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Three Part Question

In [ventilated preterm babies with pulmonary hypertension and hypoxia] does [addition of inhaled nitric oxide] [reduce mortality]?

Clinical Scenario

A 25 week gestation male infant, birth weight 520g, is transferred ex-utero to your Neonatal Unit for intensive care. On day 19 he remains ventilator dependent and is hypoxic on 60-95% oxygen. The Oxygenation Index (OI: a measure of respiratory failure) is 18. Chest X-ray shows clear lung fields. Echocardiogram by a senior Paediatric Cardiologist shows evidence of pulmonary hypertension. In view of these findings it is felt that a pulmonary vasodilator may help. You discuss entering the INNOVO Trial (a multicentre RCT of addition of inhaled nitric oxide (inNO) to babies with severe respiratory failure) with the parents, who agree and the baby is entered into the control (no addition of inNO) arm. In spite of this, parents ask for "everything" (including inNO) to be tried. Reluctantly you agree and inNO is administered as per the trial protocol (you inform the trial co-ordinators). The baby does not improve, and dies 24 hours later. Was it reasonable to administer inNO to this baby?

Search Strategy

Cochrane Library and PubMed.
(nitric oxide) AND (premature) AND (randomised clinical trial)

Search Outcome

Cochrane 1 trial, Pubmed 4 randomised trials, one author split dataset across 2 papers(²)

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Skimming JW et al, 1997, USA	23 preterms randomised to either 5 or 20ppm inNO	Open RCT (1b)	Arterial blood oxygen tension, 15mins after intervention	Equal increases in primary outcome, both groups	Short term physiological study No control group
Subhedar NV et al, 1997, UK	42 preterm babies (<32wk) randomised to inNO alone; dexamethasone alone; both; neither	Open RCT (1b)	Death before discharge and/or CLD	RR 1.05, 95% CI 0.84- 1.25 for inNO v controls	Neither treatment prevented CLD or death
Kinsella JP et al, 1999, USA	80 preterm babies, <34wk, randomised to 5ppm inNO or control.	Double blind RCT, single centre (1b)	Survival to discharge	RR 1.11, 95% CI 0.70- 1.8	Exp. Group had imroved PaO2 at 60min Study underpowered
The Franco-Belgium Collaborative NO trial Group, 1999, France/Belgium	204 preterm babies, randomised to 10ppm inNO or control	Open, multi centre, RCT	OI at 2h	Median 8.4 (inNO) v 12.4 (control); p= 0.005. Greatest in near-term infants	Study underpowered Baseline OI higher in the experimental group

Comment(s)

None of the above studies is able to answer our original question. The largest studies were under powered and failed to show important benefits for inNO in preterm babies. The smaller studies showed short-term physiological changes e.g. Subhedar: transient fall in OI with 5ppm inNO; Skimming: equal increases in oxygen tension after 15min of either 5 or 20ppm inNO. The possible longer-term side effects of inNO are not known. In spite of this, inNO is being routinely used in many UK neonatal units, without the safeguards implicit in participation in a clinical trial (5).

Clinical Bottom Line

Preterm infants should not be treated with inhaled nitric oxide outside of prospective, randomised-controlled trials. Long-term follow up of these babies is needed.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. Skimming JW, Bender KA, Hutchison AA, Drummond WH. Nitric oxide inhalation in infants with respiratory distress syndrome. J Pediatr 1997 Feb;130(2):225-230.
2. Subhedar NV, Ryan SW, Shaw NJ. Open RCT of inhaled nitric oxide and early dexamethasone in high risk preterm infants. Arch Dis Child Fetal Neonatal Ed 1997 Nov;77(3):F185-190 AND F191-197.
3. Kinsella JP, Walsh WF, Bose CL et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial. The Lancet 1999 Sep 25;354 (9184): 1066-1071.
4. The Franco-Belgium Collaborative NO trial Group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. Lancet 1999 Sep 25;354(9184):1066-1071.[erratum appears in Lancet 1999 Nov 20;354(9192):1826].
5. Royal College of Paediatrics and Child Health. Safeguarding informed parental involvement in clinical research involving newborn babies and infants. A Position Statement. December 1999.