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

Abstract

Chetan C, Suryawanshi P, Patnaik A, Soni SB, Rath C, Pareek P, Gupta B, Garergrat RR, Verma A, Singh, Y. Oral versus intravenous sildenafil for pulmonary hypertension in neonates: a randomised trial. BMC Pediatr. 2022 May27; 22(1):311. DOI: 10.1186/s12887-022-03366-3. PMID: 35624452. Persistent pulmonary hypertension (PPHN) involves persistent pulmonary vascular resistance, which occurs in approximately 2 in every 1000 live infants.1 This is associated with sequelae, including chronic lung disease, neurodevelopmental complications, and death. The current well-understood management of PPHN includes inhaled nitric oxide (iNO), which is used as the first-line treatment of PPHN in higher-resourced countries.1 However, less-resourced countries have limited availability to iNO. There is some literature on other treatments, including sildenafil; however as recommended in the 2017 Cochrane review which evaluated five randomised clinical trials and several case reports that sildenafil has the potential to increase survival in neonates with PPHN, particularly in settings where iNO is not available.2 Subsequently, Chetan et al., at a single centre in a level III neonatal intensive care unit in an urban centre in India, developed an open labelled, parallel, randomised trial to determine if oral versus intravenous sildenafil have similar efficacy, safety, and response in the management of mild-to-moderate pulmonary hypertension in late preterm and term neonates. Pulmonary hypertension was defined as pulmonary arterial pressure (PAP) >25 mmHg on echocardiography within 72 h of birth. The primary outcome sought the time taken for PAP to <25 mmHg, comparing 6 hourly oral sildenafil 1 mg/kg/dose versus IV sildenafil given with a loading dose of 0.4 mg/kg of sildenafil over 3 h followed by continuous infusion of 1.6 mg/kg/day. Once treatment was started, echocardiograms were repeated every 12 h until PAP <25 mmHg and sildenafil were tapered within 4 days and stopped. Between February 2019 and December 2020, 40 infants were randomised in this study. 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 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. This remains a small, unblinded trial with the clinicians managing the patients and performing the echocardiogram unblinded. Furthermore, the other limitations of this study were a small sample size of 40 babies which was not powered to detect a statistical or meaningful difference between the two preparations of sildenafil. Research directions could include a blinded, multicentre trial to increase further knowledge of the safety and efficacy of oral versus intravenous preparations of sildenafil in resource-limited settings. Whilst iNO will continue to be the first line, there may be scope to demonstrate sildenafil benefits as a dual therapy with iNO. Research performed in higher-resourced countries can lend further knowledge in this area. https://ebneo.org/ebneo-commentary-po-vs-iv-sildenafil-for-ph. AK receives funding from the Australian National Health and Medical Research Council (NHMRC) (APP1161379). The contents of this paper are solely the responsibility of the individual authors and do not reflect the views of the NHMRC. Open access publishing facilitated by The University of Adelaide, as part of the Wiley - The University of Adelaide agreement via the Council of Australian University Librarians. The authors have no conflicts of interest to declare.