Aprotinin Group Research Articles

Comparative evaluation of the effects of tranexamic acid and low-dose aprotinin on post-valvular heart surgery bleeding and allogenic transfusion

Bleeding diathesis and allogenic transfusion after complex heart surgery, such as heart valve surgery, may result in complications such as transfusion reaction, viral infection, postoperative infection, haemodynamic disturbance, prolonged stay in the intensive care unit and hospital, renal and respiratory failure and mortality. In this prospective, double-blind, randomized, placebo-controlled clinical trial, 90 patients were randomly divided into three groups: aprotinin, tranexamic acid and control. Chest-tube drainage, transfusion requirements and renal and neurological complications were evaluated. We found that chest-tube drainage during the first (P < 0.0001) and second 24 h (P = 0.001) after admission to the intensive care unit were significantly lower in the aprotinin group. The amounts of transfused packed red blood cells (P < 0.0001) and platelets (P = 0.02) were significantly lower in the aprotinin and tranexamic acid groups. The quantity of transfused fresh frozen plasma (P = 0.034) was significantly lower in the aprotinin group only. We did not find any neurological complications or renal failure in the three groups. Our data suggest that in valvular heart surgery, low-dose aprotinin is significantly better than tranexamic acid or a placebo for reduction of postoperative bleeding and allogenic transfusion, without increasing adverse outcomes.

High‐dose aprotinin, blood product transfusions, and short‐term outcome in neonates and infants: a pediatric cardiac surgery center experience

The efficacy of aprotinin, the most popular antifibrinolytic agent in congenital cardiac surgery, was still uncertain in small infants when its prophylactic use was suspended for safety reasons. The aim of this study is to describe associations between the prophylactic use of high-dose aprotinin, the need for blood product transfusions, and short-term outcome in neonates and infants with cardiac surgery. This retrospective study included all patients younger than 1 year undergoing surgery with cardiopulmonary bypass through 42 months, before and after withdrawal of aprotinin. Each patient who received aprotinin was matched with a control with similar baseline and surgical characteristics, who have not received any antifibrinolytic agent. Associations between the use of aprotinin and the exposure to red blood cells, fresh frozen plasma, and platelet transfusions were estimated from a logistic regression model, and the exposure to additional transfusions from a polytomous regression model. Matching resulted in two groups of 283 patients each, well balanced except for the priming volume and the ultrafiltration rate, larger in the aprotinin group. After adjustment for the priming volume and ultrafiltration rate, there was no significant association between the use of aprotinin, the exposure to any blood product transfusion, or the exposure to additional transfusions, the rate of re-exploration for bleeding, and short-term outcome. Two patients in the control group required re-exploration for bleeding. No association was found between the prophylactic use of aprotinin, blood product transfusions, and short-term outcome in this population of neonates and infants.

Evaluation of microemulsion and liposomes as carriers for oral delivery of transforming growth factor alpha in rats

The aim of the present study is to develop microemulsion and liposome carrier systems for oral administration of transforming growth factor alpha (TGF-α) and to investigate the effects of these carrier systems on the gastrointestinal efficiency in rats. Microemulsion (w/o) and liposomes (MLV) were developed and characterised. The carrier systems were administered intragastrically by gastric cannula to male Wistar rats. The highest reduction in the basal acid secretion was observed in the microemulsion containing TGF-α and aprotinin group (TAME).The gastric mucus secretion in microemulsion containing TGF-α (TME) and TAME treatment groups increased significantly compared to the other groups. TGF-α levels in both stomach and duodenum were significantly increased in the TAME group. As a result, it was determined through confocal laser scanning microscope (CLSM) studies that exogenous-applied TGF-α attached to endogenous EGF receptors. The microemulsion formulation was found to be a more suitable carrier system for oral administration of TGF-α.

EComment. Impact of clopidogrel on bleeding complications and survival in off-pump coronary artery bypass grafting

Bittner et al. [1] provide interesting data with regard to clopidogrel and Aprotinin use and long-term survival post coronary artery bypass graft (CABG). A number of issues however need to be addressed prior to adopting their recommendations. Firstly identification of Aprotinin as a potentially harmful agent was delayed due to the large number of inadequately powered studies confirming its effects on reducing blood loss, but inadequately powered with regard to complications and long-term survival [2]. Any study utilising 213 Aprotinin treated patients in two limbs is underpowered, and risks repeating previous mistakes. Secondly univariate analysis of survival (Kaplan-Meier) is statistically unsafe in situations where numerous significant factors determine long-term survival, hence the technique of Cox regression analysis. As Bittner has not adjusted for any significant confounding variables the conclusions drawn are potentially incorrect. We have recently described [3] age, diabetes, left ventricle function, body mass index, peripheral vascular disease, dialysis, left internal mammary artery (LIMA) usage, EuroSCORE, and creatinine kinase muscle-brain isotype (CKMB) as factors that would need to be included in the Cox analysis. The risk survival figure obtained would then need to be plotted at the mean of the covariates to assess the effect of clopidogrel. Thirdly from their analysis it is impossible to separate the timing of stopping of clopidogrel and its use post operatively, on the benefit on long term survival. Assessment of platelet function pre operatively may enable an 'optimum' platelet inhibition range to be identified where the rate of bleeding and blood product utilisation is at a minimum and long-term survival is at a maximum. In addition the dose and anti platelet effect of aspirin was not mentioned in the manuscript. Fourthly recommending Aprotinin usage would seem incongruent with their data as the combined clopidogrel Aprotinin group had the worst long-term survival of 79.7% compared to clopidogrel alone 93.8%. Lastly, no studies exist as to the beneficial effect of blood transfusion on long term survival, in the absence of catastrophic haemorrhage [4]. This makes the recommendation of a technique that increases transfusion requirements as a ‘high risk approach’. Adopting a surgical strategy that involves increased blood product administration and the utilisation of Aprotinin seems intuitively incorrect, however adequately powered and analysed studies are needed. Conflict of Interest: None declared

Is tranexamic acid really an alternative to aprotinin?

In the April 2011 issue, Schindler et al. [1] presented tranexamic acid as an adequate alternative to aprotinin for antifibrinolytic therapy in pediatric congenital heart surgery. They compared postoperative blood loss and transfusion requirements between two periods of time – a former one with aprotinin and a later one with tranexamic acid – and noted no difference. This conclusion cannot be drawn from their results. The precondition for such study must be that the aprotinin and the tranexamic acid groups are comparable. This precondition is more than questionable because there are striking differences between the two groups: significant differences were observed in the preoperative coagulation values (Table 1), the time of aortic clamping and the amount of intraoperative platelets (Table 2), the postoperative fluid balance (Table 3) and the postoperative coagulation values (Table 4) [1]. For example, the higher preoperative laboratory values of fibrinogen and platelets favour the aprotinin group, whereas the higher amount of intraoperative platelets, the more negative postoperative fluid balance and the shorter postoperative PTT favour the tranexamic acid group. The authors themselves admit that there was a lower average mortality and an increase in the ‘surgical performance’ during the tranexamic acid period. This may simply explain why tranexamic acid was not inferior to aprotinin. The opposite is the case if the two periods of time are really comparable as we could demonstrate recently [2]. Due to the lack of prospective randomized controlled trials, currently retrospective cohort studies are needed to assess the effectiveness (and the side effects) of antifibrinolytic drugs in pediatric cardiac surgery. However, these retrospective cohort studies have to be well controlled which is not the case for the present study by Schindler et al. [1] Therefore, the question if tranexamic acid is a suitable substitute to aprotinin to reduce blood loss and transfusion requirements in pediatric cardiac surgery remains open. With regard to possible side effects [2–5], its off-label use should be limited to individual cases where the probable benefits outweigh the risks.

The Effect of Antifibrinolytic Prophylaxis on Postoperative Outcomes in Patients Undergoing Cardiac Operations

Antifibrinolytic agents such as aprotinin and epsilon aminocaproic acid limit postoperative bleeding and blood transfusion in patients undergoing cardiac operations using cardiopulmonary bypass (CPB). Recent evidence suggests that these agents have adverse side effects that influence operative mortality and morbidity. We studied postoperative bleeding, transfusion rates, and operative outcomes in our patients in order to assess the efficacy of these agents during cardiac operations requiring CPB. We reviewed records of 520 patients undergoing a variety of cardiac operations between January 2005 and May 2009. We measured multiple variables including pre-operative risk factors, antifibrinolytic agent used, and outcomes of operation, such as measures of bleeding and blood transfusion, as well as serious operative morbidity and mortality. Postoperative bleeding rates varied significantly between patients receiving aprotinin and those receiving aminocaproic acid (P < 0.05). There was an associated 12% decrease in operative site bleeding in aprotinin-treated patients compared with aminocaproic acid. There was no significant difference in the transfusion rates of packed red blood cells between patients receiving aminocaproic acid or aprotinin (P > 0.05), though individuals in the aprotinin group did receive FFP more frequently than patients in the aminocaproic acid group (P < 0.05). There was no significant difference in morbidity and mortality rates between patients in either drug group (P > 0.05). Our study shows that aprotinin is more effective at controlling operative site bleeding than aminocaproic acid. Reduced operative site bleeding did not portend better outcome or differences in transfusion requirements. Aminocaproic acid remains a safe and cost-effective option for antifibrinolytic prophylaxis because of unavailability of aprotinin.

Differential effects of aprotinin and tranexamic acid on outcomes and cytokine profiles in neonates undergoing cardiac surgery

Factors contributing to postoperative complications include blood loss and a heightened inflammatory response. The objective of this study was to test the hypothesis that aprotinin would decrease perioperative blood product use, reduce biomarkers of inflammation, and result in improved clinical outcome parameters in neonates undergoing cardiac operations. This was a secondary retrospective analysis of a clinical trial whereby neonates undergoing cardiac surgery received either aprotinin (n = 34; before May 2008) or tranexamic acid (n = 42; after May 2008). Perioperative blood product use, clinical course, and measurements of cytokines were compared. Use of perioperative red blood cells, cryoprecipitate, and platelets was reduced in neonates receiving aprotinin compared with tranexamic acid (P < .05). Recombinant activated factor VII use (2/34 [6%] vs 18/42 [43%]; P < .001), delayed sternal closure (12/34 [35%] vs 26/42 [62%]; P = .02), and inotropic requirements at 24 and 36 hours (P < .05) were also reduced in the aprotinin group. Median duration of mechanical ventilation was reduced compared with tranexamic acid: 2.9 days (interquartile range: 1.7-5.1 days) versus 4.2 days (2.9-5.2 days), P = .04. Production of tumor necrosis factor and interleukin-2 activation were attenuated in the aprotinin group at 24 hours postoperatively. No differential effects on renal function were seen between agents. Aprotinin, compared with tranexamic acid, was associated with reduced perioperative blood product use, improved early indices of postoperative recovery, and attenuated indices of cytokine activation, without early adverse effects. These findings suggest that aprotinin may have unique effects in the context of neonatal cardiac surgery and challenge contentions that antifibrinolytics are equivalent with respect to early postoperative outcomes.

Early Postoperative Outcomes and Blood Product Utilization in Adult Cardiac Surgery

Aprotinin was a commonly used pharmacological agent for homeostasis in cardiac surgery but was discontinued, resulting in the extensive use of lysine analogues. This study tested the hypothesis that early postoperative adverse events and blood product utilization would affected in this post-aprotinin era. Adult patients (n=781) undergoing coronary artery bypass, valve replacement, or both from November 1, 2005, to October 31, 2008, at a single institution were included. Multiple logistic regression modeling and propensity scoring were performed on 29 preoperative and intraoperative variables in patients receiving aprotinin (n=325) or lysine analogues (n=456). The propensity-adjusted relative risk (RR) for the intraoperative use of packed red blood cells (RR, 0.75; 95% confidence interval [CI], 0.57 to 0.99), fresh frozen plasma (RR, 0.37; 95% CI, 0.21 to 0.64), and cryoprecipitate (RR:0.06; 95% CI, 0.02 to 0.22) were lower in the aprotinin versus lysine analog group (all P<0.05). The risk for mortality (RR, 0.53; 95% CI, 0.16 to 1.79) and neurological events (RR, 0.87; 95% CI, 0.35 to 2.18) remained similar between groups, whereas a trend for reduced risk for renal dysfunction was observed in the aprotinin group. In the post-aprotinin era, with the exclusive use of lysine analogues, the relative risk of early postoperative outcomes such as mortality and renal dysfunction have not improved, but the risk for the intraoperative use of blood products has increased. Thus, improvements in early postoperative outcomes have not been realized with the discontinued use of aprotinin, but rather increased blood product use has occurred with the attendant costs and risks inherent with this strategy.

Haemostatic effect of aprotinin during craniosynostotic surgery in children

Aprotinin has been used in our hospital since the year 2003 to reduce bleeding during craniosynostotic surgery in children. The aim of this retrospective study was to investigate its effect, primarily on bleeding and secondarily on the need for transfusion. Thirteen children were treated with aprotinin from 2003 to 2008, while 39 were not treated in the period 1993-2002. Information on blood loss and need for transfusion during the operations in all 52 children was collected from their medical records. There was a significant difference in both blood loss and need for transfusion. Estimated blood volume was used to correct for difference in the children's age and size. In the aprotinin group, blood loss was 3.9% of circulating blood volume vs. 22.0%, and the need for transfusion was 0.0% vs. 21.1%. Blood loss and need for blood transfusion were significantly reduced in the aprotinin group. No allergic or other possible aprotinin-specific complications were registered in the aprotinin group.

Efficacy and Safety of Aprotinin in Neonatal Congenital Heart Operations

Aprotinin has been associated with significant morbidity and mortality in adults, leading to its withdrawal from the market and clinical substitution with the lysine analogs, tranexamic acid and ε-aminocaproic acid. Neonates undergoing cardiopulmonary bypass are especially at risk for perioperative bleeding, yet little data exist comparing lysine analogs with aprotinin. Neonates undergoing cardiopulmonary bypass (January 2006 to December 2009) were included in this single-institution, retrospective cohort study. Preoperative, intraoperative, and postoperative data were analyzed. The relationship between demographic, surgical risk data, and outcomes were analyzed. Markers of effectiveness included transfusion requirement, duration of operation, duration of ventilation, and intensive care unit length of stay. Markers of safety included reexploration, renal dysfunction, neurologic complications, and death. Of 423 included neonates, 271 (64%) received aprotinin and 152 (36%) a lysine analog. Infants who received aprotinin had a higher baseline creatinine and lower weight and gestational age. The aprotinin group experienced shorter time to surgical closure, lower blood product use, and lower rates of reexploration and postoperative renal dysfunction compared with the lysine-analog group. There was no difference in duration of ventilation or intensive care unit stay, neurologic outcomes, or death. Neonates who received aprotinin had significantly lower intraoperative transfusion requirements and shorter surgical closure times. The aprotinin group was less likely to require surgical reexploration and had a lower rate of renal injury. These data illustrate the need for further research regarding safety and efficacy of aprotinin in a larger sample of children undergoing cardiac operations.

Postoperative complications following the Fontan procedure: the role of aprotinin

To determine how the anti-inflammatory properties of aprotinin impact on postoperative complications in children undergoing the Fontan procedure. We included all patients between 14 months and 18 years (n=56) undergoing a Fontan operation at our institution between January 2005 and June 2009. The study group (n=29) included patients from January 2005 through December 2007 all of whom received aprotinin. The control group (n=27) included all patients from January 2008 through June 2009 who did not receive aprotinin. We reviewed all medical records and collected preoperative, intraoperative and postoperative data. Duration and volume of chest tube drainage were the primary outcome measures. Of the 20% of patients who had postoperative arrhythmias, multivariate logistic regression analysis demonstrated only aprotinin was associated with significantly decreased postoperative arrhythmias (P=0.01). Renal function and fenestration or Fontan thrombosis did not differ significantly; there was no statistically significant difference in volume or duration of chest tube drainage. Median duration of chest tube drainage was 7 days in the aprotinin group and 8 days for patients who did not receive aprotinin (P=0.36). The anti-inflammatory properties of aprotinin may be protective against postoperative arrhythmias. Aprotinin does not confer increased risks of prolonged chest tube drainage, renal dysfunction or thrombosis in patients undergoing the Fontan procedure.

Requerimientos transfusionales y morbimortalidad en cirugía cardiaca en relación al empleo de antifibrinolíticos: aprotinina comparada con ácido tranexámico

To evaluate transfusion requirements, morbidity and mortality when 2 antifibrinolytic agents (aprotinin and tranexamic acid) were used in patients undergoing cardiac surgery.Comparison of the effects of 2 antifibrinolytic agents in 243 patients undergoing cardiac surgery between December 2006 and June 2008. We recorded the surgical procedures used, blood product transfusions required, complications (particularly renal), mortality, and length of hospital stay.The patients were distributed into 2 groups to receive tranexamic acid (n = 144) or aprotinin (n = 99). The incidence of transfusion in the tranexamic acid group (31.94%) was nonsignificantly lower than in the aprotinin group (38.38%) (PF = .31). The mean (SD) number of units of packed red blood cells transfused was 0.67 (1.18) in the tranexamic acid group and 1.01 (1.54) in the aprotinin group (P = .07). The mean preoperative hemoglobin concentration in the tranexamic acid group (11.79 [1.71] mg/dL) was significantly lower than in the aprotinin group (12.35 [1.70] mg/dL) (P < .01). Incipient postoperative renal failure tended to occur more frequently in the aprotinin group (19.6% compared to 16%; P = .47). Mortality at 1 year was 9.02% in the tranexamic acid group (compared to 14.14% in the aprotinin group; PF-.21); the trend for mortality related to postoperative renal failure was similar (7.6% in the tranexamic acid group compared to 12.4% in the aprotinin group; P = .22). No significant differences were observed in postoperative complications or length of hospital stay. However, the lack of randomization and the small sample size do not allow for definitive conclusions.This study, subject to the aforementioned limitations, shows that tranexamic acid is as effective as aprotinin for reducing transfusion requirements in cardiac surgery in Spain.

Removal of aprotinin from low-dose aprotinin/tranexamic acid antifibrinolytic therapy increases transfusion requirements in cardiothoracic surgery

This retrospective study investigated whether withdrawal of aprotinin from combined low-dose aprotinin/tranexamic acid (TXA) antifibrinolytic therapy altered postoperative blood loss and transfusion requirements in patients undergoing cardiothoracic surgery employing cardiopulmonary bypass (CPB). The study included data from patients receiving a combination of low-dose aprotinin (2×10(6)KIU in CPB prime; n=615) and 2000mg TXA or patients receiving TXA only (n=587). In both groups, TXA was given after protamine administration. Study endpoints were blood loss, transfusion requirements and reoperation. There were no differences in EuroSCORE, CPB time, antiangial medication and baseline coagulation parameters between groups. There were more males in the TXA group (85%) as compared to the TXA+aprotinin group (77%; P=0.02). Postoperative blood loss (0.80±0.69 vs. 0.66±0.52l; P=0.001) and transfusion of fresh frozen plasma (0.6±0.7 vs. 0.4±0.6U; P<0.001), packed cells (3.9±5.5 vs. 2.7±3.3U; P<0.001) and platelets (0.7±0.6 vs. 0.5±0.6U; P<0.001) was higher in the TXA group than in patients receiving combined therapy, respectively. There were more reoperations for bleeding in the TXA group (53 vs. 34, respectively; P=0.03) with similar mortality and deterioration in glomerular filtration rate. In conclusion, withdrawal of aprotinin from combined antifibrinolytic therapy is associated with increased blood loss, transfusion requirements and reoperations.

Aprotinin Improves Functional Outcome but Not Cerebral Infarct Size in an Experimental Model of Stroke During Cardiopulmonary Bypass

Aprotinin, a nonspecific serine protease inhibitor, has been used to decrease bleeding and reduce the systemic inflammatory response after cardiopulmonary bypass (CPB). Studies have variably linked aprotinin administration with both improved as well as adverse cerebral consequences after cardiac surgery. We designed this study to determine whether an antiinflammatory dose of aprotinin could improve the histologic and functional neurologic outcome in a rat model of focal cerebral ischemia during CPB. After surgical preparation, the animals were randomized into 2 groups: an aprotinin group (60,000 kIU/kg IV) and a control group (0.9% NaCl IV). Normothermic CPB was performed for 60 minutes during which time a partial overlapping 60 minutes of right middle cerebral artery occlusion was induced. Cytokines (tumor necrosis factor-alpha, interleukin [IL]-1beta, IL-6, and IL-10) were measured at baseline, the end of CPB, then 2 and 24 hours after CPB. On postoperative day 3, the animals underwent functional neurologic testing and histologic assessment of cerebral infarct volume. There was a reduction in systemic inflammation in the aprotinin group compared with the control group, demonstrated by lower levels of IL-1beta (P = 0.035) and IL-6 (P = 0.047). The aprotinin group also had a better functional neurologic performance (median [interquartile range]: aprotinin 27 [8] vs control 32 [6]; P = 0.042). However, there was no difference in cerebral infarct volume (aprotinin 306 [27] mm(3) vs control 297 [52] mm(3); P = 0.599). In this experimental model of stroke occurring during CPB, aprotinin decreased the systemic inflammatory response to CPB. Although there was no difference in the cerebral infarct volume, there was a small improvement in the short-term functional neurologic outcome in the aprotinin group.

Effects of Aprotinin or Tranexamic Acid on Proteolytic/Cytokine Profiles in Infants After Cardiac Surgery

After cardiopulmonary bypass (CPB), elaboration of cytokines, and subsequent induction of interstitial proteases, such as matrix metalloproteinases (MMPs), can result in a complex postoperative course. The serine protease inhibitor, aprotinin, which has been used in congenital heart surgery putatively for modulating fibrinolysis is now unavailable, necessitating the use of lysine analogues such as tranexamic acid (TXA). The present study tested the hypothesis that distinctly different plasma profiles of signaling molecules and proteases would be differentially affected after the administration of aprotinin or TXA in the context of congenital cardiac surgery and CPB. Thirty-seven patients (age, 4.8 +/- 0.3 months) undergoing corrective surgery for ventricular septal defect and tetralogy of Fallot received either aprotinin (n = 22) or TXA (n = 15). Using a high throughput multiplex suspension immunoassay, plasma was serially quantified for cytokines and MMPs: before aprotinin or TXA (baseline), after separation from CPB, and 4, 12, 24, and 48 hours post-CPB. Tumor necrosis factor-alpha increased initially after CPB in both the aprotinin and TXA groups, but at 24 and 48 hours post-CPB was approximately 50% lower in the aprotinin group (p < 0.05). The IL-10 levels were threefold higher in the TXA group compared with the aprotinin group immediately post-CBP (p < 0.05). Plasma levels of MMP types associated with inflammation, MMP-8, and MMP-9, were twofold higher in the late post-CPB period in the TXA group when compared with the aprotinin group. After ventricular septal defect or tetralogy of Fallot repair in children, cytokine induction occurs, which is temporally related to the emergence of a specific MMP profile. Moreover, these unique findings demonstrated differential effects between the serine protease inhibitor aprotinin and the lysine analogue TXA with respect to cytokine and MMP induction in the early postoperative period. The different cytokine-proteolytic profile between these antifibrinolytics may in turn influence biologic processes in the postoperative period.

Effects of Aprotinin on Short-Term and Long-Term Outcomes After Coronary Artery Bypass Grafting Surgery

Recent studies demonstrated that aprotinin use would increase the short-term and long-term mortality and complications after coronary artery bypass grafting (CABG). This study was to investigate effects of aprotinin during isolated primary CABG on short-term and long-term outcomes in Chinese patients. We studied 5,103 consecutive Chinese patients who underwent isolated primary CABG from 1999 to 2005. Of all the patients, 4,122 received aprotinin during operation (aprotinin group) and 981 received no aprotinin or other antifibrinolytic therapy (control group). Short-term and long-term mortality and major complications were analyzed with multivariate regression analysis. Propensity adjustment method was used to minimize the selection bias between the two groups, and propensity matching method was used to yield two well-matched groups for further comparison. Blood loss after operation was significantly reduced in the aprotinin group compared with the control group (p < 0.001). Aprotinin use was neither associated with the perioperative mortality (p = 0.45, relative risk, 1.34) or major complications, nor was it associated with long-term mortality (p = 0.21, relative risk, 1.26) and major adverse cardiac and cerebrovascular events (p = 0.82, relative risk, 0.98). After propensity adjustment for the baseline characteristics, we obtained similar results. In addition, comparison between the two well-matched groups showed no significant difference either in baseline characteristics or in short-term and long-term outcomes. Aprotinin use during isolated primary CABG reduced blood loss significantly, but was not associated with short-term or long-term mortality and complications. Aprotinin use in relatively low-risk CABG patients was effective and safe in a Chinese (Asian) population.

Avaliação da aprotinina na redução da resposta inflamatória sistêmica em crianças operadas com circulação extracorpórea

To evaluate if the hemostatic high-dose aprotinin seems to reduce the inflammatory process after extracorporeal circulation (ECC) in children. A prospective randomized study was conducted on children aged 30 days to 4 years submitted to correction of acyanogenic congenital heart disease with ECC and divided into two groups: Control (n=9) and Aprotinin (n=10). In the Aprotinin Group the drug was administered before and during ECC and the systemic inflammatory response and hemostatic and multiorgan dysfunctions were analyzed on the basis of clinical and biochemical markers. Differences were considered to be significant when P<0.05. The groups were similar regarding demographic and intraoperative variables, except for a greater hemodilution in the Aprotinin Group. The drug had no benefit regarding time of mechanical pulmonary ventilation, permanence in the postoperative ICU and length of In this series, hemostatic high-dose aprotinin did not minimize the clinical manifestations or serum markers of the inflammatory systemic response.

Can We Safely Reduce Blood Loss During Lumbar Pedicle Subtraction Osteotomy Procedures Using Tranexamic Acid or Aprotinin?

Retrospective, observational study. To compare the safety and efficacy of 2 pharmaceutical antifibrinolytic agents, aprotinin and tranexamic acid, in controlling blood loss during lumbar pedicle subtraction osteotomy (PSO) in adults. Reconstructive spinal surgeries, in particular lumbar PSOs, have been associated with large blood losses despite interventions (intraoperative blood salvaging, controlled hypotensive anesthesia). Since the 1990s, intraoperative administration of antifibrinolytics (aprotinin, tranexamic acid, e-aminocaproic acid) has gained popularity. This study assesses the safety and efficacy of 2 antifibrinolytics, aprotinin and tranexamic acid, during adult lumbar PSO procedures at one institution. A retrospective comparative analysis of 44 consecutive adults undergoing posterior spinal fusion procedures with lumbar PSO at one institution was performed. Patients were analyzed according to treatment group: controls (10), aprotinin (14), and tranexamic acid (20). There were no significant differences in demographic (gender, age, comorbidities) or surgical traits (length of surgery, levels fused/exposed, preoperative hematocrit, bone graft source, primary/revision) between the 3 groups. The aprotinin group had significantly less intraoperative blood loss (1114 +/- 992 mL; P < 0.01) than the tranexamic acid and control group (2102 +/- 1076 mL and 2260 +/- 1580 mL, respectively). The aprotinin group received significantly less blood (577 +/- 806 mL; P < 0.002) during the surgical procedure than the tranexamic acid (1838 +/- 1096 mL) and the control group (1502 +/- 1241 mL). There were no major intraoperative complications for any of the treatment groups. There were no postoperative cases of seizures, MI, CVA, DVT, or PE with any of the treatment groups. There was one acute tubular necrosis event in the aprotinin group, which resolved before discharge but did required several days of dialysis. The aprotinin treatment group lost significantly less blood and received significantly fewer blood transfusions than both the tranexamic acid and control groups without significant differences in intra- and postoperative complications. These results may justify further study of aprotinin and other antifibrinolytics for this specific indication (3-column lumbar osteotomies in the adult spinal deformity population). A multicenter randomized comparative analysis would be ideal.

Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis

IntroductionAntifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding. Because of safety concerns, aprotinin was withdrawn from the market in 2007. Since then, tranexamic acid (TXA) has become the antifibrinolytic treatment of choice in many heart centers. The safety profile of TXA has not been extensively studied. Therefore, the aim of this study was to evaluate safety and efficiency of TXA compared with aprotinin in cardiac surgery.MethodsSince July 1, 2006, TXA has been administered at a dose of 50 mg/kg tranexamic acid before cardiopulmonary bypass (CPB) and 50 mg/kg into the priming fluid of the CPB. Prior to this, all patients were treated with aprotinin at a dose of 50,000 KIU per kilogram body weight. Safety was evaluated with mortality, biomarkers, and the diagnosis of myocardial infarction, ischemic stroke, convulsive seizures, and acute renal failure in the intensive care unit (ICU), intermediate care unit (IMCU), and hospital stay. Efficiency was evaluated by the need for transfusion of blood products and total postoperative blood loss.ResultsAfter informed consent, 893 patients were included in our database (557 consecutive patients receiving aprotinin and 336 patients receiving TXA). A subgroup of 320 patients undergoing open-heart procedures (105 receiving TXA and 215 receiving aprotinin) was analyzed separately. In the aprotinin group, a higher rate of late events of ischemic stroke (3.4% versus 0.9%; P = 0.02) and neurologic disability (5.8% versus 2.4%; P = 0.02) was found. The rate of postoperative convulsive seizures was increased in tendency in patients receiving TXA (2.7% versus 0.9%; P = 0.05). The use of TXA was associated with higher cumulative drainage losses (PANOVA < 0.01; Ptime < 0.01) and a higher rate of repeated thoracotomy for bleeding (6.9% versus 2.4%; P < 0.01). In the subgroup of patients with open-chamber procedures, mortality was higher in the TXA group (16.2% TXA versus 7.5% aprotinin; P = 0.02). Multivariate logistic regression identified EURO score II and CPB time as additional risk factors for this increased mortality.ConclusionsThe use of high-dose TXA is questioned, as our data suggest an association between higher mortality and minor efficiency while the safety profile of this drug is not consistently improved. Further confirmatory prospective studies evaluating the efficacy and safety profile of TXA are urgently needed to find a safe dosage for this antifibrinolytic drug.

Effects of novel synthetic serine protease inhibitors on postoperative blood loss, coagulation parameters, and vascular relaxation after cardiac surgery

Although aprotinin has been widely used to reduce perioperative blood loss after cardiopulmonary bypass, recent concerns have led to its withdrawal. This study investigated effects of the novel synthetic serine protease inhibitors CU-2010 and CU-2020 on blood loss, coagulation parameters, and coronary relaxation in a canine model. Thirty-seven dogs were divided into 5 groups: control (n = 5), aprotinin (n = 8, Hammersmith scheme of intravenous bolus, prime, and continuous infusion), Hammersmith CU-2010 (n = 8, 1.6 mg/kg Hammersmith scheme), continuous CU-2010 (n = 8, 1.6 mg/kg continuous infusion), and CU-2020 (n = 8, 8.9 mg/kg Hammersmith scheme). All animals underwent 90-minute cardiopulmonary bypass. End points were blood loss during first 2 hours after protamine and activated clotting, partial thromboplastin, and prothrombin times. At end of experiments, coronary rings were removed for in vitro testing of relaxation to acetylcholine and sodium nitroprusside. Hammersmith and continuous CU-2010, CU-2020, and aprotinin groups all had reduced blood loss (43 + or - 4, 43 + or - 8, 52 + or - 7, 61 + or - 7, respectively, vs control 149 + or - 24 mL, P < .05). After protamine, activated clotting time and partial thromboplastin time normalized in control, aprotinin, and Hammersmith CU-2010 groups but remained elevated in continuous CU-2010 and CU-2020 groups. Prothrombin time and vascular relaxation did not differ between groups. CU-2010 and CU-2020 significantly reduced blood loss after cardiac surgery, with prolonged partial thromboplastin and activated clotting times, demonstrating improved antithrombotic profile. Neither aprotinin nor the novel serine protease inhibitors influenced vascular relaxation.