The aim of this study was to evaluate the effects of inhaled nitric oxide (iNO) therapy on oxygenation and mortality in children with acute respiratory distress syndrome (ARDS). Thirty-three children with ARDS and an arterial SatO2 <88% despite mechanical ventilation were analyzed. Patients in the iNO group were prospectively enrolled and treated with conventional therapy plus iNO. The control group consisted of retrospectively analyzed patients treated only with conventional therapy. A significant increase in PaO2/FiO2 ratio (25.6%) and decrease in oxygenation index (19.5%) was observed after 4 h of iNO treatment, when compared to baseline values. A positive response to iNO was detected in 69% of patients, and there was no difference between pulmonary and extrapulmonary ARDS. There was no difference in mortality and duration of mechanical ventilation between iNO and control group.

Key words: Acute respiratory distress syndrome, Children, Inhaled nitric oxide.

Inhaled nitric oxide (iNO) therapy was shown to improve arterial oxygenation in patients with acute respiratory distress syndrome (ARDS) for the first time in 1993 [1]. Since then, numerous studies have evaluated the use of iNO therapy in adults with ARDS [2-4] while, only one randomized controlled study has been conducted in children [5]. We conducted this study to evaluate the additional benefit of inhaled nitric oxide over conven-tional therapy in terms of oxygenation mortality and duration of mechanical ventilation in children with ARDS.

Thirty-three children, aged 2-9 years, admitted to the pediatric intensive care unit of University Children’s Hospital in Belgrade with ARDS were enrolled in this study. Children were selected if they had arterial SatO₂ <88% despite mechanical ventilation (ventilation with low tidal volume [6], FiO₂ >0.6 and PEEP ≥8 cm H₂O). ARDS was defined according to the American-European consensus conference on ARDS published in 1994 [7]. The iNO group comprised of 16 prospectively enrolled patients with ARDS. These patients were treated with conventional therapy plus iNO. The control group consisted of 17 retrospectively analyzed patients who were treated with conventional therapy alone, due to lack of other therapeutic modalities.

The institutional ethics committee approved this study and informed consent was taken before starting iNO therapy. Baseline hemodynamic data, gas exchange values, and ventilator settings were recorded. PaO₂/FiO₂ ratio and oxygenation index were calculated. Following these baseline measurements (M₀), iNO was initially administered during a 4-h response test. In the first 30 min, iNO was given at 20 ppm, and for the next 30 min, the dose was reduced to 10 ppm, regardless of the response. Then the dose was reduced to 5 ppm and maintained for 3 h to complete the 4-h response test. Hemodynamic and respiratory parameters were measured at the end of 30 min (M_{30 min}) and at 4 h (M_{4 h}). The conventional therapy and ventilator settings were not changed during the 4 h. A positive response to iNO was defined as an increase in PaO₂/FiO₂ ratio ≥10 mmHg after 4 h of iNO therapy when compared to the baseline value [8]. In patients who showed a positive response, iNO was continued at 5 ppm and respiratory measurements were further taken at 12 hourly intervals for 72 h. When SatO₂ ≥88% was achieved with FiO₂ <0.6, iNO was gradually disconnected over 6-12 h. Methemoglobin levels were assessed during iNO therapy.

iNO was administered following the guidelines and techniques previously described [8,9]. It was delivered through a commercially available delivery device (Pulmonox Mini Messer, Austria), which incorporated continuous NO and NO2 monitoring in the distal inspiratory limb.

Conventional therapy included treatment of the underlying illness, mechanical ventilation, hemodynamic support, and administration of inotropes, steroids and nutrition. Regarding mechanical ventilation, a protocol with low tidal volume was used [6], while FiO2 was adjusted to maintain PaO2 between 55 and 65 mmHg. All patients were sedated and paralyzed. Surfactant therapy, prone positioning, and recruitment maneuvers were not applied in any patient regardless of the group.

TABLE I Comparison of the Baseline Characteristics 

At the end of the 4-h response test, we observed a significant increase in PaO2/FiO2 ratio by 25.6% (P<0.001), and decrease in OI by 19.5% (P<0.001) as compared to baseline values (Table II). A positive response to iNO was detected in 69% of patients and a significant increase in PaO2 compared to the baseline value was observed during the initial 12 h (P<0.001). There was no difference between pulmonary and extrapulmonary ARDS (45.5% vs 54.5%; P=0.36).

TABLE II	Effect of Inhaled Nitric Oxide (iNO) on Gas Exchange, Respiratory and Hemodynamic Parameters 

During 4-h Response Test	

Fig. 1 Course of PaO2 throughout 72h in patients with positive response to inhaled nitric oxide therapy and in patients without response to inhaled nitric oxide.

Twenty-four hours after the onset of iNO therapy, there was no difference in PaO2 compared to baseline value, and no difference between patients who had showed positive response to iNO and those who did not (Fig.1). PaO₂/FiO₂ ratio at 12 h, at 24 h and at 36 h, was significantly higher in responders as compared to non-responders (P<0.001, P=0.022 and P=0.011 respectively) and OI at 12 h, at 24 h and at 36 h was significantly lower in responders as compared to non-responders (P=0.009, P=0.028 and P=0.031, respectively).

Our results show that iNO acutely improves oxygenation in ARDS patients, which is consistent with other reports in children [5,10] and adults [2-4]. In our study, 69% of patients showed a positive response to iNO, which is much less than the 100% response rate reported in other pediatric studies [10,11]. Some studies suggested that the response to iNO was associated with the etiology of ARDS [12]. Rialp, et al. observed an increase in PaO2/FiO2 ratio only in patients with pulmonary ARDS, while no improvement in oxygenation was seen in extra-pulmonary ARDS [13]. However, in our study, improvement in oxygenation was not affected by the etiology of ARDS.

In addition, we observed a significant improvement in oxygenation during initial 12 h that resolved by 24 h. This initial improvement in PaO2 allowed for a reduction of FiO2 and a decreased intensity of mechanical ventilation throughout 36 h, which potentially reduced ventilator lung injury. Dobyns, et al. [5] reported a sustained improvement in oxygenation over 72 h, but this effect was observed only in some patients. In another study, Fioretto, et al. [10] began early iNO therapy at 1.5 h after ARDS was diagnosed. They observed not only the highest percentage of improvement in PaO₂/FiO₂ ratio, OI, and a response rate of 100%, but also demonstrated a sustained improvement in oxygenation over 4 days. Results of experimental studies also support the idea that early iNO could be more effective [14]. In the present study, we began iNO administration early, in the first 24 h after establishing the diagnosis of ARDS; however; we did not observe a sustained response in oxygenation.

Recently, a systemic review by Afshary, et al. [15] showed that iNO transiently improves oxygenation in the first 24h in ARDS patients, but no significant effects of iNO on mortality or other clinical outcomes were observed. Since most of the patients in those studies were adults, they concluded that there is insufficient data to support or refute the routine use of iNO in pediatric ARDS patients.

15. Afshari A, Brok J, Moller AM, Wetterslev J. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults. Cochrane Database Syst Rev. 2010;7:CD002787.