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Aprotinin reduces the blood loss and transfusion of blood products in children undergoing major surgery. Aprotinin has been associated with severe side effects in adults, and tranexamic acid and aminocaproic acid have been found to be safer alternatives in adults. This systematic review addresses the question of whether tranexamic acid and aminocaproic acid are equally effective as aprotinin for reducing blood loss and transfusion in children undergoing major surgery.A systematic review of the literature was conducted to identify all randomized controlled trials of aprotinin, tranexamic acid, and aminocaproic acid involving children undergoing cardiac or scoliosis surgery.Twenty-three cardiac studies, totaling 1893 patients, met the inclusion criteria. None of the studies directly compared aprotinin to an alternative antifibrinolytic. Five scoliosis studies, totaling 207 patients, met the inclusion criteria. Data on blood loss and use of blood products in the first 24 postoperative hours were extracted. Only homogenously distributed outcomes were pooled.Tranexamic acid showed a homogeneously distributed reduction of blood loss by 11 mL/kg (95% confidence interval [CI] 9–13 mL/kg). Outcomes of blood loss reduction by aprotinin and aminocaproic acid were too heterogeneously distributed to be pooled, so the effect on blood loss could not be evaluated. Both aprotinin and tranexamic acid significantly reduced packed red cell transfusion (4 mL/kg, 95% CI 2–7 mL/kg and 7 mL/kg, 95% CI 5–10 mL/kg, respectively). Type of antifibrinolytic was not a determining factor that explained differences in outcome among trials in a meta-regression analysis. In the scoliosis studies, aprotinin and tranexamic acid significantly reduced blood loss compared with placebo (385 mL, 95% CI 727–42 mL and 682 mL, 95% CI 1149–214 mL, respectively).There is no evidence that suggests that, compared with aprotinin, alternative antifibrinolytics such as tranexamic acid were less effective in reducing blood loss in major pediatric surgery.