Oral versus intravenous sildenafil for pulmonary hypertension in neonates: a randomized trial

Abstract

Background Sildenafil is the drug of choice for neonatal pulmonary hypertension in developing countries where inhaled nitric oxide is not available. Available as oral and intravenous preparation – no study has been done in the past to compare the two forms. Each has its own benefits – but requires comparison in terms of efficacy and safety. This study was done to compare the efficacy of oral versus intravenous (IV) sildenafil in infants with mild to moderate pulmonary hypertension. Methods An open labelled randomized trial was conducted in a neonatal intensive care unit of urban tertiary hospital in western India between February 2019 to December 2020. Infants born after 34 weeks of gestation with Pulmonary arterial pressure (PAP) > 25 mm Hg measured by echocardiography, within 72 h of birth, were enrolled for the study. Participants were randomly assigned to receive sildenafil either orally or by intravenous route. Primary outcome was the time taken for PAP to decrease below 25 mm Hg. Secondary outcomes were time taken for oxygenation index to decrease by 25%, duration of invasive and non-invasive mechanical ventilation, nasal oxygen, hospital stay, time to achieve full feeds, mortality, and side effects. Results Forty patients were enrolled. The baseline characteristics of neonates in both groups were similar except for APGAR scores at 1 min and 5 min, with oral group having lower score [MEDIAN (IQR) 5.00 (4.00- 7.00) and 7.00 (6.00- 8.00)] compared to IV group [MEDIAN (IQR) 7.00 (6.00–8.00) and 9.00 (8.00–9.00)] respectively. Time taken for PAP to decrease below 25 mm was not statistically different between the oral and intravenous groups. Systemic hypotension occurred in 4 neonates of the intravenous group but none in the oral group. Conclusion Oral and intravenous sildenafil had equal efficacy at reducing PAP in neonatal pulmonary hypertension, albeit intravenous sildenafil use was associated with a greater complication rate. Trial registration Trial was registered in the clinical trials registry of India [CTRI/2019/04/018781][25/04/2019].

Comparison of Different Treatments of Persistent Pulmonary Hypertension of the Newborn: A Systematic Review and Network Meta-Analysis*

“…After reviewing the full text, 65 articles that did not meet the inclusion criteria or met the exclusion criteria were excluded (exclusion reasons: 33 articles, not an RCT; nine, not meet the inclusion criteria; five, duplicate; five, no outcomes needed; five, only the abstract was available; four, review; three, with less than ten newborns included; and one, letter; details in Table S7 , http://links.lww.com/CCM/H502). Finally, 23 articles with an acceptable RoB enrolled 902 newborns were included in our analysis (13–35). Figure 1 illustrates a flow diagram of the search process; and Table S1 (http://links.lww.com/CCM/H502) summarizes the characteristics and RoB of the 23 trials included in the study.…”

“…Wood et al (17) examined the effects of treatment with iNO at 20 ppm for 4 hours followed by 6 ppm (20/6NO) on neonates (20/6NO). Furthermore, an increasing number of studies were performed on drugs, such as sildenafil, bosentan, milrinone, and MG. Sildenafil is administered orally at a dose of 1–3 mg/kg/dose every 6–8 hours (OSID) (21, 22, 24, 27–29, 32, 34, 35) or as IV formulations (IVSID) (33, 34). MG is administered IV (IVMG) or nebulize inhalation (NEBMG) (23, 31).…”

EBNEO commentary: Oral versus intravenous sildenafil for pulmonary hypertension in neonates

“…Complications of hypotension (n = 4) and reduced cardiac contractility (n = 1) were seen in the IV group requiring inotropes, compared to none in the oral group. 3 Whilst there was no difference in the median time for sildenafil tapering between the two groups, this was in the context of 12 hourly echocardiograms. Perhaps, more frequent intervals of echocardiogram performed whilst on sildenafil may have found a difference between the two groups.…”

“…Both groups had similar follow‐up rates of 17/20 in the oral group and 15/20 in the IV group, and the sildenafil could be tapered after a median of 48 h in both groups. Complications of hypotension ( n = 4) and reduced cardiac contractility ( n = 1) were seen in the IV group requiring inotropes, compared to none in the oral group 3 …”

A real‐world pharmacovigilance study of FDA adverse event reporting system events for sildenafil

“…Sildenafil is widely recognized for its intrinsic safety, and its potential adverse events (AEs) are frequently disregarded in clinical assessment and practice. Although some common AEs such as headaches, 7 and more severe AEs like heart attacks 8 have been documented, these data primarily originate from succinct clinical trials, case studies, and meta-analyses, often constrained by specific systems due to rigorous diagnostic and selection criteria. [9][10][11] Furthermore, the sample size is relatively modest, and limitations exist in terms of follow-up duration.…”