• 
• 

Three Part Question

In [preterm infants with pulmonary hypoplasia], does [inhaled nitro oxide] added to invasive ventilation, versus invasive ventilation alone, result in [improvement in hypoxic respiratory failure]?

Clinical Scenario

A 28 week gestation baby is delivered by spontaneous vaginal delivery following prolonged preterm rupture of membranes of 6 weeks. He requires intubation and ventilation at delivery in view of respiratory distress and receives surfactant. He is transferred to the neonatal unit and is placed on volume guided ventilation, has a UVC and UAC inserted, receives antibiotics and is commenced on parental nutrition. His oxygen saturations are 80% in 100% oxygen. Despite increasing his tidal volume, changing to high frequency oscillation ventilation, repeating surfactant, and commencing inotropic support to maintain his blood pressure he still remains hypoxic. CXR shows the endotracheal tube, UAC and UVC in a good positions, the lungs look small and there is no pneumothorax. An echo shows pulmonary hypertension. Despite multiple inotropes and significant ventilator settings, he remains in hypoxic respiratory failure with an OI of 25. You wonder if inhaled nitric oxide would be of benefit.

Search Strategy

MEDLINE
EMBASE (1974-2016 Week 23)
SCORPUS
All searched between 3-6th June 2016
MEDLINE:
((MeSH infant, extremely premature OR infant, premature, OR premature birth) OR (MeSH infant, low birth weight OR infant, very low birth weight OR infant, extremely low birth weight))
AND (KW “pulmonary hypoplasia” OR MeSH oligohydramnios OR MeSH “fetal membranes premature rupture” OR KW “prolonged rupture of membranes) AND (MeSH “nitric oxide” OR KW “inhaled nitric oxide” OR KW “iNO”)
EMBASE:((MeSH prematurity OR MeSH “low birth weight”) AND (MeSH infant OR KW neonate OR MESH newborn)) AND (MeSH “lung hypoplasia” OR MeSH oligohydramnios” OR MeSH “premature fetus membrane rupture” OR KW “prolonged rupture of membranes) AND (MeSH “nitric oxide” OR KW “inhaled nitric oxide”)
SCORPUS((Ti=premature OR Ti=preterm* OR Ti=”low birth weight”) AND (Ti=infant* OR Ti=neonate* OR Ti=newborn OR Ti=baby)) AND Ti=”pulmonary hypoplasia” OR Ti= oligohydramnios OR Ti=”prolonged rupture of membranes” OR Ti=”premature rupture of membranes” OR Ti= “prolonged premature rupture of membranes” OR Ti= “premature prolonged rupture of membranes”) AND (Ti=”nitric oxide” OR Ti=”inhaled nitric oxide”)) AND (“respiratory failure” OR “acute respiratory failure” OR “oxygenation index”

Search Outcome

MEDLINE
19 studies identified, 12 excluded after review and application of inclusion/exclusion criteria
EMBASE
42 studies identified, 40 excluded after review and application of inclusion/exclusion criteria
SCORPUS
24 studies identified, 23 excluded after review and application of inclusion/exclusion criteria

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Chock VY 2009 America	<34 weeks gestation >401grams Assisted ventilation Respiratory failure < 4hours despite surfactant Pulmonary hypoplasia on CXR with USS PROM or oligohydramnios > 5 days	Design: Retrospective subset analysis of 2 RCT's - PiNO Trial (Van Meurs et al. 2005) and Larger Preemie Pilot )Van Meurs et al. 2007). Block stratification by centre and gestation, over telephone. Both were double blinded with external personnel setting up gas supply and monitors and mock equivalent for placebo Intervention: 5-10ppm iNO or placebo, (oxygen) Setting: 16 US hospitals in National Institute for Child Development Neonatal Research Network 2001-2003 Primary outcomes: Mortality +/- bronchopulmonary dysplasia, (oxygen dependence at 36 weeks post menstrual age) Secondary outcomes: IVH>grade 2, PVL, days on mechanical ventilation, days on oxygen, change of oxygen from baseline, neurodevelopment at 18-22 months, (Bayley Scales of Infant Development) Ethics approval and written parental consent Results: 12 babies - 6 in each arm Mean gestation iNO 27+/-2 v placebo 29+/-3 Mean weight iNO 1039+/-355g v placebo 1179+/-369g Mean GA at ROM iNO 18+/-3 weeks v placebo 19+/-3 weeks	Change in PaO2	iNO group increase of 39 +/-50 mmHg v decrease 11+/-15 in placebo group	Small numbers. Initial RCTs's were powered to detect effect, but as this was retrospective subset analysis it was no longer powered for analysis. Placebo babies were sicker - higher OI and inotrope requirement, (blamed on an outlier) although not significant Unmeasured variability in severity of pulmonary hypoplasia, (not all had echo)
			Mortality	iNO 2/6 v placebo 4/6 p 0.57
			BPD	iNO 2/5 v placebo 2/2 p 0.43
			Mortality or BPD	iNO 3/6 v placebo 6/6 p 0.18
Aikio O 2012 Finland	<32 weeks gestation Mechanical ventialtion <12 hours old OI>25, arterial-alveolar oxygen pressure ration <0.1 Received surfactant PPHN on echo with specific diagnostic criteria Excluded if lethal congenital abnormality/chromosomal or other severe abnormality, septic shock, severe birth asphyxia	Design: Prospective cohort study Cases: As above Comparators: Pairwise matched by gestation and birth month/year (mean difference 1.6yrs) 3 comparison groups - PROM, no PROM, maternal pre-eclampsia All babies screened over 12 year period (1997-2009) Setting: Oulu University Hospital, Finland - single centre Intervention: iNO 20ppm Outcomes: Not specified Ethics committee approval and written parental consent Results: iNO group mean gestation 27.8+/-2.3, weight 1311+/-647g, ROM duration 35 days (2-77)	OI 1 hour pre iNO	40	Small Single centre over 12 years - risk of unknown confounders and historical control bias Cases and comparators were intrinsically different - comparators - no PPHN, av OI 7.2, therefore not a true comparison, More like a case study for the information I want
			OI 1 hour post iNO	8.4
			BPD in iNO group	12/17
Semberova J 2015 ?Ireland	< 32 weeks gestation ≤1500g PROM≥7 days OI≥10 despite surfactant iNO	Design: Retrospective case series Setting: 2007-2012 single centre ?Dublin, Ireland Identification of cases: Not clear if consecutive Intervention: iNO mean dose 16.5+/-5.3ppm Outcomes OI response at 1 and 24 hours post iNO Survival to discharge Chronic lung disease (oxygen requirement at 36 weeks post menstrual age) IVH >grade 2 PVL NEC>Bells 2 ROP >stage 2 Pneumothorax/PIE Local research ethics committee approval Results: 22 cases identified mean gestation 26.2+/-2.2 weeks, mean weight 931+/-250g,PROM 41.5+/-26.5 days	OI pre iNO	29.7+/-15.2	Case series and not clear if consecutive and complete inclusion of cases Small but actually larger than any other case series, or the 1 RCT, or 1 cohort study in literature
			OI 1 hour post iNO	9.2+/-5.7 p<0.0001
			Survival to discharge	19/22
			CLD	11/19

Comment(s)

Meta-analysis of use of iNO in preterm infants has concluded that it is not beneficial, however this encompasses a variety of babies of wide gestations, weights, pathology, i.e. heterogeneous sample. Several reports of benefit in some preterm babies - those with pulmonary hypoplasia. However there is limited evidence in literature. Only 1 RCT with very small numbers, not powered for analysis. 1 cohort study, but high bias and more like a case series. Several case series in literature ranging from 1 or 2 cases to 22 cases, (Semberova). Although a case series and not clear if has consecutive inclusion of cases, it has the least bias. Given the limited evidence and likely difficulty in acquiring more - rare condition and ethical considerations of randomising an infant to placebo arm when already on all the current treatments, and absence of apparent side effects, (although short term) it would be prudent to trail iNO.

Clinical Bottom Line

The evidence is limited, but difficult to get more. In the meantime a trail of iNO would be appropriate for preterm infants who have pulmonary hypoplasia and are in hypoxic respiratory failure after discussion with the rest of the team and parents. If there is no response in the first hour then it should be discontinued.

References

1. Chock VY, Van Meurs KP, Hintz SR, Ehrenkranz RA, Lemons JA, Kendrick DE and Stevenson DK Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia American Journal of Perinatology 2009 26(4):317-22
2. Aikio O, Metsola J, Vuolteenaho R, Perhomaa M and Hallman M Transient defect in nitric oxide generation after rupture of fetal membranes and responsiveness to inhaled nitric oxide in very preterm infants with hypoxic respiratory failure Journal of Pediatrics 161(3):397-403
3. Semberova J, O’Donnell SM, Franta J and Miletin J Inhaled Nitric Oxide in preterm infants with prolonged preterm rupture of membranes: a case series. Journal of Perinatology 35(4):304-306