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Increased pulmonary vascular resistance is common in congenital heart disease and is exacerbated by cardiopulmonary bypass (CPB). We investigated whether CPB is responsible for pulmonary endothelial dysfunction and contributes to postoperative pulmonary hypertension.We infused the endothelium-dependent vasodilator acetylcholine (ACH) into the pulmonary circulation of pulmonary hypertensive children with congenital heart disease either before (n= 12) or after (n=22) surgical repair on CPB. The dose response to ACH (10−1 to 10–6 M) was recorded for all hemodynamic variables. Nine additional postoperative patients were studied with ACH followed by inhalation of 80 ppm nitric oxide, an endothelium-independent smooth muscle relaxant. Plasma levels of cyclic GMP (cGMP) were measured before and after ACH and nitric oxide administration. Pulmonary vasodilation with 10−1 M ACH was seen in all preoperative patients but was markedly attenuated in postoperative patients. Baseline pulmonary vascular resistance (5.6±1.0 U m2) fell 46±5% in preoperative patients but declined only 11±4% from baseline (5.8±0.9 U m2) in postoperative patients (P<.002). However, inhalation of 80 ppm nitric oxide after ACH infusion in postoperative patients lowered pulmonary vascular resistance by 33±4% (P<.0002 compared with postoperative ACH response) with minimal effects on the systemic circulation. This finding suggests that the capacity for smooth muscle relaxation and pulmonary vasodilation was present in postoperative patients but could not be induced by ACH. Plasma levels of cGMP in postoperative patients were unchanged after acetylcholine infusion but rose more than threefold during pulmonary vasodilation with nitric oxide (P<.0001). This finding is consistent with the purported role of cGMP as the second messenger effecting smooth muscle relaxation in this process.CPB may be responsible for postoperative dysfunction of the pulmonary endothelial cell and may contribute to postoperative pulmonary hypertension in children. Inhaled nitric oxide is a potent pulmonary vasodilator after CPB with minimal systemic circulatory effects. It may have important diagnostic and therapeutic applications in patients with congenital heart disease.