Prostacyclin and milrinone by aerosolization improve pulmonary hemodynamics in newborn lambs with experimental pulmonary hypertension

Aerosolized prostacyclin (PGI₂) produces selective pulmonary vasodilation in patients with pulmonary hypertension (PH). The response to PGI₂ may be increased by phosphodiesterase type 3 inhibitors such as milrinone. We studied the dose response effects of aerosolized PGI₂ and aerosolized milrinone both alone and in combination on pulmonary and systemic hemodynamics in newborn lambs with N_ω-nitro-L-arginine methyl ester (L-NAME)-induced PH. We hypothesized that coaerosolization of PGI₂ with milrinone would additively decrease pulmonary vascular resistance (PVR), prolong the duration of action of PGI₂, and selectively dilate the pulmonary vasculature. Near-term lambs were delivered by C-section and instrumented and PH was induced by l-NAME (bolus 25 mg/kg; infusion 10 mg · kg^-1 · h^-1) and indomethacin. In the first set of experiments, PGI₂ was aerosolized at random doses of 2, 20, 100, 200, 500, and 1,000 ng · kg^-1 · min^-1 followed by milrinone at doses of 0.1, 1, and 10 μg · kg^-1 · min^-1 over 10 min. In the second set of experiments, milrinone at 1 μg · kg^-1 · min^-1 was aerosolized in combination with PGI₂ at doses of 20, 100, and 200 ng · kg^-1 · min^-1 over 10 min. Pulmonary arterial pressures (PAP) and PVR decreased significantly with increasing doses of aerosolized PGI₂ and milrinone. The combination of PGI₂ and milrinone significantly reduced PAP and PVR more than either of the drugs aerosolized alone. Addition of milrinone significantly increased the duration of action of PGI₂. When aerosolized independently, PGI₂ and milrinone selectively dilated the pulmonary vasculature but the combination did not. Milrinone enhances the vasodilatory effects of PGI₂ on the pulmonary vasculature but caution must be exercised regarding systemic hypotension.