OBJECTIVE To investigate whether generation and liberation of bradykinin and histamine contribute to generalized edema formation in pediatric cardiopulmonary bypass surgery. DESIGN Prospective observational study. SETTING Pediatric heart surgery of a university hospital. PATIENTS Forty-one neonates, infants, and children undergoing cardiopulmonary bypass to correct congenital cardiac anomalies. INTERVENTIONS Plasma concentrations of bradykinin and histamine were determined before, during, and after cardiopulmonary bypass. Fluid balance was evaluated by control of fluid intake and output. MEASUREMENTS AND MAIN RESULTS The susceptibility to generalized edema formation increased significantly (r = -.457; p <.005) with decreasing age. Approximately three times higher plasma concentrations of bradykinin (p <.001) were found at the onset of anesthesia and during the total observation period in patients with a fluid retention of >6% of body weight compared with patients with a lower retention rate. Plasma bradykinin reached significantly (p <.01) higher peak concentrations of 237.9 +/- 58.6 fmol/mL during cardiopulmonary bypass and of 227.5 +/- 90.7 fmol/mL during the early postoperative period in patients with severe edema formation in contrast to only 86.6 +/- 10.9 and 65.5 +/- 26.8 fmol/mL in patients with minor fluid retention. A tendency (p =.06) to slightly increasing histamine concentrations from 2.07 +/- 0.13 nmol/L at baseline to 3.32 +/- 1.41 nmol/L during 90 mins of cardiopulmonary bypass was only observed in patients with high fluid retention. CONCLUSIONS Bradykinin seems to be essentially involved in the enhancement of microvascular permeability in pediatric cardiopulmonary bypass surgery, although a dominant causal role cannot be claimed by this study. Histamine, however, doesn't appear to play a major role and may only contribute as a cofactor. To what extent an increased expression of bradykinin-1 and bradykinin-2 receptors or a reduced potential of bradykinin-degrading enzymes is involved is the object of a further clinical study.