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Inhaled nitric oxide (iNO) has been used for patients with increased pulmonary vascular resistance (PVR) shortly after Fontan operation, but repeat deterioration of PVR during or shortly after its withdrawal remains a major concern. Milrinone, a phosphodiesterase type 3 (PDE3) inhibitor, can also reduce PVR for postoperative patients with pulmonary hypertension. We hypothesized that iNO, in conjunction with milrinone, can provide additive benefits for pulmonary hemodynamics and reduce the occurrence of iNO withdrawal failure/rebound. Thirty-one patients with marked elevation of transpulmonary pressure gradient (TPG, >10 mm Hg) or central venous pressure (CVP, >15 mm Hg) after modified fenestrated Fontan operation were prospectively randomized into two groups, that is, group iNO (iNO at approximately 10 ppm, n = 15) and group iNO + Mil (iNO at approximately 10 ppm and milrinone at 0.5 microg/kg/min, n = 16). Hemodynamics, arterial blood oxygenation, and occurrence of withdrawal failure/rebound were compared between the two groups. Combined application of iNO and milrinone resulted in (i) more significant decrement of CVP (19.6 +/- 3.5% in group iNO + Mil vs. 15.2 +/- 4.6% in group iNO, P < 0.05) and TPG (18.2 +/- 4.8% in group iNO + Mil vs. 15.3 +/- 2.6% in group iNO, P < 0.05), (ii) more significant increment of systolic systemic arterial pressure (8.7 +/- 2.7% in group iNO + Mil vs. 5.2 +/- 3.1% in group iNO, P < 0.05), and (iii) more significant improvement of arterial oxygen saturation (9.3 +/- 3.2% in group iNO + Mil vs. 6.8 +/- 2.8% in group iNO, P < 0.01). Occurrence of iNO withdrawal failure during its weaning or rebound after its discontinuation was significantly lower in group iNO + Mil. The combined use of iNO and milrinone provided additive benefits as compared with exclusive use of iNO for patients with elevated PVR after Fontan procedure.