MANUSCRIPT CITATION

Ellsworth K, Ellsworth M, Weaver A, Mara K, Clark R, William A. Carey W Association of Early Inhaled Nitric Oxide With the Survival of Preterm Neonates With Pulmonary Hypoplasia JAMA Pediatrics 2018; 172(7)e180761. PMID: 29800952.

REVIEWED BY

Rashmi Mehta
Paediatrics Level 3 trainee, University Hospitals of Birmingham: Heartlands

Harsha Gowda
Neonatal Consultant, University Hospitals of Birmingham: Heartlands

TYPE OF INVESTIGATION

Treatment

QUESTION

In a cohort of preterm infants of less than 29 weeks gestation, with Preterm Premature Rupture of Membranes (PPROM) and presumed pulmonary hypoplasia (PH) (Patient population), what is the effect of inhaled nitric oxide (iNO) (Intervention) on mortality (Outcome) compared to infants who did not receive iNO (Comparison), when initiated within first seven days  of life (Time)?

METHODS

• Design: Retrospective cohort analysis with propensity score matching. The current review focuses on subset of infants with presumed PH and PPHN withing the matched cohort.
• Allocation: No allocation
• Blinding: Unblinded
• Follow up: Infants were followed until death, transfer or discharge home.
• Setting: The study used data from Pediatrix Medical Groups Clinical Data Warehouse, which included data from more than 350 neonatal intensive care units in 35 US states and Puerto Rico.
• Patients: Eligible patients included singleton neonates born between 22⁺⁰ to 28⁺⁶ gestation with birth weight of 400 grams or more and clinical diagnosis of PH as cause of their respiratory distress. There were no predetermined criteria for the diagnosis of either PH or PPHN. The neonates diagnosed with aneuploidy, congenital diaphragmatic hernia, congenital heart disease, hydrops or major congenital anomalies and who died in the delivery room or not admitted for neonatal intensive care (eg, for comfort care measures only) were excluded.
• Interventions: Use of iNO within first 7 days of life.
• Primary outcomes: Primary outcome was in-hospital mortality, defined as death prior to discharge home or transfer.
• Analysis and sample size: The sample size included 302 matched infants of which 210 infants belonged to the subgroup of PH with PPHN. In this subgroup 110 infants (52%) had PPROM.
• Patient follow-up: (% included in analysis): 100%

MAIN RESULTS

Patient characteristics: Table 1 (SD: Standardised difference)

Primary outcome:  Table 2 ( HR: Hazard Ratio, CI: Confidence interval)

In infants who received iNO, there was 33% reduced risk of in-hospital mortality in infants with PH and PPHN, compared to their matched referent group. However, this difference was not significant (HR, 0.67; 95% CI, 0.45-1.01). The mortality was similar in exposed and referent groups of infants with PH and no PPHN.  The results from the sensitivity analysis were consistent with those found in main analysis.

CONCLUSION

In the cohort of infants with PH, with or without PPHN, no significant difference in association of mortality was observed between the group exposed to iNO and the referent group. In the study, the authors did not specify the defining characteristics of either PH or PPHN. This may have led to variation in severity of the PH. The sample size of the subset of infants with PPHN and PH is small and only this subset considered in the review. Large prospective randomised study with higher power, may establish the advantage of using iNO in this group of infants and inform characteristics of infants who may or may not benefit from iNO.

COMMENTARY

Pulmonary Hypoplasia (PH) is a decrease in the size and volume of the lungs due to reduced number of cells, alveoli and airways (1). As amniotic fluid is essential for foetal lung development, mid-trimester anhydroamnios /oligohydroamnios can contribute to the development of PH. PH resulting from Preterm Premature Rupture of Membranes (PPROM) is associated with high mortality and co-morbidities (2). Definite diagnosis of PH can only be established at post-mortem using lung body ratio (3). As a surrogate, a presumed diagnosis of PH could be made using clinical indicators such as difficult ventilation, low lung volume on chest radiograph and pulmonary hypertension on echocardiography.

Inhaled Nitric oxide (iNO), a specific pulmonary vasodilator, acts via the cyclic guanosine phosphate on the endothelial cells of pulmonary vessels leading to muscle relaxation and reduction in the pulmonary artery pressures, hence reversing the hypoxia and pulmonary hypertension (4).

The Cochrane systematic review by Barrington et al (2017) found that use of early rescue iNO did not improve mortality rates in preterm infants of less than 35 weeks gestation with respiratory failure complicated by persistent pulmonary hypertension (PPHN) (5). However, the review does not specifically reflect on subgroup of infants with PH and PPHN secondary to PPROM. In clinical practice iNO is often used in this subgroup of patients, although the evidence is sparse in literature.

Ellsworth et al (2018) conducted a retrospective cohort study with propensity score matching to determine whether iNO treatment within first week of life was associated with improved survival in extremely preterm infants (6). For this analysis, from the 302 matched neonates included in the original study, only the 210 belonging to the subgroup of infants with PH and PPHN were considered. Fifty-two percent (n= 110) of the infants in this subgroup had PPROM. From this subgroup, a 33% reduced risk of in-hospital mortality was observed in infants who received iNO compared to matched referents was observed. However, this difference was not statistically significant.

Propensity score matching would enable to reduce the differing baseline characteristics of the exposed and the referent groups. There were no defining criteria for either the PH or PPHN diagnosis, and the presence or absence of these conditions was at the discretion of the treating neonatologist. The doses of iNO, oxygenation indices and the echocardiography findings were not taken into account. The sample size of the subgroup is small and therefore the effect of iNO therapy may have been underestimated. The other limitations of the study include presence of confounding factors and incomplete representation of infants in subgroup analysis leading to ascertainment bias. Among the PH with PPHN and PH without PPHN subgroups, no significant difference in mortality has been found in group exposed to iNO and referent group.

A large prospective randomised study, powered for iNO treatment analysis with clear defining criteria of PH and PPHN, could establish the effect of using iNO in this group of infants with PPROM, PH and PPHN and help to tease out characteristics of those infants who may or may not benefit from iNO.

REFERENCES:

1. Askenazi SS, Perlman M. Pulmonary hypoplasia: lung weight and radial alveolar count as criteria of diagnosis. Arch Dis Child 1979; 54(8): 614–618
2. Kilbride HW, Yeast J, Thibeault DW. Defining limits of survival: lethal pulmonary hypoplasia after mid trimester premature rupture of membranes. Am J Obstet Gynecol 1996; 175(3 Pt 1):675–681.
3. De Paepe M, Friedman R, Gundogan F, Pinar H. Postmortem lung weight/body weight standards for term and preterm infants. Pediatr Pulmonol 2005; 40: 445–8
4. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation. 1991; 83(6): 2038-2047.
5. Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2017;1(1):CD000509.
6. Ellsworth KR, Ellsworth MA, Weaver AL, Mara KC, Clark RH, Carey WA. Association of Early Inhaled Nitric Oxide With the Survival of Preterm Neonates With Pulmonary Hypoplasia. JAMA Pediatr. 2018;172(7):e180761.