective research is needed to evaluate which administration protocols will most benefit patients, as well as to determine the comparative effectiveness of these drugs in the context of other blood conservation strategies.

The safety and efficacy of antifibrinolytic therapy in neonatal cardiac surgery.

BackgroundNeonates undergoing open-heart surgery are particularly at risk of postoperative bleeding requiring blood transfusion. Aprotinin has attained high efficacy in reducing the requirement for a blood transfusion following a cardiopulmonary bypass, but is seldom studied in the neonatal age group. The aim of this study was to compare the efficacy and adverse effects of aprotinin and tranexamic acid in neonates undergoing open-heart surgery at a single centre.MethodsBetween October 2003 and March 2008, perioperative data of 552 consecutive neonatal patients undergoing open-heart surgery in Children’s Hospital Boston were reviewed. Among them, 177 did not receive antifibrinolytic therapy (Group A); 100 were treated with tranexamic acid only (Group B); and 275 patients received aprotinin with or without tranexamic acid (Group C). Except for antifibrinolytic therapy, the anaesthesiological and surgical protocols remained identical. Postoperative complications and in-hospital mortality were the primary study endpoints.ResultsBody weight and Risk Adjustment for Congenital Heart Surgery (RACHS-1) scores were statistically comparable among the three groups. No statistically significant differences were observed between the duration of hospitalization, chest tube drainage, reexploration for bleeding, and kidney function impairment. In Group C, less blood was transfused within 24 hours than in GroupB. Operative mortality was similar among the three groups.ConclusionNo further risk and kidney injury were observed in the use of aprotinin in neonatal cardiac surgery, aprotinin demonstrated a reduced requirement for blood transfusion compared with tranexamic acid. Our data provide reasonable evidence that aprotinin and tranexamic acid are safe and efficacious as antifibrinolytic modalities in neonatal patients undergoing cardiac surgery.

Use of aprotinin to reduce blood loss and transfusion in major orthopedic surgery: a meta-analysis.

Conflicting reports have been published regarding the effectiveness and safety of aprotinin in reducing blood loss and transfusion in patients undergoing orthopedic surgery. We performed a meta-analysis to evaluate the effectiveness and safety of aprotinin in reducing blood loss and transfusion in major orthopedic surgery. MEDLINE, PubMed, EMBASE and Cochrane databases were searched for relevant studies. Only randomized controlled trials were eligible for this study. The weighted mean difference in blood loss, and number of transfusions per patient and the summary risk ratio of transfusion requirements, and deep-vein thrombosis (DVT) were calculated in the aprotinin-treated group and the control group. Eighteen randomized controlled trials involving 1276 patients were included. The use of aprotinin reduced total blood loss by a mean of 498.88 ml (95% confidence interval [CI]; -735.03 to -262.72), intra-operative blood loss by a mean of 246.11 ml (95% CI; -352.11 to -140.11), post-operative blood loss by a mean of 169.11 ml (95% CI; -234.06 to -105.55), the number of blood transfusions per patient by 0.93 units (95% CI; -1.36 to -0.51). Aprotinin led to a signficant reduction in transfusion requirements (RR 0.59; 95% CI; 0.51 to 0.69) and no increase in the risk of DVT (RR 0.58; 95% CI; 0.38 to 1.08). The meta-analysis shows that aprotinin could significantly reduce blood loss and blood transfusion requirements in patients undergoing orthopedic surgery, and it did not appear to increase the risk of DVT.

Hemostatic efficacy of latest-generation fibrin sealant after hepatic resection: a randomized controlled clinical study.

This randomized, controlled, single-blinded multicenter study evaluated the efficacy of latest-generation fibrin sealant containing synthetic aprotinin as fibrinolysis inhibitor as supportive treatment for hemostasis after elective partial hepatectomy. Adult subjects undergoing resection of at least one liver segment were assigned to treatment with fibrin sealant or manual compression with a surgical gauze swab if persistent oozing necessitated additional hemostatic measures after primary control of arterial and venous bleeding. The primary outcome measure was the proportion of subjects with intraoperative hemostasis at 4 min after start of randomized treatment application. Secondary efficacy outcome measures included intraoperative hemostasis at 6, 8, and 10 min, intra- and postoperative rebleedings, transfusion requirements, and drainage volume. Seventy subjects were randomized. Hemostasis at 4 min was achieved in 29/35 (82.9 %) fibrin sealant subjects compared with 13/35 (37.1 %) control subjects (p < 0.001). Significantly more fibrin sealant subjects achieved hemostasis at 6 (p < 0.001), 8 (p = 0.028), and 10 min (p = 0.017). The number of rebleedings was low in both study arms. Transfusion requirements and 48-h drainage volumes were similar between the study arms. No adverse events related to study treatment were reported. Fibrin sealant was shown to be safe and superior to manual compression in the control of parenchymal bleeding after hepatic resection. The use of synthetic aprotinin as fibrinolysis inhibitor further improves the safety margin of fibrin sealant by eliminating the risk of transmission of bovine spongiform encephalopathy and other bovine pathogens.

The Efficacy of Antifibrinolytic Drugs in Children Undergoing Noncardiac Surgery

Children undergoing major surgery are frequently exposed to a high risk of blood loss often requiring transfusion. Although the risks associated with blood product transfusion have considerably decreased over the last decade, transfusion is still associated with significant morbidity and mortality. Thus, rigorous efforts should be made to decrease surgical bleeding and the need for blood product transfusion. Antifibrinolytic drugs have been shown to be effective when used in both adult and pediatric surgical patients. While there are data in adults to support safety, data remain limited for pediatric patients. Since the restriction of aprotinin use in 2008, the most commonly used antifibrinolytic drugs have been the lysine analogs, tranexamic acid (TXA), and ε-aminocaproic acid, which inhibit the conversion of plasminogen to plasmin and decrease the degree of fibrinolysis. We performed a systematic review of the literature pertaining to the efficacy of antifibrinolytic drugs in children undergoing noncardiac surgery. During spine surgery, both TXA and ε-aminocaproic acid decrease blood loss and transfusion requirements; however, this information comes from small, mainly retrospective trials. Two prospective, randomized, controlled trials have tested the efficacy of TXA in children undergoing craniofacial surgery and have reported that TXA decreases transfusion requirements. Two pharmacokinetic trials were also recently published and are summarized in this review. No data have been published regarding the efficacy of TXA administration in the pediatric trauma population. Further data are still needed in this field of study, and we discuss some perspectives for future research.

Back to the future: medical reversals and perioperative medicine

While most of us were enjoying the pleasures of an idle summer, a publication in Mayo Clinic Proceedings created a stir in the esoteric world of evidence-based medicine. The subject of interest was medical reversal, a phenomenon in which ‘‘a medical practice is found to be inferior to some lesser or prior standard of care’’. Prasad et al. reviewed original articles published in the New England Journal of Medicine from 2001 to 2010 in their endeavour to determine if new evidence advanced, confirmed, or rejected current medical practices. Seven hundred fiftysix (56%) of the 1,344 manuscripts reviewed found a new therapy superior to an older treatment, 138 (10%) confirmed the utility of a current therapy, and 165 (12%) found new practices inferior to present care. One hundred forty-six (40%) of the 363 studies evaluating an existing medical practice found the current therapy inferior to a lesser or earlier standard of care. These rejections of current practice for an older treatment (or no treatment at all) cut across classes of medical care, including anesthesia. Cited examples from perioperative medicine included bispectral index monitoring, mild hypothermia for an intracranial aneurysm clipping, use of a pulmonary artery catheter for high-risk surgical patients, coronary revascularization before elective vascular surgery, epidurals in early labour, and use of aprotinin in cardiac surgery. The reaction to Prasad’s findings was swift and critical. An accompanying editorial stated, ‘‘[T]he proportion of medical reversals seems alarmingly high. At a minimum, it poses major questions about the validity and clinical utility of a sizeable portion of everyday medical care.’’ The blog, Science-Based Medicine, noted, ‘‘[T]his highlights the fact that some current practices are useless or less than optimal and need to be reexamined.’’ Even the New York Times got in on the action by leading with the headline, ‘‘Medical Procedures May Be Useless, or Worse.’’ Both the evidence base for medical practice and the practice itself were under attack. Patients and clinicians alike could be left wondering how a supposedly science-based practice could have been wrong so frequently. Prasad identified a common narrative among the reversals noting that, ‘‘[a]lthough there is a weak evidence base for some practice, it gains acceptance largely through vocal support from prominent advocates and faith that the mechanism of action is sound. Later, future trials undermine the therapy, but removing the contradicted practice often proves challenging.’’ Does this sound familiar? Let us consider the saga of perioperative beta-blockade from Prasad’s perspective of medical reversal. In 1996, Mangano published results of a 200-patient placebo-controlled trial evaluating a seven-day perioperative course of atenolol on a composite outcome of cardiac mortality and morbidity. Six patients who died in hospital were excluded. Of those surviving to hospital discharge, 12 of 99 placebo patients died within six months of surgery compared with four of 95 patients receiving atenolol (crude relative risk [RR] 0.35; 95% confidence interval [CI] 0.1 to 1.0). Several years later, Poldermans G. L. Bryson, MD (&) Department of Anesthesiology, The Ottawa Hospital, The University of Ottawa, 1053 Carling Avenue, Box 249C, Ottawa, ON K1Y 4E9, Canada e-mail: glbryson@ottawahospital.on.ca

No Effect of Aprotinin (Trasylol) on Degradation of Exogenous and Endogenous Glucagon in Human, Mouse and Rat Plasma

Traditionally, aprotinin (Trasylol™) has been added to plasma samples prior to glucagon analysis. However, the evidence for the need of aprotinin is sparse and based on results obtained when radioimmunoassay (RIA) techniques were still in their infancy. Using RIAs directed against both the C-terminus and a mid-region of glucagon, we challenged the classical view that aprotinin is necessary. Glucagon concentrations in pools of human, mouse and rat plasma (n=30, 25 and 16 of each, respectively) with and without addition of increasing amounts of exogenous glucagon (5, 10, 20, 40 and 60 pM) were similar irrespective of whether or not aprotinin had been added. To investigate whether individual variation occurs in human samples, we measured plasma from 20 patients with gastrointestinal diseases and 20 healthy subjects with or without addition of aprotinin. Again, measured amounts of glucagon, endogenous or added, were not affected by the presence of aprotinin. The effect of aprotinin, present at blood sampling or added later (30 and 60 minutes), on endogenous glucagon values was investigated in T2DM patients (n=5), before and after insulin-induced hypoglycemia. There were no differences between the four treatments. In conclusion, we found no support for use of aprotinin for prevention of glucagon degradation.

Antifibrinolytika und Blutgerinnung in der Kinderchirurgie - Was ist anders als beim erwachsenen Patienten?

More than 30 years ago the pioneering work of Andrew and co-workers showed that the coagulation system of children is different than from adult. They have introduced the term of "developmental hemostasis" to describe this phenomenon. They were able to show that the concentration of coagulation factors and inhibitors are age-dependent and therefore reference limits from adult practice cannot be transferred to children one to one. Numerous studies showed that the perioperative loss of blood, and thus the use of homologous blood could be limited by administering antifibrinolytic substances such as aprotinin. Other antifibrinolytics acting substances like Epsilon-aminocaproic acid (EACA) or tranexamic acid (TXA) tended to be misfits in routine clinical practice. In 2006, the publication of a retrospective study carried out by Mangano et al, in which considerable safety concerns were expressed with regard to aprotinin led to a significant rethinking of its clinical use. Two years later the results of the BART (Blood Conservation using antifibrinolytics in a Randomized Trial) study confirmed that there was an increased postoperative mortality associated with the use of aprotinin compared to TXA and EACA. In a few adult studies so far tranexamic acid was found to be comparably as effective as aprotinin. Although TXA is a long known drug available on the market for more than 50 years, the studies connecting factors of indication, dosage regimen and safety are limited especially in children and infants. This article highlights the differences in the coagulation system in children compared to adult as well as indication, dosage regimens and possible side effects of antifibrinolytic agents in children.

Pharmacologic Methods to Reduce Postoperative Bleeding in Adult Cardiac Surgery. A Mini-review

Because blood for transfusion is a scarce resource and since allogeneic transfusion may even be harmful, there is a growing awareness among surgeons and anesthesiologists regarding the use of multimodal blood conservation programs in cardiac surgery in order to reduce bleeding, transfusion and re-exploration. Pharmacologic methods should be part of a multimodal blood conservation programs. Three drugs for anti-fibrinolytic prophylaxis have been available for more than two decades: Aprotinin, tranexamic acid and epsilon aminocaproic acid. These drugs can be administered intravenously and topically in the pericardium during cardiac surgery. However, aprotinin marketing was temporarily suspended in 2007/2008 based on results from a randomized study indicating a risk for increased mortality associated with the use of aprotinin. This mini-review on the use of anti-fibrinolytic drugs and other pharmacologic methods to reduce perioperative bleeding in cardiac surgery is provided as aprotinin probably will become increasingly available again in several western countries. A number of randomised and observational studies suggest a minor advantage of aprotinin over the synthetic lysine analogues, which in contrast are cheaper and without the risk of anaphylactic reactions. Other drugs that have been used in order to reduce bleeding in cardiac surgery are recombinant activated factor VIIa, desmopressin and prothrombin complex concentrate, but the value and risks of these drugs in cardiac surgery needs further clarification. Every patient should be evaluated individually according to the risk/benefit ratio of any drug used. Safety issues as well as cost-effective analyses should be in focus in future clinical studies.

Antifibrinolytics attenuate inflammatory gene expression after cardiac surgery

Anti-inflammatory effects of tranexamic acid and aprotinin, used to abate perioperative blood loss, are reported and might be of substantial clinical relevance. The study of messenger ribonucleic acid synthesis provides a valuable asset in evaluating the inflammatory pathways involved. Whole-blood messenger ribonucleic acid expression of 114 inflammatory genes was compared pre- and postoperatively in 35 patients randomized to receive either placebo, tranexamic acid, or aprotinin. These results were further confirmed by reverse transcription-polymerase chain reaction. Of the 23 genes exhibiting independently altered postoperative gene expression levels, 8 were restricted to the aprotinin group only (growth differentiation factor 3, interleukin 19, interleukin 1 family member 7, transforming growth factor α, tumor necrosis factor superfamily 10, tumor necrosis factor superfamily 12, tumor necrosis factor superfamily 13B, vascular endothelial growth factor α), whereas both aprotinin and tranexamic acid altered gene expression of 3 genes as compared with placebo (FMS-related tyrosine kinase 3 ligand, growth differentiation factor 5, interferon-α8). In general, less upregulation of pro-inflammatory, and more upregulation of anti-inflammatory, genes was observed for patients treated with antifibrinolytics. Gene expression affected by aprotinin coded mostly for proteins that function through serine proteases. This study demonstrates that the use of tranexamic acid and aprotinin results in altered inflammatory pathways on the genomic expression level. We further demonstrate that the use of aprotinin leads to significant attenuation of the immune response, with several inhibitory effects restricted to the use of aprotinin only. The results aid in a better understanding of the targets of these drugs, and add to the discussion on which antifibrinolytic can best be used in the cardiac surgical patient.

The Association of Postcardiac Surgery Acute Kidney Injury with Intraoperative Systolic Blood Pressure Hypotension

Background. Postoperative acute kidney injury (AKI) is associated with high mortality and substantial cost after aortocoronary bypass graft (CABG) surgery. We tested the hypothesis that intraoperative systolic blood pressure variation is associated with postoperative AKI. Methods. We gathered demographic, procedural, blood pressure, and renal outcome data for 7,247 CABG surgeries at a single institution between 1996 and 2005. A development/validation cohort methodology was randomly divided (66% and 33%, resp.). Peak postoperative serum creatinine rise relative to baseline (%ΔCr) was the primary AKI outcome variable. Markers reflective of intraoperative systolic blood pressure variation were derived for each patient including (1) peak and nadir values (absolute and relative to baseline) and (2) excursion episodes beyond selected thresholds (by duration, frequency, and duration × degree). Each marker of systolic blood pressure variation was then separately evaluated for association with AKI using linear regression models with adjustment for several known risk factors (age, aprotinin use, congestive heart failure, previous myocardial infarction, baseline creatinine, bypass time, diabetes, weight, concomitant valve surgery, gender, and preoperative pulse pressure). Results. An association was identified between systolic blood pressure relative to baseline and postoperative AKI (P < 0.006). Conclusions. In CABG surgery patients, intraoperative systolic blood pressure decrease relative to baseline systolic blood pressure is independently associated with postoperative AKI.

Retrospective cohort analysis of a single dose of aprotinin use in children undergoing cardiac surgery: a single‐center experience

The great difference in side effects of aprotinin was noted in adult and pediatric fields in recent reports because aprotinin was suspended for safety reasons. The aim of this study is to describe associations between aprotinin using and red blood cells transfusion, renal injury, and mortality in pediatric with cardiac surgery. We retrospectively reviewed a cohort of 507 consecutive children who received a single dose of aprotinin (March-November 2007 before the FDA's decision for withdrawal of aprotinin) and a cohort of 494 consecutive children who did not receive aprotinin or other antifibrinolytic drugs (December 2007-August 2008). The two groups' demographics were assessed by the Aristotle basic complexity (ABC) propensity score. Postoperative blood loss was significantly reduced in the aprotinin group [P < 0.001, 95% confidence intervals (CI): 0.00-0.00], but postoperative red blood cell transfusion was not different between two groups (P = 0.4, 95% CI: 0.393-0.412). No statistical significant differences were noted in postoperative dialysis [0.39% vs. 0.40%, P = 0.98, OR: 0.974, 95% CI: 0.137-6.944] and intra-hospital mortality (2.37% vs. 1.82%, P: 0.547, OR:1.306, 95% CI: 0.546-3.129)) and reoperations for bleeding, thrombotic, and respiratory morbidity between two groups; however, the aprotinin group had temporarily a higher rate of 1.5-fold increased creatinine (class R) in the first postoperative 72 h (22.95% vs. 13.93%, P < 0.001, OR: 1.840, 95% CI: 1.323-2.560), a longer duration of mechanical intubation [6.50 (4.50-24.00) h vs. 6.00 (4.50-22.00) h, P = 0.004, 95% CI: 0.002-0.005] and a 0.55% increased clinical mortality (although not statistically significant). More complex surgery had a higher rate of the increased creatinine (class R) in the first postoperative 72 h (ABC level 3 + 4 vs. level 1 + 2, P = 0.017, OR: 0.599, 95% CI: 0.392-0.915). The multivariate analysis showed that age (<1 year), CPB >100 min, and the larger amount of transfusion (≥14 ml·kg(-1) ) were also important risk factors for the postoperative renal dysfunction (class R). Except reducing postoperative bleeding, we did not find other benefits of aprotinin. However, much higher postoperative creatinine levels, longer duration of mechanical ventilation, not less postoperative RBCs transfusion, and a 0.55% increased clinical mortality (although not statistically significant) were found in the aprotinin populations.

The risks associated with aprotinin use: a retrospective study of cardiac cases in Nova Scotia

In light of the concerns about the safety of aprotinin, we wanted to determine if aprotinin use during cardiac surgery was associated with an increased risk of mortality and morbidity compared with the use of tranexamic acid (TXA). We hypothesized that use of aprotinin is associated with a higher risk of adverse outcomes than use of TXA in our patient population. In this retrospective study at a single surgical centre, we examined primary in-hospital outcomes of postoperative mortality, new acute renal failure, and perioperative blood transfusion, and we also investigated secondary outcomes of stroke, infection, and prolonged stay in the intensive care unit (ICU). The effect of the type of antifibrinolytic on outcome was evaluated for aprotinin cases matched 1:1 with TXA cases using propensity score. This study included 3,340 patients who received antifibrinolytics during cardiac surgery (376 patients received aprotinin and 2,964 patients received TXA). Patients who received aprotinin were more often elderly and female; they were more commonly presented with congestive heart failure, atrial fibrillation, renal failure, and lower hemoglobin, and they underwent complex and/or urgent surgery. In the matched sample, in-hospital mortality was significantly higher in the aprotinin group (10.9%) compared with the TXA group (5.9%), and ICU stay >72 hr was significantly increased in the aprotinin group (30.0%) compared with the TXA group (21.7%). There was no significant difference in blood product administration between the two groups. Aprotinin was associated with an increased risk of in-hospital mortality and morbidity following cardiac surgery, and aprotinin was not associated with a decrease in blood product requirements. Continued use of aprotinin in cardiac surgery should follow careful consideration, weighing the demonstrated risks and potential advantages compared with other TXA.

Coronary artery bypass grafting after aprotinin: Are we doing better?

Cardiac surgery patients are treated with antifibrinolytic agents to reduce intra- and postoperative bleeding. Until 2007, lysine analogues (aminocaproic acid and tranexamic acid) and serine protease inhibitors (aprotinin) were recommended. In 2008, the U.S. Food and Drug Administration prohibited aprotinin use because of associated postoperative complications, including cerebrovascular accidents and renal failure. This work aimed at reevaluating the efficacy and safety of aprotinin versus tranexamic acid in patients undergoing elective coronary artery bypass surgery. Two groups were enrolled in this study. Group A (n=256), operated from January 2005 to August 2007, was treated with the half-Hammersmith aprotinin regime whereas group B (n=104), operated after 2008, was treated with the full-dose tranexamic acid regime. All patients were of low-risk profile, and underwent an elective, on-pump coronary artery bypass surgery. The main outcome measures were safety, assessed inrelation to thrombosis-related cardiac, cerebral, and renal events; and efficacy, investigated in terms of postoperative bleeding and infusions of blood products. Postoperatively, group B demonstrated greater bleeding during the operative and first postoperative days, and total bleeding (P values ≤ .001); a greater requirement of blood and/or blood products infusions (P=.024); higher postoperative acute renal failure rates (P=.028); lower platelet count (P=.002); and a higher postoperative increase in troponin levels (P<.0001). Among low-risk patients undergoing coronary artery bypass surgery, the half-Hammersmith aprotinin-based antifibrinolytic management proved to be more efficacious in terms of bleeding and consumption of blood products, with no evidence of associated increased rates of postoperative complications. Accordingly, the usage of aprotinin should be reconsidered for treatment among cohorts of low-risk cardiac patients.

Aprotinin, transfusions, and kidney injury in neonates and infants undergoing cardiac surgery

A significantly increased risk of acute kidney injury (AKI) with the prophylactic use of aprotinin has been reported in adults undergoing cardiac surgery, but not in children. Blood product transfusions have also been shown to carry an independent risk of AKI. The present study assessed associations between AKI, aprotinin, and transfusions in neonates and infants undergoing cardiac surgery. All neonates and infants undergoing surgery with cardiopulmonary bypass over a 42 month period, before and after the withdrawal of aprotinin, were included retrospectively. AKI was assessed by the Acute-Kidney-Injury-Network classifications. A propensity score was used to balance treated and untreated groups. Three hundred and ninety patients received aprotinin and 568 patients did not. Inverse probability of treatment weighting resulted in good balance between groups for baseline and surgical characteristics. Controls underwent surgery with smaller bypass circuits and fewer transfusions. After adjustment for the use of miniaturized circuits and for the year of surgery, no significant association between the incidence of AKI, dialysis, and aprotinin was noted. Red blood cell transfusions were associated with an increased risk of AKI and dialysis: odds ratios (ORs) 1.64 (1.12-2.41) and 2.07 (1.13-3.73), respectively; as were fresh frozen plasma transfusions, ORs 2.28 (1.68-3.09) and 3.11 (1.95-4.97), respectively. Platelet transfusions were associated with an increased risk of dialysis: OR 2.20 (1.21-4.01). Blood product transfusions, but not the prophylactic use of aprotinin, are significantly associated with AKI after cardiac surgery in neonates and infants.