The present study summarizes a retrospective data set of 60 preterm infants with continuous intravenous sildenafil treatment and represents the biggest cohort to date of preterm infants with intravenous sildenafil treatment of early-PH and late-PH. According to our results, we could demonstrate that PH severity, the incidence of RVD and the end-diastolic RV/LV ratio decreased significantly during the first 24 h during sildenafil treatment. Sildenafil treatment is associated with a rapid improvement in oxygenation impairment in the mayor part of the infants, illustrated and evaluated with established oxygenation indices (OI, SOPI, and P/F ratio), both shown in ELBW and non-ELBW preterm infants. The mortality rate of infants responding to sildenafil was significantly lower compared to non-Responder. Nevertheless, about 40% of the preterm infants did not demonstrate a response to sildenafil treatment and were classified as non-Responder.
In recent prospective trials intravenous sildenafil treatment was evaluated in neonates with a gestational age >34 weeks , but data on intravenous sildenafil in ELGAN and ELBW preterm infants <28 GA are still lacking[13,14]. Several studies analyzed oral sildenafil treatment and only two recent studies were identified analyzing intravenous sildenafil treatment including ELBW infants with PH [15,17,30,31]. In most of these infants PH was diagnosed secondary to the timepoint of BPD diagnosis (36 weeks of GA). These studies overall report beneficial effects of sildenafil on echocardiographic grading of BPD-PH and oxygenation indices. A prospective multicenter, randomized, placebo-controlled trial on preterm infants <29 weeks of GA at risk for PH is ongoing (SILDI-SAFE trial) [32]. Our study adds new insights on preterm and ELBW-infants with sildenafil treatment for primary early-PH in the first days of life, and with almost a third of the population classified as ELGANs and nearly half of the cohort classified as ELBW infants.
The response to sildenafil according to the improvement in oxygenation indices in our cohort was documented in 58% of the infants, without influence of GA or birth weight on the response to sildenafil. The updated Cochrane review from 2017 on sildenafil treatment for PH in neonates highlighted, that sildenafil is effective in reducing mortality compared to placebo, with a number needed to treat of 3 patients to have a beneficial outcome[16]. Additionally, oxygenation indices improved in the first 24 hours after administration of sildenafil. Nevertheless, these data are summarizing the effect of an oral sildenafil treatment. The most recent trial on intravenous continuous sildenafil was published in 2021 by Pierce et al. The study group conducted a multinational, double-blind, placebo-controlled trial, and randomized infants (>34 weeks of GA) with PPHN or at risk for PPHN to receive either intravenous sildenafil (0.1mg/kg bolus infusion over 30 minutes, followed by 0.03 mg/kg/h continuous infusion) or placebo (0.9% saline or 10% dextrose)[13]. All infants were on iNO treatment, which were the same conditions as in our study population. The authors concluded that intravenous sildenafil was not superior to placebo regarding the endpoints: treatment failure rate (need for additional drug for PPHN therapy, need for ECMO, or death prior to discharge, and time on iNO after starting sildenafil in infants without treatment failure). This phase III study raises the question, whether continuous intravenous sildenafil is effective to treat PPHN in preterm and term infants. However, the findings of the study are contrarious to other studies revealing a significant effect of intravenous sildenafil in this population[14,23]. The dose regime of sildenafil used in the phase III trial was half of the dose which was described by Steinhorn et al, using a bolus infusion of 0.4mg/kg over 3h, followed by a maintenance dose of 1.6mg/kg/d [23]. The missing effect between placebo and sildenafil could potentially be biased by lower plasmatic sildenafil levels due to lower concentrations of the bolus and continuous infusion, and in total cumulative half of the dose used in the open-label, dose-escalation trial by Steinhorn et al.
In our study, infants were treated with the dose regime provided by Steinhorn et al, but a bolus infusion was only administered in 50% of the infants, due to the decision of the attending physician. The severity of oxygenation impairment and PPHN in our cohort is comparable with the before mentioned studies, as the median OI at baseline prior to sildenafil start in our cohort was 26.2 (12.0/47.3) and both studies predominantly included infants with an OI >15 and <60. In 4 infants of our cohort the continuous sildenafil dose was doubled to 3.2 mg/kg/d after cessation of the bolus infusion as rescue procedure in case of severe PPHN or oxygenation failure, without difference in response to sildenafil between subgroups (see Table 2).
Non-Responder in our cohort suffered significantly more often from lung-hypoplasia, and LUTO or congenital-renal-disorder. Infants with LUTO or congenital-renal-disorder mainly suffer from lung-hypoplasia due to oligo- or anhydramnion. Preterm infants suffering from lung-hypoplasia seem to be prone to respond to sildenafil, which potentially can be explained by a higher degree of structural lung abnormality (vasculopathy: excessive muscularization, intima thickening, rarefaction of pulmonary arteries and vessels) and higher grade of oxygen impairment at baseline. As sildenafil is a rescue-therapy, the use of sildenafil in these infants needs to be evaluated carefully.
Our results illustrate, that intravenous sildenafil treatment is associated with a significant and rapid reduction of the PH severity. This is in line with previous studies on infants with PPHN and neonates suffering from PH due to congenital lung disease or BPD-PH [15,19,30,31,33]. According to our results, the RVD improves significantly during the continuous sildenafil infusion. Several studies analyzed the relationship between sildenafil treatment and right ventricular diastolic and systolic function, as shown by magnet resonance tomography scans, in right heart catheterization and in animal models for right ventricular dysfunction[34–38]. In summary, sildenafil has afterload-reducing effects with improvement of RV unloading, leads to an improvement of diastolic RVD, improves RV myocardial remodeling due to upregulation of gene-markers for hypertrophy and inflammation, and there are conflicting results regarding the improvement of the RV systolic function. During the sildenafil treatment the RV/LV ratio decreases significantly, potentially illustrating the effect of RV unloading and higher preload of the left-ventricle in preterm infants. The incidence of LVD initially decreased from baseline to 24 h in non-Responder, followed by a significant increase from 24h to 48h after start of sildenafil treatment in non-Responder. Sildenafil possibly can lead to a deterioration of a preexisting LV dysfunction, due to a aggravation of the LV dysfunction caused by a higher LV preload and filling pressures, which is in line with previous findings of sildenafil treatment in infants with a congenital diaphragmatic hernia[19]. On the other hand, results from adult RCT trials revealed beneficial effects of sildenafil on LV function[39].
Limitations
Our data provide important information in these patient population and we hypothesize that continuous sildenafil treatment in preterm infants with early- and late-PH seems to be well tolerated. However, this need to be interpreted carefully, as the frequent use of concomitant vasoactive treatment could have mitigated an arterial hypotension as drug related adverse event during the sildenafil treatment. During the treatment period in 11 infants a severe arterial hypotension (5mmHg <GA for >60 minutes) was identified in the documentation system, but these episodes were not related to the sildenafil treatment, as the episodes occurred unrelated to the start of the bolus or continuous sildenafil infusion. The present study was conducted retrospectively and not designed to evaluate the safety profile of sildenafil. This needs to be considered when planning future prospective randomized-controlled trials.
A comparator cohort is missing and as mentioned before, prospective randomized trials are warranted. Therefore, it is important to get knowledge from retrospective studies as provided by our results. Furthermore, the interpretation of the echocardiographic data is at risk for bias because echocardiographic assessment is based to some extent on a qualitative grading. Finally, sildenafil treatment was started as rescue-therapy in critically ill infants with a high-degree of preexisting comorbidities. This can have biased the incidence of the response rate of infants to sildenafil treatment.