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
. 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 . 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 , FiO2
>0.6 and PEEP ≥8
cm H2O). ARDS was
defined according to the American-European consensus conference
on ARDS published in 1994 . 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
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 (M30
min) and at 4 h (M4
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
after 4 h of iNO therapy when compared to the baseline value
. 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
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 , 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.
Statistical analyses were performed by using
Student t test, Wilcoxon rank test, ANOVA with LSD post
hoc test, chi-square and Fishers exact test. Differences were
considered significant at P<0.05.
Table I shows the baseline
characteristics of the two groups. The iNO was administered
after a median of 17.56 ± 8.51 h from establishing the diagnosis
of ARDS, and patients were receiving mechanical ventilation for
a median of 29.44 ± 15.91 h before enrollment.
TABLE I Comparison of the Baseline Characteristics
56.5 ± 24.8
58.9 ± 29.0
PRISM III score
20.56 ± 4.79
21.82 ± 5.33
57.07 ± 6.96
58.34 ± 5.17
58.19 ± 11.88
53.06 ± 9.85
PEEP, cm H2O
10.13 ± 1.15
10.12 ± 0.93
Paw, cm H2O
18.62 ±1 .09
18.53 ± 1.12
33.39 ± 6.82
32.12 ± 4.99
Date are presented as mean ± SD unless otherwise
indicated; iNOG: inhaled nitric oxide group; MOSF:
multiple organ system failure; PRISM III score:
Pediatric Risk of Mortality score; PEEP: positive
end-expiratory pressure; Paw: mean airway pressure; OI:
oxygenation index (mean airway pressure x FiO2,
x100/PaO2; cm H2O/mmHg).
At the end of the 4-h response test, we
observed a significant increase in PaO2/FiO2
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
||57.07 ± 6.96
||64.71 ± 9.16*
||71.68 ± 11.94*†
||58.19 ± 11.88
||58.25 ± 11.04
||55.19 ± 8.36
||33.39 ± 6.82
||29.53 ± 5.67
||26.89 ± 6.09*
||137.75 ± 13.47
||135.63 ± 13.07
||133.31 ± 15.74
||61.50 ± 3.10
||60.94 ± 2.95
||61.25 ± 2.86
|Date are presented
as mean ± SD; M0: baseline measurements before iNO
therapy; M30 min : measurements at 30 min; M4 h:
measurements et 4h; OI: oxygenation index; HR: heart
rate; MAP: mean arterial pressure; * P<0.05 compared
with M0; †P <0.05 compared with M30 min.
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).
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
The median length of iNO therapy was 4.1 ±
0.71 days (range 2.25 – 5.21). No adverse events were noted
during iNO treatment. Methemoglobin concentration did not exceed
1% of total hemoglobin. There was no difference in the duration
of mechanical ventilation and the use of neuromuscular blockers
and length of stay in intensive care between patients in the iNO
and control groups. The mortality between patients treated with
conventional therapy plus iNO and conventional therapy alone was
comparable (43.8% vs 47.1%; P=0.30).
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 . Rialp, et al. observed an
increase in PaO2/FiO2
only in patients with pulmonary ARDS, while no
improvement in oxygenation was seen in extra-pulmonary ARDS
. 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.  reported a sustained improvement in
oxygenation over 72 h, but this effect was observed only in some
patients. In another study, Fioretto, et al.  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 . 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.
As observed in other studies [2,3,5,10], our
results demonstrate that iNO neither reduced the duration of
mechanical ventilation nor intensive care stay. In contrast to
the study of Fioretto, et al. , we did not find any
differences regarding mortality in pediatric ARDS patients
treated with conventional therapy plus iNO and patients treated
with conventional therapy alone.
Recently, a systemic review by Afshary, et
al.  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.
In conclusion, treatment with iNO improves
short-term oxygenation and allows early reduction of ventilator
parameters in children with ARDS. This improvement in
oxygenation is not influenced by etiology of ARDS. Recognizing
the limitations of this study due to small number of cases and
retrospective controls, randomized controlled clinical trials
are warranted to further verify potential role of iNO therapy in
Contributors: All authors contributed
equally in all aspects of this work; Funding: None;
Competing interests: None stated.
What This Study Adds?
• Inhaled nitric oxide does not
affect long-term outcomes in children with acute
respiratory distress syndrome.
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