Safety and tolerability of continuous inhaled iloprost in critically ill pediatric pulmonary hypertension patients: A retrospective case series

Abstract

Inhaled iloprost (iILO) has shown efficacy in treating patients with hypoxic lung disease and pulmonary hypertension, inducing selective pulmonary vasodilation and improvement in oxygenation. However, its short elimination half‐life of 20–30 min necessitates frequent intermittent dosing (6–9 times per day). Thus, the administration of iILO via continuous nebulization represents an appealing method of drug delivery in the hospital setting. The objectives are: (1) describe our continuous iILO delivery methodology and safety profile in mechanically ventilated pediatric pulmonary hypertension patients; and (2) characterize the initial response of iILO in these pediatric patients currently receiving iNO. Continuous iILO was delivered and well tolerated (median 6 days; range 1–94) via tracheostomy or endotracheal tube using the Aerogen® mesh nebulizer system coupled with a Medfusion® 400 syringe pump. No adverse events or delivery malfunctions were reported. Initiation of iILO resulted in an increase in oxygen saturation from 81.4 ± 8.6 to 90.8 ± 4.1%, p < 0.05. Interestingly, prior iNO therapy for >1 day resulted in a higher response rate to iILO (as defined as a ≥ 4% increase in saturations) compared to those receiving iNO <1 day (85% vs. 50%, p = 0.06). When the use of iILO is considered, continuous delivery represents a safe, less laborious alternative and concurrent treatment with iNO should not be considered a contraindication. However, given the retrospective design and small sample size, this study does not allow the evaluation of the efficacy of continuous iILO on outcomes beyond the initial response. Thus, a prospective study designed to evaluate the efficacy of continuous iILO is necessary.

Safety and Tolerability of Continuous Inhaled Iloprost Therapy for Severe Pulmonary Hypertension in Neonates and Infants

“…Additionally, iloprost has also been successfully used as part of strategies to wean and bridge off ECMO support by specifically targeting PH and therefore reducing right ventricular afterload and improving cardiac output. Other studies have speculated that the addition of iloprost to iNO utilizes both the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways and provides a synergistic effect [10,19]. Since all of our patients were already on maximal doses of iNO prior to initiation of iloprost therapy, the contribution of a synergistic effect in the improved oxygenation status among our patients cannot be established.…”

“…Therapies for PH target the components of vascular remodeling and belong to three classes: phosphodiesterase inhibitors, endothelin receptor antagonists, and prostanoids [4][5][6]. Prostanoids are analogs of prostacyclin, which when bound to receptors, cause increases in cyclic adenosine monophosphate that result in a cascade of phosphorylation events that subsequently results in smooth muscle relaxation and reduced cell proliferation, thereby reducing pulmonary vascular resistance and inhibiting the remodeling associated with PH [6][7][8][9][10][11][12][13]. Although guidelines recommend inhaled nitric oxide (iNO) as first line therapy to decrease PVR in infants with PPHN, and is the only approved PH therapy for PPHN, it does not improve survival and about 40% of neonates may fail to respond to iNO alone [7].…”

“…Iloprost is a more chemically stable prostaglandin analog and may be administered intermittently or continuously via inhalation. The inhaled administration specifically targets the lung vessels with less systemic effects and possibly less ventilation perfusion mismatch than intravenous epoprostenol, especially in infants with developmental lung disorders [6][7][8][9][10][11][12][13].…”

“…Little is known about the safety and tolerability of inhaled iloprost in the neonatal and infant population. The use of continuous iloprost to prevent fluctuations in pulmonary artery pressures and maintain a steady and consistent PVR-lowering effect has recently been described [10]. The aim of this study is to evaluate the safety, tolerability and outcomes including ECMO and death after continuous inhaled iloprost in neonates and infants with refractory PH in the NICU.…”

Safety and Tolerability of Continuous Inhaled Iloprost Therapy for Severe Pulmonary Hypertension in Neonates and Infants

“…Therapies for PH target the components of vascular remodeling and belong to three classes: phosphodiesterase inhibitors, endothelin receptor antagonists, and prostanoids [ 4 , 5 , 6 ]. Prostanoids are analogs of prostacyclin, which when bound to receptors, cause increases in cyclic adenosine monophosphate that result in a cascade of phosphorylation events that subsequently result in smooth muscle relaxation and reduced cell proliferation, thereby reducing pulmonary vascular resistance and inhibiting the remodeling associated with PH [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Although inhaled nitric oxide (iNO) is recommended as first line therapy to decrease PVR in infants with PPHN, and is the only approved PH therapy for PPHN, it does not improve survival and about 40% of neonates may fail to respond to iNO alone [ 7 ].…”