Pulmonary hypertension (PH) is a frequently occurring complication in neonates with high risk factors such as intrauterine hypoxia, congenital diaphragmatic hernia (CDH), bronchopulmonary dysplasia (BPD), respiratory distress syndrome (RDS), and meconium aspiration syndrome (1-3). Therefore, it is necessary to better understand the current treatment regimens for neonatal PH.
Inhaled nitric oxide (iNO) remains the gold standard for the treatment of persistent PH. However, there are some shortcomings with the use of iNO: (I) it is not available in many medical facilities due to its high cost; (II) approximately 40% of patients have no response to iNO (4); and (III) hemodynamic instability after inhalation of NO may lead to an inability to discontinue treatment or rebound PH (4-6). Although novel iNO donor drugs that significantly decrease pulmonary vascular resistance (compared to iNO itself) have been developed in recent years, these drugs have only been studied experimentally in animal models, and their safety and efficacy in humans are unknown (7,8). Therefore, other treatments are urgently needed to address above conditions.
These treatments include systemic and inhaled vasodilators such as phosphodiesterase (PDE)-5 inhibitors, prostaglandins, the PDE-3 inhibitor milrinone, and endothelin (ET)-1 receptor antagonists (9). Prostaglandins and milrinone are effective therapeutic options in neonates with PH, but there is a lack of clinical trials evaluating the efficacy and long-term sequelae of these agents in neonates (10,11). PDE-5 inhibitors include dipyridamole, zaprinast, pentoxifylline, tadalafil, and sildenafil. Dipyridamole has a significant systemic vasodilatory effect, which causes systemic hypotension; however, zaprinast, tadalafil, and pentoxifylline have not been adequately studied (11-13).Sildenafil has been widely studied in neonatal animal models and neonatal populations as an off-label drug, and it is one of the first medications recommended for use in neonatal PH. Sildenafil improves pulmonary vasodilation via activation of cGMP-dependent protein kinase and inhibition of calcium influx through the L-type calcium channel in vascular smooth muscle cells (14,15). A mechanism in which sildenafil modulates the synthesis of hydrogen sulphide (H2S) and cell proliferation in pulmonary arterial smooth muscle cells by affecting the enzymes cystathionine γ-lyase (CSE) and cystathionine-β-synthase has recently been proposed (16). In summary, sildenafil provides benefit in both the respiratory (increased oxygen index) and circulatory (increased peripheral blood volume) systems, which result in acute improvement in ventilation perfusion.
The first report of successful application of sildenafil for neonatal PH was published in the early 2000s. Kleinsasser et al. demonstrated the pulmonary vasodilator properties of enteral sildenafil in adult pig models with significant increases in intrapulmonary shunt flow (17). Subsequent studies gradually extended the applicable population to include adults, children, and neonates. Baquero et al. was the first to examine the feasibility of this treatment in the newborn population using a small, randomized, placebo-controlled pilot study in which oxygenation index (OI) was improved and the subsequent survival rate was substantially increased (18). Later, randomized controlled trials also confirmed the efficacy of sildenafil, and then studied interventions including sildenafil vs. placebo or no treatment, sildenafil vs. another pulmonary vasodilator, and sildenafil and another pulmonary vasodilator vs. another pulmonary vasodilator or placebo (12,19). The role of sildenafil has been examined in more clinical retrospective studies to improve PH treatments, but there is no clear guidance regarding the choice of a specific route of sildenafil administration, with the current route of administration being more empirical or experimental.
Various medical units have tried different routes of sildenafil administration, including intravenous, oral, inhalable, and sublingual routes, which may produce different effects. However, there is currently no consensus regarding the best route of administration of sildenafil. The present narrative review provides the reader with information on the history of sildenafil for neonatal PH, current sildenafil practices with reported outcomes, and future directions, and evaluates the advantages and disadvantages of the different modes of administration. For the review of outcomes, we have included clinical studies that were completed in neonates with PH and that are available in English or with English translation. We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/tp-20-277).
Optimal dose and route of sildenafil administration for PH
Oral sildenafil was the first route of administration introduced, and is used worldwide. The generally accepted dose of 0.5–2.0 mg/kg 4 times daily up to a maximum of 8 mg/kg/day, is based primarily on expert opinions and case reports (20,21).
Oral sildenafil in term neonates
Beghetti et al. performed a systematic review on the use of oral sildenafil in the neonatal population prior to 2014 (22),and we have added relevant retrospective studies published in recent years (4,23,24) (Table 1). Notably, no improvement in the oxygen index over 36 hours (P<0.05) may be an independent predicting risk factor for mortality (4), which suggests the importance of comparing the various indicators before and after taking sildenafil over time. Some randomized and quasi-randomized controlled trials of sildenafil compared with a placebo or other pulmonary vasodilators have also assessed the safety and efficacy of oral sildenafil. We selected controlled trials over approximately 10 years, and the sample criteria for most studies were term or near-term neonates with persistent PH, excluding congenital anomalies (25-31) (Table 1).
Oral sildenafil in preterm neonates
The application of sildenafil therapy in preterm neonates has generally been limited to PH that is secondary to BPD, which generally occurs at a much later age (21). A systematic review and some retrospective studies have shown that, in the treatment of BPD-associated PH, sildenafil can reduce pulmonary artery pressure and improve respiratory score (32-39) (Table 2). Some recent studies have suggested that the early prophylactic use of sildenafil in preterm neonates at a high risk of BPD can reduce the possibility of developing BPD; however, 2 randomized controlled trials did not support this hypothesis (40,41) (Table 2).
The pharmacokinetics of oral sildenafil
The maximal plasma concentrations of oral sildenafil in neonates are reached within 0.5–1.5 hours with 40% bioavailability (42). Ahsman et al. included 11 neonates who received 0.5 mg/kg of sildenafil 3 or 4 times daily via a nasogastric tube, and the dose was titrated up to a maximum of 10 mg/kg/day (20). They found that all of the neonates with an average plasma concentration area under the curve over 24 hours (AUC24, sildenafil + metabolite of sildenafil) >2,650 ng/h/mL survived. Notably, enteral administration of sildenafil resulted in a higher rate of conversion to metabolites than the other routes of administration, but the relatively small sample size may make it impossible to explain the pronounced variability in the absorption of sildenafil and its metabolites (43). However, the efficacy of oral sildenafil had a potential relationship with the plasma concentration of sildenafil although there was high variability in the maximal dose, the number of days to achieve this maximal dose, and the duration of therapy. Therefore, the minimum effective plasma concentration would be the key point of future research and may help to determine whether to continue sildenafil treatment.
The U.S. Food and Drug Administration approved the intravenous formulation of sildenafil in 2009. This type of administration is generally used in critically ill patients in developed countries. Mukherjee et al. performed the first known pharmacokinetic trial in which the population pharmacokinetics of sildenafil in term neonates was examined. In all, 36 term neonates received intravenous sildenafil within 72 hours of birth, and the dosing regimen consisted of a loading infusion of fixed duration, ranging from 5 minutes to 3 hours to reach the target concentration in a reasonable time, and a continuous maintenance infusion of variable duration ranging from 2.6 to 168 hours was used to maintain a more stable plasma concentration (44,45). This regimen became the basis for the use of intravenous sildenafil by neonatologists and in future research.
Intravenous sildenafil infusion in term neonates
There are two main types of intravenous infusion: continuous intravenous infusion and intermittent intravenous infusion.
Steinhorn et al. performed a dose-escalation trial that was based on previous pharmacokinetic studies and involved 36 near-term and term neonates (postnatal age 17–51 hours).A loading dose of 0.4 mg/kg was delivered over 3 hours followed by a maintenance infusion of 1.6 mg/kg/day,and the target plasma concentration was achieved with greater short-term and sustained improvement in oxygenation (46). The safety of this dosing regimen has been verified via pharmacokinetic modelling of intravenous sildenafil in neonates with CDH (47). Kipfmueller et al. reviewed 26 neonates (postnatal age ≤24 hours) with CDH who received the same sildenafil dosing regimen, and observed that approximately 40% of neonates showed persistent improvement in oxygenation (48). A retrospective review involving 9 term neonates (postnatal age 7–33 days) with CDH who received continuous intravenous sildenafil (100–290 μg/kg/h) after CDH repair reported that the OI and fraction of inspired oxygen (FiO2) were significantly reduced, and the ratio of right-to-left to left-to-right patent ductus arteriosus (PDA) flow decreased over the subsequent 96 hours (49). However, previous studies have focused only on the short-term improvements. In future prospective studies, the long-term effect of continuous intravenous infusion or the beneficial effects beyond improved oxygenation should be investigated. Notably, an open-label, multicentre, randomized controlled trial evaluating the efficacy and safety of intravenous sildenafil compared with iNO treatment is ongoing (50).
Stultz et al. reported the outcomes of 2 full-term neonates with PH after CDH repairs who received 0.4–2 mg/kg of sildenafil every 6 hours. The infusion time ranged from 1 to 3 hours and showed increased oxygenation and decreased respiratory support periods (51). The retrospective, matched‐cohort analysis from Darland et al. verified the feasibility of intermittent intravenous sildenafil in neonates, and found that 30% of neonates receiving intravenous sildenafil required a hypotension intervention compared to 10% in the other cohort, but there was no statistically significant difference (P=0.24) (45). However, the limitations of this study, including its retrospective nature and small sample size, suggest that the conclusion of the study may not be correct. Some scholars have found that the occurrence of hypotension has a certain correlation with the infusion rate. The hypotensive effects seemed to occur most commonly during relatively rapid loading infusions administered over 5 to 30 minutes, especially at higher dose levels. Furthermore, slower loading infusion administered over 3 hours at the highest dose level was not found to cause hypotension (44). Therefore, when choosing an infusion regimen, slower loading and continuous infusions should be considered to avoid adverse effects.
Intravenous sildenafil in preterm neonates
At present, very few studies have reported the outcomes of intravenous sildenafil in premature and low birth weight neonates, as it is now generally accepted that the incidence rate of PH in preterm neonates is much lower than that of term neonates. Notably, intravenous preparations have not been widely used in clinical practice in these populations, and there are few studies on this route of administration in preterm neonates. Intravenous sildenafil (loading dose of 0.1 mg/kg over 45 minutes, followed by a continuous infusion of 0.5–1.2 mg/kg/day) was used to rescue of 6 critically ill extremely preterm neonates suffering from PH, and sildenafil seemed to effectively correct the hemodynamic instability (52).
The pharmacokinetics of intravenous sildenafil
Mukherjee et al. performed a study of the population pharmacokinetics of intravenous sildenafil, which emphasized the rapid maturation of metabolic clearance in the early postnatal period, and found that the sildenafil clearance tripled at 7 days of age, which may have been attributed to the rapid maturation of cytochrome P450 3A4 (CYP3A4) and CYP2C9 (44). Thakkar et al. showed that the median metabolite-to-parent ratio was higher in neonates receiving co-medications that induced CYP enzymes, and Gonzalez et al. demonstrated that enzyme inhibitors, such as fluconazole, could be used to increase plasma concentrations (43,53), which provides additional evidence for the above speculations. Future research can further determine the most appropriate dose by measuring the value of the CYP enzymes and the plasma concentration of sildenafil, and dynamically monitoring the above indicators to adjust the dose and reduce side effects. Co-medications to decrease the risk of adverse events and observe whether there is a correlation between the specific CYP enzyme levels and the occurrence of adverse reactions can be applied in future.
Promising alternative routes of sildenafil administration
Martell et al. established a piglet model of PH induced by meconium aspiration and found that intratracheal sildenafil was linked to a rapid decrease in mean pulmonary arterial pressure (54). Inhalable sildenafil has the ability to overcome the limitations of intravenous and oral administration routes, such as short dosing intervals and systemic adverse events. Studies, especially animal experiments evaluating the feasibility of aerosolized formulations of sildenafil, are ongoing. Rashid et al. reported the effect of a poly-lactic-co-glycolic acid (PLGA) particle-based formulation of sildenafil in hypoxia-induced PH rat models and monitored the sildenafil pharmacokinetics in these rats. The authors demonstrated that inhalable sildenafil showed promising results for dose reductions and longer dosing intervals (55).
Novel inhalable sildenafil citrate spray-dried microparticles have been successfully implemented, and their safety has been verified through in vitro and in vivo studies, which revealed that the drug was easily deposited in the lungs and prolonged the elimination half-life (56). However, the intratracheal administration of sildenafil is still in the animal experiment stage, and it has not been clinically tested. As a substitute for the oral and intravenous forms of sildenafil, inhalable sildenafil has broad prospects for the treatment of neonatal PH.
A case report described a term neonate with structural cardiac and pulmonary defects accompanied by symptomatic PH and found that sublingual administration (4 mg/2 mLsmall syringe four times daily) substantially increased sildenafil exposure (57), most likely due to rapid mucosal absorption and partial bypass of first-pass metabolism. Sublingual administration offers the possibility of an obvious increase in the effective OI (1); however, more trials are required to better assess the safety and efficacy of this method.
In conclusion, sildenafil for neonatal PH may be given via four routes: the intravenous, oral, inhalable, and sublingual routes. We have summarized the optimal dose, advantages, and deficiencies of each route of sildenafil administration from the available literature (Table 3). There is a scarcity of human neonatal term and preterm sildenafil data, especially from pharmacokinetic studies, which are urgently needed to identify the optimal indications, timing, dose, and routes to sildenafil in neonatal PH.
Adverse effects of sildenafil use in neonates
We must also consider whether the advantages of sildenafil treatment outweigh its side effects in individual patients. The high selectivity of sildenafil makes it more prone to PDE-5 inhibition, but it also inhibits PDE-1, PDE-6, and PDE-11 to a lesser extent. Among these 3 receptors, PDE-6 receptors are present in rod and cone cells of the retina. A cohort of term and preterm neonates exposed to sildenafil was found not to exhibit a correlation with ocular complications, and these results did not support the necessity of a routine ophthalmological examination (58-61). A recent study compared a sildenafil group to a control group in preterm neonates with BPD, and found that neonates in the sildenafil group had a higher prevalence of severe retinopathy of prematurity (ROP) than the control group; however, there was no statistically significant association (62). A large multicentre trial is needed to resolve this controversy.
Sildenafil is a vasodilator that likely acts on the whole body to cause transient hypotension. Neonates with PH generally have a distinct right-to-left shunting across the foramen ovale or ductus arteriosus, and sildenafil infusion may promote hypotension via direct delivery to the systemic vascular system (46). Recently, a large, novel sildenafil exposure-safety study involving 232 hospitalized neonates reported that neither dosing nor exposure was associated with systemic hypotension in a multivariable analysis (63). However, hypotension is more common with intravenous than with oral sildenafil, and it may be of clinical significance to evaluate this adverse effect in a retrospective study of intravenous sildenafil.
In general, it is necessary to monitor for adverse events at all times in the treatment of neonatal PH. If sildenafil is not tolerated, a lower dose or switching to an alternative therapy should be considered.
Conclusion and perspective
Sildenafil for neonatal PH may be administered via four routes: the intravenous, oral, inhalable, and sublingual routes. This review indicates that intravenous sildenafil may be the preferred route of administration. The lack of randomized controlled trials in the contemporary literature means that the observed clinical improvements may not be directly attributed to sildenafil, and more large multicentre randomized controlled trials should help to resolve this controversy. Randomized controlled trials on the different routes of administration
s, such as oral vs. intravenous sildenafil or oral vs. sublingual sildenafil, should be performed regardless of sample size. Taking the advantages of the intravenous formulation into account, more neonatologists should try to use intravenous sildenafil treatment in different critical neonates. Recent studies on the application of inhalable sildenafil in animal models have indicated a potential for the use of this administration route in clinical practice. The pharmacokinetics of sildenafil and its primary metabolite in neonates have not been well studied, and the optimal doses used in different routes of administration must be examined in the future.
We would like to thank all colleagues who contributed to this study and AME Editing Service for the language service.
Funding: The study is funded by grants from the Department of Finance of Jilin Province, China (Grant Number: JLSCZD2019-012).
Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/tp-20-277
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tp-20-277). The authors have no conflicts of interest to declare.
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