{'fraction_non_alphanumeric': 0.02069781194559432, 'fraction_numerical': 0.002562586240883107, 'mean_word_length': 4.832183908045977, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Towards rational use of inhaled Nitric Oxide in preterm babies

On the basis of best available evidence, learned authorities do not recommend routine use of inhaled nitric oxide (iNO) in preterm infants in hypoxic respiratory failure (1). Yet published audits, mainly from resource rich health systems, show that iNO continues to be used in a significant minority of very preterm infants, in increasing proportions in the most immature (2,3). The forces that drive this usage are probably the intensivist’s instinct to try everything when approaching the end of the therapeutic line in a baby with failing oxygenation. This is understandable, but iNO is an expensive treatment, and no health system has infinite resources, so the continuing widespread use in preterm infants is cause for concern, review and rationalisation. Implementation of findings from clinical trials into practice should always be cognisant of the generalisability. Most of the clinical trials of INO in preterm infants for hypoxic respiratory failure, enrolled on the basis of oxygenation alone, usually oxygenation index (OI). These trials did enrol on the basis of range of severe OIs and included a range of gestations and birthweights. So the evidence is clear that if you are faced with a preterm baby in whom the only information you have in relation to pulmonary hypertension (PH) is a high OI, then administration of iNO will not generally improve this baby’s outcome. But questions remain as to whether this generalisation applies all preterm babies. In this edition of Acta Paediatrica, the study of Cheng et al. (4) highlights some of the unanswered questions around the use of iNO in the very preterm infant. iNO is a vasodilator that relieves pulmonary vasoconstriction in PH. Yet none of the clinical trials used an assessment for PH in the enrolment criteria. Instead, they made the pragmatic but flawed assumption that oxygenation is a surrogate marker for PH. Not all babies with oxygenation failure have PH and not all babies with PH have oxygenation failure (5). Cheng et al. ask the important question whether introduction of neonatologist performed cardiac ultrasound (NPCU) into their programme, and so more accurate assessment of pulmonary artery pressure (PAP), had changed the pattern of usage and outcome of iNO in preterm infants. The study is limited by its retrospective design, and incomplete ultrasound assessment of babies in the period after ultrasound was introduced, only 64% had an ultrasound assessment. After introduction of NPCU, iNO was used in more preterm babies and it was used earlier (median 1.8 hours) and for shorter duration, but there was no differences in other outcomes. It is difficult to interpret from this data whether introduction of NPCU led to a rationalisation of the use of iNO, particularly as the numbers increased in the later ultrasound epoch. It is possible that the ultrasound findings encouraged more treatment with iNO. The paper does not give us the population denominator in each time epoch to allow interpretation of this. The evidence from clinical trials is not only confounded by a lack of assessment of PAP but also a continuation of two misconceptions in the design of those trials; firstly, that PH is a common primary problem in preterm respiratory disease and secondly that neonatal PH represents just one haemodynamic, that of high pulmonary vascular resistance with reduced pulmonary blood flow, and right to left shunt through the foetal channels, the classic persistent foetal circulation. Nothing is simple in biological systems and many factors play into preterm PAP. Firstly, the natural fall in PAP during the postnatal period is slower than many imagine. Even in well-term babies, it is not uncommon to find pulmonary pressures close to systemic for the first six to eight hours of life (6). Some of this is due to overshoot of the natal increase in pulmonary blood flow as a result of left to right shunt through the ductus before closure. The laws of fluid dynamics dictate that pulmonary pressure is the product of resistance and flow. Postnatally, resistance falls and flow rises so pressures stay much the same. This increase in blood flow is often exaggerated in the preterm infant with failure of ductal constriction. The second is that positive pressure ventilation in itself will increase PAP, particularly at higher ventilation pressures. PAP has to be higher in this situation to maintain pulmonary blood flow in the face of high positive intrathoracic pressure. So when using ultrasound to assess for PH in a two-hour-old baby on high-pressure ventilation, defining pathological from physiological can be difficult. What is clear is that it should be more than just a measure of PAP. In both circulations, pressure is only important in as much as how it reflects in flow. iNO is associated with a wide range of response in terms of improvement in oxygenation. At one end of the spectrum, there is no (or muted) change; at the other end, a baby will go from 100% oxygen to air in a matter of minutes.