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

Abstract

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 Nomega-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 microg.kg(-1).min(-1) over 10 min. In the second set of experiments, milrinone at 1 microg.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.

A multicentre randomized-controlled trial of inhaled milrinone in high-risk cardiac surgical patients

“…36 Therefore, future preventive or therapeutic strategies in PH and RV failure should consider combining therapies that would target multiple sites of action as previously reported. 10,18,24,55 In summary, in high-risk cardiac surgical patients, iMil has favourable hemodynamic effect, no systemic hypotension, and is associated with an increased CO with a modest overall reduction in SPAP. Reduction in RV afterload after iMil can vary amongst patients and can be explained by variable PK/PD relationships.…”

Pharmacotherapy of Pulmonary Hypertension

“…Recent studies have shown a potential effect on the pulmonary vascular bed as well as synergistic effects with inhaled prostanoids [68,100,101]. In animal studies, milrinone decreases pulmonary artery pressure and resistance and acts additively with iNO [83,102]. Clinical reports indicate that milrinone may decrease rebound pulmonary hypertension after iNO is stopped [27], and may enhance pulmonary vasodilation of infants with PPHN refractory to iNO [103].…”

Pharmacotherapy for Pulmonary Hypertension

“…Our experience suggests that inhaled PGI 2 is well tolerated and may assist in recovery without ECMO in infants with severe pulmonary hypertension and inadequate response to iNO [82]. Although the optimal dosing of inhaled PGI 2 in critically ill mechanically ventilated infants is not known, short-term studies in newborn lambs with pulmonary hypertension suggest that doses up to 500 ng/kg/min produce progressive improvements in PA pressure, PVR and pulmonary blood flow [83]. In our clinical experience, doses of 50–100 ng/kg/min produce rapid improvement in oxygenation in infants that are refractory to iNO [84].…”