Early inhaled nitric oxide in moderately hypoxemic preterm and term newborns with RDS: the RDS subgroup analysis of the Franco-Belgian iNO Randomized Trial.
The French-Belgian iNO trial investigated the effect of inhaled nitric oxide treatment in moderately hypoxemic newborns. We wish to report the results in the RDS subgroup, with particular attention given to neurological effects. A prospective randomized controlled trial comparing inhaled nitric oxide and conventional therapy in severe neonatal respiratory failure and persistent hypoxemia was conducted by the Franco-Belgian iNO study group. The global results have been published elsewhere [1]. Respiratory distress syndrome (RDS) is a condition that can lead to severe hypoxemia. In this context, the hypoxemia may result from intrapulmonary shunting or persistent pulmonary hypertension [2]. Inhaled nitric oxide (iNO) as a selective pulmonary vasodilator has been proposed in this indication [2]. The aim of the Franco-Belgian iNO trial was to assess whether inhaled nitric oxide given at an early stage of respiratory distress reduced deterioration towards refractory hypoxemic respiratory failure in premature and near-term infants. As randomization was stratified by type of lung disease and gestational age, we tested this hypothesis in the RDS subgroup among the very premature (<33 weeks) and near-term (‡ 33 weeks) infants. We also sought to determine whether this effect was associated with neurological morbidity. The primary hypothesis concerning the RDS group was that in cases of hypoxemia after conventional openlung approach therapy, administering iNO at an early stage would reduce the oxygen index (OI) within 2 h and avoid development towards severe refractory hypoxemia [3]. The study included infants admitted to 33 neonatal intensive care units at less than 7 days of age with RDS between April 1995 and June 1997. The primary endpoint criterion was treatment success, the definition of which was based on OI at 2 hafter inclusion. Success was defined as an OI reduction of at least 33% or at least 10 points. One hundred and thirty infants were in the RDS group: 68 in the control group and 62 in the iNO treatment group. Eight of those assigned to the control group received iNO before the primary endpoint because of deterioration. Results are reported in Table 1. The treatment groups had similar baseline characteristics. The success rate was higher in the iNO treatment group (OR, 2.25 [1.06; 4.75]). Analysis by gestational age subgroups showed the same trend in the very preterm (OR, 2.22 [0.89; 5.55]) and the near-term infants (OR, 2.27 [0.63; 8.33]). This effect was not due to an increase in PaO2. There was no increase in neurological complications. Mortality as well as pulmonary morbidity was not affected by treatment. This was not a double-blinded trial. Outcome measurement bias was minimized by the objectivity of the outcome criterion. Bias related to the adjuvant therapy cannot be excluded. The cranial ultrasound scans for periventricular leukomalacia (PVLM) were reviewed by a practitioner blinded to treatment. We used a dose of 10 ppm. Compared with the 5-ppm dose used by Kinsella et al., it did not increase either the effectiveness or the hemorrhagic complications [4]. OI improvement after iNO was transient. Inhaled nitric oxide used at an early stage of respiratory distress syndrome significantly reduced the rate of deterioration of hypoxemia 2 h after treatment initiation without modifying mortality or pulmonary morbidity and without an excess of neurological anomalies. Eur J Pediatr (2003) 162: 646–647 DOI 10.1007/s00431-002-1134-2