BACKGROUND: Concerns regarding the safety of transfused blood have led to the development of a range of interventions to minimise blood loss during major surgery. Anti-fibrinolytic drugs are widely used, particularly in cardiac surgery, and previous reviews have found them to be effective in reducing blood loss, the need for transfusion, and the need for re-operation due to continued or recurrent bleeding. In the last few years questions have been raised regarding the comparative performance of the drugs. The safety of the most popular agent, aprotinin, has been challenged, and it was withdrawn from world markets in May 2008 because of concerns that it increased the risk of cardiovascular complications and death. OBJECTIVES: To assess the comparative effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) on blood loss during surgery, the need for red blood cell (RBC) transfusion, and adverse events, particularly vascular occlusion, renal dysfunction, and death. SEARCH STRATEGY: We searched: the Cochrane Injuries Group's Specialised Register (July 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 3), MEDLINE (Ovid SP) 1950 to July 2010, EMBASE (Ovid SP) 1980 to July 2010. References in identified trials and review articles were checked and trial authors were contacted to identify any additional studies. The searches were last updated in July 2010. SELECTION CRITERIA: Randomised controlled trials (RCTs) of anti-fibrinolytic drugs in adults scheduled for non-urgent surgery. Eligible trials compared anti-fibrinolytic drugs with placebo (or no treatment), or with each other. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: This review summarises data from 252 RCTs that recruited over 25,000 participants. Data from the head-to-head trials suggest an advantage of aprotinin over the lysine analogues TXA and EACA in terms of reducing perioperative blood loss, but the differences were small. Compared to control, aprotinin reduced the probability of requiring RBC transfusion by a relative 34% (relative risk [RR] 0.66, 95% confidence interval [CI] 0.60 to 0.72). The RR for RBC transfusion with TXA was 0.61 (95% CI 0.53 to 0.70) and was 0.81 (95% CI 0.67 to 0.99) with EACA. When the pooled estimates from the head-to-head trials of the two lysine analogues were combined and compared to aprotinin alone, aprotinin appeared more effective in reducing the need for RBC transfusion (RR 0.90; 95% CI 0.81 to 0.99).Aprotinin reduced the need for re-operation due to bleeding by a relative 54% (RR 0.46, 95% CI 0.34 to 0.62). This translates into an absolute risk reduction of 2% and a number needed-to-treat (NNT) of 50 (95% CI 33 to 100). A similar trend was seen with EACA (RR 0.32, 95% CI 0.11 to 0.99) but not TXA (RR 0.80, 95% CI 0.55 to 1.17). The blood transfusion data were heterogeneous and funnel plots indicate that trials of aprotinin and the lysine analogues may be subject to publication bias.When compared with no treatment aprotinin did not increase the risk of myocardial infarction (RR 0.87, 95% CI 0.69 to 1.11), stroke (RR 0.82, 95% CI 0.44 to 1.52), renal dysfunction (RR 1.10, 95% CI 0.79 to 1.54) or overall mortality (RR 0.81, 95% CI 0.63 to 1.06). Similar trends were seen with the lysine analogues, but data were sparse. These data conflict with the results of recently published non-randomised studies, which found increased risk of cardiovascular complications and death with aprotinin. There are concerns about the adequacy of reporting of uncommon events in the small clinical trials included in this review.When aprotinin was compared directly with either, or both, of the two lysine analogues it resulted in a significant increase in the risk of death (RR 1.39, 95% CI 1.02, 1.89), and a non-significant increase in the risk of myocardial infarction (RR 1.11 95% CI 0.82, 1.50). Most of the data contributing to this added risk came from a single study - the BART trial (2008). AUTHORS' CONCLUSIONS: Anti-fibrinolytic drugs provide worthwhile reductions in blood loss and the receipt of allogeneic red cell transfusion. Aprotinin appears to be slightly more effective than the lysine analogues in reducing blood loss and the receipt of blood transfusion. However, head to head comparisons show a lower risk of death with lysine analogues when compared with aprotinin. The lysine analogues are effective in reducing blood loss during and after surgery, and appear to be free of serious adverse effects.

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Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion

Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints.

https://www.annalsthoracicsurgery.org/article/0003-4975(92)90066-D/pdf

Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study.

Concern about the side effects of allogeneic red blood cell transfusion has increased interest in methods of minimizing perioperative transfusion.We performed meta-analyses of randomized trials evaluating the efficacy and safety of aprotinin, desmopressin, tranexamic acid, and epsilon-aminocaproic a

Drugs to minimize perioperative blood loss in cardiac surgery : Meta-analyses using perioperative blood transfusion as the outcome

The inflammatory response to cardiopulmonary bypass

Intraoperative administration of the proteinase inhibitor aprotinin causes reduction in blood loss and homologous blood requirement in patients undergoing cardiac surgery. To ascertain the blood-saving effect of aprotinin and to obtain further information about the mode of action, 40 patients undergoing primary myocardial revascularization were randomly assigned to receive either aprotinin or placebo treatment. Aprotinin was given as a bolus of 2 x 10(6) kallikrein inactivator units (KIU) before surgery followed by a continuous infusion of 5 x 10(5) KIU/h during surgery. Additionally, 2 x 10(6) KIU were added to the pump prime. Strict criteria were used to obtain a homogeneous patient selection. Total blood loss was reduced from 1,431 +/- 760 ml in the control group to 738 +/- 411 ml in the aprotinin group (P less than 0.05) and the homologous blood requirement from 838 +/- 963 ml to 163 +/- 308 ml (P less than 0.05). In the control group, 2.3 +/- 2.2 U of homologous blood or blood products were given, and in the aprotinin group, 0.63 +/- 0.96 U were given (P less than 0.05). Twenty-five percent of patients in the control group and 63% in the aprotinin group did not receive banked blood or homologous blood products. The activated clotting time as an indicator of inhibition of the contact phase of coagulation was significantly increased before heparinization in the aprotinin group (141 +/- 13 s vs. 122 +/- 25 s) and remained significantly increased until heparin was neutralized after cardiopulmonary bypass (CPB).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization.

In a prospective randomised study 20 patients undergoing coronary bypass surgery were assigned to two groups. Patients in group I (n = 10) received initially 250 IU heparin X kg-1 before the start of extracorporeal circulation. Patients in group II (n = 10) were given the same amount of heparin and in addition 1 000 units of purified human antithrombin III (AT III) concentrate. A highly significant lower heparin coefficient [2.69 +/- 0.57 IU X kg-1 X min-1, which is a parameter of heparin consumption (units of heparin X kg-1 given per minute during the time of heparinisation)], was found in group II compared to group I (3.73 +/- 0.56 IU X kg-1 min-1). Heparin sensitivity, measured as an increase in the ratio of activated coagulation time (ACT) X IU heparin-1 X kg-1 as a response to initial heparin dose, was found to be significantly higher (1.22 +/- 0.30 sec X IU heparin-1 X kg-1) in patients receiving AT III as measured in the control group (0.95 +/- 0.23 s X IU heparin-1 X kg-1). Mean values of ACT during the period of heparinisation were comparable (group I: 533 +/- 81 s, group II: 512 +/- 62 s) in the two groups. The substitution of AT III led to an increase of plasma AT III activity of 1.4% per substituted unit AT III X kg-1. AT III plasma activity, corrected to initial haematocrit levels to avoid dilution dependency, decreased as a consequence of extracorporeal circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombin III substitution for optimization of the heparin effect during extracorporeal circulation in heart surgery

Because of relative shortage of homologous stored blood, and the dangers of transmission infectious diseases and isoimmunisation, we tried to reduce blood requirement in cardiac surgery. In 139 patients undergoing coronary artery bypass surgery different techniques of autotransfusion were applied. A 52% reduction of whole blood transfusion compared to a control group of patients could be obtained by preoperative isovolaemic haemodilution. The application of haemoseparation reduced the amount of whole blood used by 55%. When the two techniques were combined the use of whole blood was reduced by 70% compared to the control group of patients. In contrast retransfusion of blood remaining in the oxygenator is not advisable because only a small amount of blood can be saved in this way and in addition it results in a higher risk of postoperative bleeding. Our results will be discussed reviewing the literature.

Reduction of whole blood requirements in coronary surgery with hemoseparation and isovolemic hemodilution

Sufentanil-nitrous oxide/oxygen anesthesia was compared to halothane-nitrous oxide/oxygen anesthesia in 44 infants and children undergoing cardiac surgery. Patients were randomly assigned to one of the two techniques studied, with 22 patients in each group. The mean weight was 8.3 (4.4-15.8) kg in the sufentanil (S) group and 11.7 (5.2-18) kg in the halothane (H) group. All patients were premedicated with IM atropine 0.01 mg/kg, morphine 0.2 mg/kg, and flunitrazepam 0.04 mg/kg. In the S group 1 micrograms/kg S was given intravenously for induction, followed by a cumulative dose of 4 micrograms/kg S until the beginning of surgery. In the H group anesthesia was induced with H 0.5-1.0 vol.% and for deepening of anesthesia increasing H concentrations of 0.5-1.0-1.5 vol.% were applied. Following intubation all patients were ventilated with nitrous oxide/oxygen (1:1). There were no significant differences between the two groups in systolic, diastolic and mean arterial blood pressures or in heart-rate response to induction and intubation. Peripheral arterial oxygen saturation increased significantly in cyanotic patients in both groups following induction. There were dose-dependent decreases in heart rate and small but significant decreases in mean and diastolic arterial pressure in the S group during deepening of anesthesia. There was a significantly greater decrease in systolic, diastolic and mean blood pressures during the same period in the H group whereas the reduction in heart rate was minimal. In addition, in 5 of 22 patients receiving H there were episodes of nodal rhythms with dramatic decreases in systemic arterial pressure and peripheral arterial oxygen saturation in cyanotic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Sufentanil-N2O2/O2 or halothane-N2O/O2 anesthesia in surgery of infants and children with congenital heart defects. Hemodynamics and plasma catecholamines].

Clinical experience concerning the placement of Swan-Ganz catheters (SGC) via the external jugular vein is presented. After puncture of either the right or left external jugular vein, placement of SGC was possible in 90 per cent of patients. Compared to techniques involving puncture of the internal jugular vein this method has less complications. The placement of 167 SGC could be done without any problems, thus proving that the external jugular vein is a safe way of insertion. The external jugular vein as a primary route can be recommended if the vein is visible, especially in cases where puncture of the internal jugular vein may be difficult and could only be performed with an increased risk of complications.

Barankay A

Papers

Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization.

Antithrombin III substitution for optimization of the heparin effect during extracorporeal circulation in heart surgery

Reduction of whole blood requirements in coronary surgery with hemoseparation and isovolemic hemodilution

[Sufentanil-N2O2/O2 or halothane-N2O/O2 anesthesia in surgery of infants and children with congenital heart defects. Hemodynamics and plasma catecholamines].

[Experiences with Swan-Ganz-catheter placement in the external jugular vein].