Cytokines (IL-1ß, IL-6, and IL-8) have been associated with the systemic inflammatory response syndrome known to occur in patients undergoing cardiopulmonary bypass. We hypothesized that the placental dysfunction which has been found to complicate fetal cardiac bypass (FCB) may be in part a function of a cytokine mediated acute phase reaction. To test this hypothesis, we conducted a controlled study to characterize the effect of cardiac bypass on plasma levels of IL-1ß, IL-6, and IL-8 in fetal sheep. 9 mixed-breed pregnant ewes at 118-122 days of gestation were assigned randomly to either of 2 groups: `fetal cardiac bypass group' (n=5) or `control group' (n=4). After surgical exposure and instrumentation, previously described techniques were used to perform 30 minutes of FCB in study group fetuses, while control group fetuses were exposed and instrumented identically, but did not undergo bypass. Placental and systemic hemodynamics were monitored in both groups. Pre- and post-FCB blood samples were analyzed for IL-1β, IL-6, and IL-8 using previously described ELISA protocols. Pre-FCB IL-6 levels were zero in all study and control fetuses. IL-6 levels consistently increased in all study animals (to an average post-FCB level of 53.0±24.2 pg/ml; p=.01), while they remained at zero in all control animals. FCB produced no significant changes in IL-1ß and 8. The decrease in placental blood flow (PBF) from pre- to post-FCB in study group fetuses (33.3±6.4 ml/kg) was significantly greater than the decrease in control fetuses (9.3±2.3 ml/kg; p=.0002). Placental vascular resistance (PVR) increased significantly(from.43±.11 pre-FCB to.52±.14 post-FCB; p=.01) in study group fetuses, but was essentially unchanged (.388±.10 pre-FCB to.394±.10 post-FCB; p=.40) in control fetuses. The difference in PVR changes between the 2 groups was highly significant (p=.004). In conclusion, FCB produces significant and consistent increases in fetal plasma IL-6, which correspond with increased PVR and decreased PBF. It appears that IL-6 may have an important role in placental dysfunction during and after FCB. Further investigation is necessary to elucidate its specific role in the impairment of placental function or as a marker of placental injury.