The goal of this project is to contribute to the development, of fetal cardiac surgery. Certain congenital heart defects are uncorrectable after birth, and infants affected with these defects have a poor prognosis. For some of these defects there is a clear advantage for intra-uterine corrective surgery. Direct fetal surgical intervention for heart defects requires an understanding of the physiologic effects of surgical intervention and cardiopulmonary bypass (CPB) on the fetus. At present these effects are poorly understood, however three important physiologic responses which limit fetal survival have been identified. These responses are: 1) the loss of fetal cardiovascular homeostasis in the pre-CPB phase of fetal intervention, which results in hypoxia, hypercarbia, and lactic acidosis. 2) the """"""""step-function"""""""" rise in fetal vascular resistance at the institution of fetal CPB, which is associated with acute decompensation of fetal respiratory gas exchange, and 3) the gradual and sustained rise in placental vascular resistance during and after fetal CPB, which results in depressed placental blood flow and fetal demise. The specific focus of this project is to identify the mediators of and the detailed pathophysiologic mechanisms of these three responses, with an eye towards clinical application of this information. All experimental series will be performed using a highly instrumented fetal lamb CPB model, which allows continuous on line hemodynamic monitoring evaluation of organ specific and regional blood flow using radiolabelled microspheres, and evaluation of various stress, hormonal, and metabolic responses. Each of the three important physiologic responses will be systematically evaluated. Experiments examining the pre-CPB problem will focus on the role of the fetal stress response and the role of anesthetic agents in causing the changes in fetal cardiovascular homeostasis. Experiments examining the """"""""step-function"""""""" rise in fetal vascular resistance will evaluate elements in the pump-priming solution which have been implicated as the mediators of this response. Experiments examining the gradual rise in placental resistance will focus on the role of various vasoconstrictive eicosanoid products which have been implicated as mediators of this response. Identification of the mediators and mechanisms of these unwanted responses to fetal surgical intervention and CPB will allow development of a rational approach for avoiding or minimizing these problems in the clinical setting.
