The available evidence does not support the routine use of inhaled nitric oxide (iNO) in the care of premature infants. We present a case series of 22 preterm infants born after prolonged preterm premature rupture of membranes and oligohydramnios with respiratory failure. Oxygenation index decreased significantly after commencement of iNO.
Inhaled nitric oxide (iNO) reduces the combined outcome of death or treatment with extracorporeal membrane oxygenation in newborn infants with respiratory failure born at or near term.1 However, a systematic review and meta-analysis of 14 randomized controlled trials of iNO therapy in preterm infants did not show any significant effect on mortality, chronic lung disease (CLD) or other morbidities.1 An individual patient data meta-analysis from 11 of these trials did not show benefits for different subgroups of infants.2 The National Institute of Health Consensus Development Conference workshop in 2010 concluded that ‘the available evidence does not support the use of iNO in early routine, early rescue or later rescue regimens in the care of premature infants below 34 weeks of gestation’.3
Despite this lack of proven benefit, positive effects of iNO have been reported in small numbers of preterm infants born following prolonged preterm premature rupture of the membranes. Premature rupture of membranes (PROM) occurring before 37 weeks of gestation is considered preterm (PPROM). Prolonged PPROM (⩾7 days) often results in oligohydramnios and is associated with increased neonatal mortality and both long- and short-term morbidity.4 Pulmonary hypoplasia and pulmonary hypertension, resulting in respiratory failure, occur frequently in this group of patients.5, 6, 7 A comparison of 12 cases of preterm infants born after prolonged PPROM who were enrolled in a large randomized multicenter trial of iNO compared to placebo showed increased survival (4/6 versus 2/6), reduced bronchopulmonary dysplasia (2/5 versus 2/2) and severe intraventricular hemorrhage or periventricular leukomalacia (1/5 versus 1/2) among the infants treated with iNO.5 Also, improved oxygenation and survival was reported in a number of small non-randomized studies of preterm infants with severe hypoxic respiratory failure born following prolonged PPROM.6, 7, 8, 9, 10, 11, 12
At our hospital, preterm infants with severe hypoxic respiratory failure may be treated with iNO as a rescue therapy (that is, those who remain hypoxic following treatment with ventilation and surfactant) at the discretion of the attending physician. We present a case series of preterm infants delivered after prolonged PPROM treated with iNO.
We identified preterm infants born after prolonged PPROM treated with iNO at our hospital between 2007 and 2012. Infants with the following were included in the study: gestational age <32 weeks, birth weight ⩽1500 g, documented PPROM⩾7 days, oxygenation index ((OI), calculated as a fraction of inspired oxygen (FiO2) multiplied by mean airway pressure (mmHg) multiplied by 100, divided by partial pressure of arterial O2 (PaO2, mmHg)) ⩾10 despite surfactant (Curosurf, Chiesi, UK) treatment and documented iNO therapy. From their medical records, we calculated the infants’ Clinical Risk Index for Babies (CRIB) I and II scores to estimate the level of illness.13, 14 We recorded the following outcomes:
OI response at 1 and 24 h after starting iNO
Survival to discharge
CLD—oxygen therapy at 28 days of life
CLD—oxygen therapy at 36 weeks postmenstrual age
Severe intraventricular hemorrhage >grade 2
Cystic periventricular leukomalacia
Necrotizing enterocolitis ⩾Bell's stage 2
Retinopathy of prematurity >grade 2 disease
Pneumothorax and pulmonary interstitial emphysema
We also recorded the starting dose of iNO, duration of iNO therapy, ventilation mode, number of surfactant doses administered and availability of echocardiographic confirmation of suspected pulmonary hypertension. The data were analyzed using a PC-based statistics package (StatsDirect version 3.0.97, StatsDirect, Altrincham, UK). Descriptive statistics, paired t-test and Fisher's exact test were used and P<0.05 was considered statistically significant. The local research ethics committee approved the study.
We identified 22 infants who fulfilled the inclusion criteria for the study. Detailed cohort characteristics are presented in Table 1. All infants were intubated, mechanically ventilated and had received surfactant before iNO was started. Ventilation and cardiovascular support were conducted according to individual patient needs and usual departmental practice with 7/22 of the babies receiving high frequency oscillatory ventilation and 15/22 receiving inotropes. Seventeen of the 22 infants had point of care echocardiography examination before starting iNO and 16 had findings consistent with pulmonary hypertension.
iNO therapy was started at a median (interquartile range) age of 3 (2–4) hours. More details regarding iNO therapy are available in Table 1. OI dropped significantly 1 h post iNO initiation with a further gradual decrease after 24 h of iNO therapy. Initially, we observed a significant increase in PaO2 1 h after starting iNO without change in mean airway pressure, followed by a significant decrease in mean airway pressure 24 h later. Nineteen out of 22 babies survived to discharge. Two infants had multiple organ failure resulting in death at 3 and 5 days, respectively and one infant died of pulmonary hemorrhage associated with early onset sepsis at 6 h of age. All outcomes are summarized in Table 2.
We have identified three cases fulfilling the inclusion criteria, who did not get iNO treatment. Unfortunately, all of them passed away within the first day of life. These patients’ characteristics seem to have been similar to those receiving iNO, with the best OI 26.7±8.4 as compared to the pre-iNO OI in the iNO group 29.7±15.2. However, the number of such cases is very small and thus the data cannot be presented as a full comparative study.
All the infants, whose cases we present, had a substantially high mortality risk. We felt an ethical obligation to commence iNO as a potential rescue therapy, while being aware of the current lack of evidence to support our decision. The OI decreased significantly at both 1 and 24 h after starting iNO treatment, indicating a substantial improvement in the initial respiratory disease. Although the infants in our cohort had worse oxygenation than those in the iNO arm of a large randomized trial of 420 infants <1500 g with respiratory failure (PiNO; mean OI 29.7 versus 23), the outcomes, even given the small sample size, appear favorable.15 The composite outcome of CLD or death in our cohort was 64% compared to 80% in the iNO arm of the PiNO trial, severe intraventricular hemorrhage/periventricular leukomalacia occurred in 29% compared to 39%, respectively. Our results are in agreement with the published outcomes of the PiNO trial subset of cases born after prolonged PPROM,5 suggesting that this specific subpopulation might benefit from iNO. The question remains whether the incidence of CLD and the number of severe morbidities would be lower if these babies had been stabilized earlier, that is, if iNO was not used only as an ultimate rescue therapy and instead was started after the first dose of surfactant in a baby unresponsive to other measures. In our cohort, infants born between the years 2007 and 2009 received significantly more surfactant doses prior to the commencement of iNO, with 50% (5/10) receiving three doses, as opposed to only 8% (1/12) in the years 2010 to 2012 (P=0.05). The outcomes of both groups are similar in terms of the rate of death or CLD (70% in 2007 to 2009 and 58% in 2010 to 2012, respectively; P=0.61), with a significant decrease in the incidence of severe intraventricular hemorrhage/periventricular leukomalacia (50% in 2007 to 2009 versus 9% in 2010 to 2012, respectively; P=0.05).
This case series contributes to the existing evidence illustrating the benefit of iNO therapy in a subgroup of preterm infants born with a history of prolonged PPROM, oligohydramnios and suspected pulmonary hypoplasia. Larger randomized trials are desirable. In the meantime, given the evidence currently available, we would advocate iNO treatment in this particular population.
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This work was supported by the EU FP7/2007–2013 under grant agreement no. 260777 (The HIP trial).
The authors declare no conflict of interest.
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Semberova, J., O'Donnell, S., Franta, J. et al. Inhaled nitric oxide in preterm infants with prolonged preterm rupture of the membranes: a case series. J Perinatol 35, 304–306 (2015). https://doi.org/10.1038/jp.2015.2
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