EBNEO Commentary: Oral versus intravenous sildenafil for pulmonary hypertension in late preterm and term infants

February 14, 2023

MANUSCRIPT CITATION

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.

REVIEWED BY

Nilarni Jayakumar
Neonatal Registrar
Department of Neonatal Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia
Adelaide Medical School, The University of Adelaide, Adelaide, South Australia

Amy Keir
Associate Professor
Consultant Neonatologist
Department of Neonatal Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia
Adelaide Medical School, The University of Adelaide, Adelaide, South Australia
SAHMRI Women and Kids, South Australian Health and Medical Institute, North Adelaide, South Australia
Robinson Research Institute, The University of Adelaide, Adelaide, South Australia

TYPE OF INVESTIGATION

Treatment – Efficacy and Safety

QUESTION

Among late preterm and term neonates with mild to moderate pulmonary hypertension confirmed on echocardiogram within 72 hours of life in resource-limited centres (P), is treatment with sildenafil oral (I) versus intravenous (C) have similar efficacy and safety and response as defined as the time taken to reduce pulmonary artery pressures (O) assessed by echocardiography every 12 hours until pulmonary artery pressures dropped to <25mmHg (T)?

METHODS

  • Design: An open-labelled, parallel, randomised trial.
  • Allocation: Neonates were randomly assigned using computer-generated numbers to either the oral or the IV sildenafil group in a 1:1 ratio
  • Blinding: Open labelled trial with treating clinicians not blinded as they also performed the echocardiograms.
  • Follow-up period: Follow up data was collected until discharge in 18/20 in the oral group and 19/20 in the intravenous group. Three babies left against medical advice.
  • Setting: The trial was conducted in a single centre, a level III neonatal intensive care unit in an urban academic medical centre in Pune, India
  • Patients:
    • Inclusion criteria:
      • Infants >/= 34 weeks with pulmonary arterial pressure (PAP) >25mmHg on echocardiography within 72 hours of birth. Pulmonary pressures were measured by tricuspid regurgitation velocity. The study did not include details of patent ductus arteriosus, patent foramen ovale shunting or right ventricular function.The study did record the pulmonary pressure at the initial time point and then at 12 hourly intervals until 144 hours of age which is available in the Supplementary Data. .
    • Exclusion criteria:
      • Congenital heart disease (except patent ductus arteriosus, patent foramen ovale, atrial septal defect, or a single muscular ventricular septal defect of <4 mm size)
      • Congenital diaphragmatic hernia
      • Any lethal congenital anomaly
      • Contraindication for oral or IV sildenafil (systemic hypotension, necrotizing enterocolitis [NEC], or gastrointestinal bleeding)
        • Systemic hypotension was not defined
      • Neonates who were treated with inhaled nitric oxide (Oxygenation index (OI) >15 or at physician’s discretion)
    • Intervention/Comparison:
      • Oral sildenafil group: 6-hourly oral sildenafil at 1 mg/kg/dose. Sildenafil was given by dissolving a 20mg oral tablet with 20mL distilled water creating a 1mg/mL solution given via an orogastric tube.
      • IV sildenafil group: Loading dose of 0.4 mg/kg of sildenafil over 3 h followed by continuous infusion of 1.6 mg/kg/day.
      • Not all infants were nil by mouth. Upon reviewing the supplementary data 7/20 babies in the oral sildenafil group were on full feeds from the beginning compared with 2/20 babies in the intravenous sildenafil group.
      • Once treatment was started, echocardiograms were repeated every 12 hours until PAP <25mmHg and sildenafil were tapered within 4 days and stopped. During tapering, an echocardiogram was performed every 24 hours, and in the case of a rebound increase of PAP >25mmHg, sildenafil was increased back to the original dose.
    • Outcomes:
      • Primary outcome: Time taken for PAP to <25mmHg
      • Secondary outcomes:
        • Time for Oxygenation Index (OI) to decrease by 25%
        • Days on invasive ventilation, non-invasive ventilation and nasal oxygen
        • Duration of hospital stay
        • Mortality
        • Failure of treatment
        • Complications
        • Time to reach full feeds
      • Analysis and Sample Size:
        • The trial aimed to enrol 40 patients based on likely enrolment rates in their nursery over the 2 years. This sample size calculation did not use treatment effect or alpha power.
        • From February 2019 to December 2020, 2042 neonates >/= 34 weeks were admitted. Fifty-one were diagnosed with mild to moderate PPHN. 11 patients met exclusion criteria. The remaining 40 infants were randomised to the oral or sildenafil group.
      • Patient follow-up: Follow-up data for the primary outcome was 17/20 in the oral group and 15/20 in the IV group. In total, 80% were assessed for the primary outcome. 

MAIN RESULTS

Baseline Demographics: There was no statistical significance between the baseline demographics of the two groups, including median gestational age and birth weight. In the oral group, APGAR scorers at 1min and 5 min were worse (5 and 7 vs 7 and 9), and higher rates of meconium aspiration (10/20 vs 6/20, p =0.102) in the oral group, however these characteristics were not statistically significant. PAP was higher in the IV group at the onset of treatment (39mmHg vs 35mmHg p=0.093). 

Table 1: Baseline characteristics of neonates with PPHN treated with oral or IV sildenafil

Oral Sildenafil n=20 IV sildenafil n=20 P value
Maternal characteristics
Primigravida 10 (50%) 9 (45%) 0.752
Medical condition
 Hypothyroidism 3 (15%) 4 (20%)  > 0.99
 Diabetes 3 (15%) 2 (10%)  > 0.99
 Hypertensive disorder 2 (10%) 3 (15%)  > 0.99
 Haemolytic anaemia 0 1 (5%)  > 0.99
 Covid + mother 2 (10%) 0 0.487
 Anemia 0 1 (5%)  > 0.99
 Mode of delivery 0.480
  VD 7 (35%) 4 (20%)
  LSCS 13 (65%) 16 (80%)
Neonatal characteristics
 Gestation (weeks)
Median (IQR)
39.35 (36.33—40.075) 37.85 (35.40- 39.63) 0.254
 Birth weight (grams)
Median (IQR)
2792.50
(2465.00—3297.50)
2792.50
(2135.00- 3153.75)
0.286
 Male gender 15 (75%) 14 (70%)  > 0.99
 Weight for gestation age 0.762
  SGA 4 (20%) 6 (30%)
  AGA 15 (75%) 13 (65%)
  LGA 1 (5%) 1 (5%)
 APGAR at 1 min
Median (IQR)
5.00 (4.00- 7.00) 7.00 (6.00–8.00) 0.015
 APGAR at 5 min
Median (IQR)
7.00 (6.00- 8.00) 9.00 (8.00–9.00) 0.001
 Sildenafil started at hours of life
Median (IQR)
19.00 (10.25- 40.75) 30.00 (12.50- 35.00) 0.661
 Initial pulmonary pressure (mm Hg)
Median (IQR)
35.00 (32.00- 43.75) 39.00 (32.75- 58.25) 0.093
 Underlying pathology
  MAS 10 6 0.102
  Pneumoniae 4 9 0.091
  Birth asphyxia 6 6  > 0.999
  Sepsis 1 3 0.292
  TTNB 1 0 0.311
  RDS 0 1 0.311
  Idiopathic 3 0 0.072
 OI at starting sildenafil
Median [IQR]
3.80 (2.20- 3.80)
N = 15
3.70 (2.50- 8.30)
N = 19
0.302
 Full feeds at time of starting sildenafil 7 (35%)
N = 20
2 (10%)
N = 20
0.127 

Primary Outcome:  Sildenafil could be tapered in 17/20 (85%) and 15/20 (75%) neonates in the oral and IV group. The primary outcome found that the median time taken for pulmonary pressures to reduce below 25mmHg was 48 hours in both the oral sildenafil (IQR 24-96 hours) and IV sildenafil (IQR 36-60 hours) group.   

Secondary Outcomes: There were no statistically significant differences between the treatment groups in terms of defined secondary outcomes. 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. Hypotension as a complication was defined as blood pressure less than 10th centile according to gestation and postnatal age.

Treatment failure occurred in 8 babies in the oral group vs 9 babies in the IV group. This was defined as the need for iNO or the need for another pulmonary vasodilator or failure to reduce PAP by 25% over 48 hours. Upon reviewing the supplementary data, it appears that a total of 8 babies from both groups were trialled to either another vasodilator or a combination of the other sildenafil preparation, milrinone, bosentan or iNO.  In the oral sildenafil group, 3 babies were trialled on another pulmonary vasodilator (one baby to IV sildenafil, one to milrinone and one to bosentan). Whilst in the IV sildenafil group, 5 babies were trialled with another pulmonary vasodilator (one baby a combination of bosantan and iNO, one baby a combination of oral sildenafil and bosentan, three babies to oral sildenafil and one to milrinone). All 8 patients, despite the trial of another pulmonary vasodilator were non responders, with high pulmonary arterial pressures without a 25% reduction in pressures over 48 hours.

CONCLUSION

This trial demonstrated that the time taken to reduce pulmonary arterial pressures in the late preterm and term population with mild to moderate pulmonary hypertension, as confirmed by an echocardiogram within the first 72 hours, was 48 hours in both the oral and IV sildenafil group. Whilst there was no mortality in this trial during the hospital stay, complications of hypotension and poor cardiac contractility were observed in the IV group.  

COMMENTARY

Persistent pulmonary hypertension (PPHN) involves persistent pulmonary vascular resistance, which occurs in approximately 2 in every 1000 live infants.2 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.2However, 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. This found that sildenafil has the potential to increase survival in neonates with PPHN, particularly in settings where iNO is not available. 3

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) >25mmHg on echocardiography within 72 hours of birth. The primary outcome sought the time taken for PAP to <25mmHg, comparing 6 hourly oral sildenafil 1mg/kg/dose versus IV sildenafil given with a loading dose of 0.4 mg/kg of sildenafil over 3 hours followed by continuous infusion of 1.6 mg/kg/day. Once treatment was started, echocardiograms were repeated every 12 hours until PAP <25mmHg 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 hours 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.1

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. 

REFERENCES

  1. 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; 22:311.
  2. Pedersen, J., Hedegaard, E.R., Simonsen, U., Krüger, M., Infanger, M. and Grimm, D. Current and Future Treatments for Persistent Pulmonary Hypertension in the Newborn. Basic Clin Pharmacol Toxicol2018, 123: 392-406.
  3. Kelly LE, Ohlsson A, Shah PS. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev. 2017;8:CD005494.

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