Efficacy of Milrinone Plus Sildenafil in the Treatment of Neonates with Persistent Pulmonary Hypertension in Resource-Limited Settings: Results of a Randomized, Double-Blind Trial

Abstract

Background The management of severe persistent pulmonary hypertension (PPHN) can be very challenging in many resource-limited centers without access to inhaled nitric oxide or extracorporeal membrane oxygenation. Objectives The current study aimed to investigate the efficacy of oral sildenafil and intravenous milrinone infusion and compare the effects of these drugs in combination versus as monotherapy in neonates with PPHN. Methods A double-blind randomized controlled trial was conducted in which neonates with PPHN were divided into three groups of 20 patients each: group 1 received oral sildenafil starting at 0.5 mg/kg every 6 h to a target maintenance dose of 2 mg/kg every 6 h; group 2 received intravenous milrinone 0.5 μg/kg/min as a continuous infusion; and group 3 received both oral sildenafil and intravenous milrinone. Results Post-treatment pulmonary artery systolic pressure was significantly lower in group 3 than in groups 1 and 2, which both received monotherapy (p = 0.031). The oxygenation index also decreased significantly in the dual-therapy group (p = 0.002) compared with the monotherapy groups. Combined use of both drugs demonstrated a beneficial synergistic effect with better outcomes and reduced mortality. Conclusion Dual therapy using sildenafil and milrinone was superior to monotherapy with either drug in neonates with severe PPHN and is recommended for use in resource-constrained settings. Registration Pan African Clinical Trial Registry identifier number PACTR201902691230243.

The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates

“…Sildenafil also has been used as a treatment for pulmonary hypertension (PH) in adults ( Galiè et al, 2015 ; Vitulo et al, 2017 ). Following its approval for the treatment of pulmonary hypertension in adults, the off-label use of sildenafil for treating pulmonary arterial hypertension in infants has increased ( Hsieh et al, 2013 ) and has spread to neonates ( Steinhorn et al, 2009 ; Pierce et al, 2021 ), which has shown that it also could be used safely with that population, with undeniable beneficial effects ( Abman, 2007 ; Mukherjee et al, 2009 ; Steinhorn et al, 2009 ; El-Ghandour et al, 2020 ; He et al, 2021 ; Kamran et al, 2021 ).…”

Life-threatening PPHN refractory to nitric oxide: proposal for a rational therapeutic algorithm

“…[ 4 , 5 , 9 , 11 , 13 – 15 , 19 , 22 , 24 , 39 , 44 , 45 , 47 , 48 , 52 ]…”

Evidence-Based Guidelines for Acute Stabilization and Management of Neonates with Persistent Pulmonary Hypertension of the Newborn

“…combination therapies utilizing agents that augment effectiveness both within a singular vasodilatory pathway and across alternate pulmonary vasodilator pathways. 36,[82][83][84][85]…”

“…And increasingly, data suggests the potential for synergistic therapeutic effects achieved with combination therapies utilizing agents that augment effectiveness both within a singular vasodilatory pathway and across alternate pulmonary vasodilator pathways. 36,[82][83][84][85]…”

“…May enhance vasodilatory effects of PH therapies including iNO, sildenafil, prostacyclins 36 82 83 84 85…”