insuficiencia respiratoria

1. 47
The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(S(1)): 47–50
© 2012 Informa UK, Ltd.
ISSN 1476-7058 print/ISSN 1476-4954 online
DOI: 10.3109/14767058.2012.665238
Nitric oxide (NO) is a cellular signaling molecule and a powerful
vasodilator. NO modulates basal pulmonary vascular tone and
it is important to reduce blood pressure and to treat hypox-
emic respiratory failure, such as persistent pulmonary hyper-
tension (PPHN) in newborns. PPHN is defined as a failure of
normal pulmonary vascular adaptation at or soon after birth,
resulting in a persisting high pulmonary vascular resistance.
iNO therapy decreases the need of extracorporeal membrane
oxygenation (ECMO) although it did not reduce mortality of
these patients. Severe meconial aspiration syndrome is associ-
ated with PPHN, resulting in severe hypoxemia; iNO adminis-
tration combined with HFV results in ameliorate oxygenation.
The cause of hypoxemic respiratory failure in patients with
congenital diaphragmatic hernia (CDH) is complex. CDH patients
experienced oxygenation improvement after iNO therapy, but
they can be often considered iNO poor responders. In some
cases iNO therapy can reduce the need of ECMO in presurgical
stabilization. The pathophysiology of respiratory failure and the
potential risks differ substantially in preterm infants. Pulmonary
hypertension can complicate respiratory failure in preterm
babies. Current evidence does not support use of iNO in early
routine, early rescue or layer rescue regimens in the care of
preterm infants.
Keywords: congenital diaphragmatic hernia, nitric oxide,
persistent pulmonary hypertension, preterm newborns,
respiratory failure
Nitric oxide: from biology to physiology
Nitric oxide, also known as nitrogen monoxide, is a binary
molecule with chemical formula NO. It is a free radical and is
an important intermediate in the chemical industry. In mammals
including humans, NO is an important cellular signaling molecule
involved in many physiological and pathological processes [1]. It
is a powerful vasodilator with a short half-life of a few seconds in
the blood. Long-known pharmaceuticals like nitroglycerine and
amyl nitrite were discovered, more than century after their first use
in medicine, to be active through the mechanism of being precur-
sors to nitric oxide. In vivo NO is synthesized from l-arginine
and oxygen by NO-synthase (NOS), a family of three isoenzymes,
all of which are expressed in the lung. Endothelial NOS (eNOS)
and neuronal NOS (nNOS) are constitutively expressed in the
human tissue [2]. Inducible NOS (iNOS), instead, are highly
expressed in response to multiple causes such as inflammation
and hypoxia. NO promotes its effects on target proteins by two
distinct signal pathways: cGMP-dependent pathway and redox-
related protein modification, the latter being independent of
cGMP. In the cGMP-dependent pathway, NO activates guanylate
cyclase, increases cGMP levels, and modulates the activity of
protein kinase G (PKG) and PKG alters the function of targeted
proteins [3]. The redox-related protein modifications induced by
NO include s-nitrosylation, nitration, and oxidation. These post-
translational protein modifications are dependent on the redox
state, and they play important roles both in physiological and
pathophysiological situations, such as the vascular relaxation [4].
The NO vasodilating action is mediated through the activation
of myosin light chain phosphatase and K+
channels in the cell-
membrane of vascular smooth muscle cell. NO can elicit effects
through cGMP independent mechanisms including interaction
with heme-containing molecules and protein containing reactive
thiol groups.
The action of cGMP is limited by phosphodiesterases. NO
bioavailability is also limited by its dangerous interaction with
superoxide radical O2
−, that resulting in the formation of the
potent pro-oxidant peroxynitrite (ONOO−
). In another catabolic
pathway, in the presence of oxygenate haemoglobin (Hb), NO is
rapidly metabolized to nitrate with formation of meta-Hb that in
the erythrocyte is reduced to ferrous-Hb [5]. In vivo NO modu-
lates basal pulmonary vascular tone in the late-gestational fetus.
Pharmacologic NO blockade inhibits endothelium dependent
pulmonary vasodilation and attenuates the rise in pulmonary
blood flow at delivery, implicating endogenous NO formation in
postnatal adaptation after birth [6]. Systematically administered
NO-donor drug such as nitroglycerin and sodium nitroprussiate
have been used to reduce blood pressure and to treat coronaric
obstruction. Many NO-donor compounds can dilate pulmonary
vasculature but the subsequent systemic hypotension is a clear
contraindication. Inhaled NO (iNO) is a selective pulmonary
vasodilator; when iNO reaches bloodstream it can be scavenged
by Hb through the catabolic pathway we know and no systemic
hypotension occurs.
iNO: administration and safety
Pharmacologic use of NO has been validated since late 90′ by
FDA (1999) and EMEA (2001) for near-term and term infants
(up gestational age of 34 weeks) affected by hypoxemic respiratory
failure and evidence of pulmonary hypertension unresponsive to
other therapy.
review ARTICLE
Nitric oxide in neonatal hypoxemic respiratory failure
Maria Carmela Muraca1, Simona Negro1, Bo Sun2 & Giuseppe Buonocore1
1Departments of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Siena, Italy and 2Department of Pediatrics and
Neonatology, Laboratory of Neonatal Medicine of Ministry of Health, Shanghai, China
Correspondence: Maria Carmela Muraca, UOC Pediatria Neonatale, Departments of Pediatrics, Obstetrics and Reproductive Medicine,
University of Siena, Policlinico Santa Maria alle Scotte, viale Bracci 36, 53100 Siena, Italy. Tel: +39-0577–586523. Fax: +39-0577–586182.
E-mail: buonocore.giuseppe@unisi.it

2. 48 M. C. Muraca et al.
The Journal of Maternal-Fetal and Neonatal Medicine
iNO is a colorless and odourless gas that readily reacts with
oxygen to form pulmonary irritant nitrogen dioxide (NO2
).
Therefore, NO gas is stored as inert nitrogen and administered
by using a delivery system with an inline sensor to detect the
flow rates of gas through the ventilator circuit and a mass flow
controller for delivery NO gas to desired concentration. Because
the pulmonary vasodilator effects of NO are transient when the
gas is discontinued, it must administered continuously with
careful monitoring of NO and NO2
concentration. The delivery
system must supply a constant amount of NO during therapy
trough the inspiration arm of the ventilator. Commercially avail-
able equipment permits the safe delivery of NO gas in sponta-
neously breathing or intubated patients on CPAP, CMV or HFV
respiratory support. Before starting iNO therapy, ventilatory
support must be optimized by regulation of tidal volume, mean
airway pressure (MAP) and eventually surfactant administration
(if necessary). Starting dose of 6–20 parts per million (ppm) is
usually effective. Inhalation of up to 80 ppm of NO did not alter
systemic blood pressure but it is associated with adverse effect.
Abrupt discontinuation of iNO can result in “rebound”
pulmonary hypertension leading to a decreased cardiac output
and systemic hypotension. Careful monitoring of FiO2
, NO, NO2
and Met-Hb must be done and NO dosage must be regular and
continuously measured. NO2
must be always under the value of
0.5 ppm. Met-Hb level must be followed: if met-Hb rises (up to
2.5%),administrationofiNOmustbereduced;met-Hbmaximum
level tolerated is 5%. iNO administration must be gradually
discontinued within 96 h after improvement in oxygenation; if
no improvement observed, carefully examination of the newborn
must be performed and pulmonary capillary dysplasia excluded.
The iNO dosage must be reduced at 5 ppm within 4–24 h after
starting and than at 1 ppm before stopping. If FiO2
remains under
0.6, iNO can be stopped and restarting if rebound pulmonary
hypertension occurs.
Although studies in newborn infants suggest that inhaled NO
is safe, the long-term effects are unknown. The elevation of cGMP
in platelet can inhibit their function and subsequent improve
haemorrhagic diathesis, with elevated risk of intraventricular
haemorrhage (IVH) and neurologic disabilities.
iNO: whom to treat
Term and near-term hypoxaemic infants with persistent
pulmonary hypertension of the newborn
Persistent pulmonary hypertension (PPHN) is defined as a failure
of normal pulmonary vascular adaptation at or soon after birth,
resulting in a persisting high pulmonary vascular resistance such
that pulmonary blood flow is diminished and unoxygenated blood
is shunted to systemic circulation, via a right-to-left shunting
through an open foramen ovale and/or a ductus arteriosus.
Potential risk factors, such as prematurity, dysmaturity, infection,
meconium aspiration syndrome (MAS), genetic anomalies, and
structural anomalies, are identified.
Hypothetically, the pathophysiological mechanisms, respon-
sible for PPHN, are classified into maladaptation, maldevelop-
ment, and underdevelopment. Maladaptation of the normal
developed pulmonary vasculature through an imbalance of
vasoactive substrates is responsible for the greater part of
PPHN and originates often from sepsis, pneumonia, MAS
or asphyxia. Maldevelopment of the pulmonary vasculature
is mainly idiopathic, but sometimes associated with chronic
fetal hypoxia, fetal anaemia, or premature closure of the ductus
arteriosus. Underdevelopment such as lung hypoplasia with
underdevelopment of pulmonary vasculature originates from
several causes, however congenital diaphragmatic hernia (CDH)
or oligohydramnios form the majority of these causes [7].
PPHN was defined based on a combination of clinical and
echocardiographical characteristics (see Tables I and II). Two
parameters were obtained to score the severity of PPHN, the
preductal to postductal difference in transcutaneous oxygen satu-
ration (δ-SO2
) and the Oxygenation Index (OI), respectively (see
equation).
MAP FiO
p O
100
2
a 2
×
×
The above equation represents the OI formula, given inspired
oxygen concentration in % (FiO2
), MAP in mmHg and partial
pressure of arterial O2
in mmHg (Pa
O2
).
Echocardiography demonstrated continuous right-to-left
shunting or bidirectional shunting through a patent ductus
arteriosus (PDA) associated with a cyanosis and preductal to
postductal difference in δ-SO2
of 5% or more. In term newborns,
OI < 15 is scored as mild PPHN, OI between 15–25 as moderate
PPHN, OI between 25–40 as severe, and more than 40 as very
severe PPHN [8].
Therapies for PPHN were aimed at lowering pulmonary
vascular resistance and improving mixing at the level of the atria
and PDA. Ventilator settings were adjusted according to the
patient’s pulmonary condition, tidal volume, and arterial blood
gas determination. Due to low risk of barotrauma, HFV can be
preferred. Patients must receive sedation, analgesia and if neces-
sary, neuromuscular blockade in order to reduce “fighting” with
respirator episodes. Inotropic agents (isoprenaline, dopamine,
dobutamine, and noradrenalin) and intravenous volume replace-
ment can be necessary. In case of failure, intravenous vasodilators
(tolazoline,epoprostenol,andenoximone)andphosphodiesterase
inhibitor (sildenafil) were started in the absence of contraindica-
tions (hypotension, renal failure, and haemorrhage). Suboptimal
lung inflation compromises the efficacy of iNO in PPHN, and
may in part explain the reported differences in the iNO response
rates [9].
Table I. Echocardiographic findings in PPHN. Table II: Guidelines for iNO
use in term and near term hypoxaemic infants with PPHN.
Measurement Findings
Echocardiographic findings in PPHN
PAP PAP > PAm
PDA (±)
PDA shunting R-L or bidirectional
Atrial shunting R-L or bidirectional through PFO
Table II. Guidelines for use of iNO in term and near-term hypoxiemic
infants with PPHN.
Guidelines for use of iNO
Patient profile EG > 34 weeks,
1° day of life,
US evidence of PPHN
OI > 25 after adequate lung recruitment
Starting dose 20 ppm
Monitoring of
met-Hb
<5%
Duration of
treatment
Typically <5 days
Discontinuation FiO2 < 0.6 and respiratory stability with reducing iNO

3. Nitric oxide in respiratory failure 49
Copyright © 2012 Informa UK, Ltd.
Lipkin et al. and Ellington divided their patients into three
groups on the basis of response to iNO administration: early,
late and poor responder. The initial dose of iNO was 10 ppm, if
needed increased to 40 ppm. The mortality rate was 16.7%, all
patients belonged to the poor response group. Follow-up, at three
years, showed reactive airway disease in five patients, no loss of
sensorineuralhearingandasignificanthigherincidenceofnormal
neurodevelopment outcome in the early response group, however
only one patient was identified as having a mild neurodevelop-
ment disability [3,10].
Meconial aspiration syndrome
MAS is defined as respiratory distress in infants born through
meconium stained amniotic fluid with characteristic radiological
changes and whose symptoms cannot be otherwise explained
[11]. Whereas, meconium is rarely found in amniotic fluid before
34 weeks of gestational age, MAS is often a disease of term and
near-term newborn. Severe MAS is often associated with PPHN,
resulting in severe hypoxemia. Randomized clinical trials (RCTs)
have demonstrated that iNO therapy decreases the need of extra-
corporeal membrane oxygenation (ECMO) although it did not
reduce mortality of these patients [12,13]. In hypoxic respiratory
failure due to MAS, Kinsella et al. found that infants responded
well to iNO administration combined with HFV, compared to
those that had received either treatment alone [14]. The response
to combined treatment with HFV and iNO reflect both the
decreased intrapulmonary shunt both the rise of the NO delivery
to its site of action.
Congenital diaphragmatic hernia
The cause of hypoxemic respiratory failure in patients with CDH
is complex. It includes pulmonary hypoplasia, surfactant dysfunc-
tion and structural-functional anomalies of vasculature of the
lung. The treatment of pulmonary hypertension is of particular
concern. Several medications have been used: tolazoline and pros-
tacyclins were tried first but they did not produce good enough
results. Prostaglandin 1E is occasionally used. If echocardio-
graphic pulmonary hypertension was ruled out in CDH patients,
iNO administration associated with HFV must be used. iNO, a
well known smooth muscle relaxant is, in turn, widely used with
variable results although there is no strong evidence of its benefits
[15,16]. Even if some CDH patients experienced oxygenation
improvement after iNO therapy, these babies can be often consid-
ered iNO poor responders. In some cases, iNO therapy can reduce
the need of ECMO in order to presurgical stabilization.
Inhibitors of phosphodiesterase like sildenafil, known for their
vasodilator action, are currently used in some cases but, again,
there is only anecdotal evidence of their benefits [17]. These
medications are coupled with inotropic agents and sometimes
with peripheral vasoconstrictors, like adrenaline at low doses,
aimed at reducing the shunting by increasing pressure in the
systemic circulation.
Respiratory failure in preterm infants – treatment and
prevention of bronchopulmonary dysplasia
The pathophysiology of respiratory failure and the potential risks
differ substantially in preterm infants. Pulmonary hypertension
can complicate respiratory failure in preterm babies. Therefore,
analysis of the efficacy and toxicity of iNO in infants born before
35 weeks is necessary. Barrington and Finer have published
a meta-analysis of 11 RCTs of iNO treatment in premature
infants of 34 weeks’ gestation. They have shown equivocal effects
on pulmonary outcomes, survival, and neurodevelopmental
outcomes. Different end point analysis were considered: (i) early
rescue treatment based on O2
criteria − (ii) later enrollment based
on increased risk of bronchopulmonary dysplasi (BPD) − and (iii)
routine use in intubated preterm babies. The aim was to deter-
mine the effect of treatment with iNO on rates of death, BPD,
IVH, or neurodevelopment disability in preterm newborn infants
(<35 weeks gestation) with respiratory disease. The conclusions
were that iNO as rescue therapy does not appear to be effective
and may increase the risk of severe IVH [18]. Early routine use
of iNO in mildly sick preterm infants may decrease serious brain
injury and may improve survival without BPD. More recently,
Donohue et al. have shown that there was a reduction of 7% in
the risk of composite outcome (death or BPD at 36 weeks) for
preterm treated compared to control, but no reduction in death
or BPD alone [19].
Further studies are needed and there are no clear evidences
in favour of using iNO for preterm infants requiring mechan-
ical ventilation. The NIH consensus development conference
concluded that current evidence does not support use of iNO
in early routine, early rescue or layer rescue regimens in the
care of preterm infants [20]. There may be a role for iNO use
in preterm infants born to mother with premature rupture of
membranes, oligohydramnios and pulmonary hypoplasia but
larger investigation is need [21–23]. The rationale for the use of
iNO in the prevention of BPD stems from animal and humans
studies supporting an anti-inflammatory role of NO and benefi-
cial effects on lung remodelling during extrauterine develop-
ment. Later use of iNO to prevent BPD also does not appear to
be effective.
iNO in adults with cardiopulmonary diseases
iNO has the ability to decrease pulmonary pressure (PAP); the
patient response to iNO test during cardiac catheterization can
predict the subsequent response to oral therapy with nifedipine
and the better mid term survival in adult patients with pulmonary
hypertension due to congenital heart disease (CHD). Pulmonary
hypertension in cardiac transplant recipients is a major cause of
death due to right heart failure. Some authors report that selec-
tive iNO administration reduce right ventricular afterload after
cardiac transplantation. The good response to iNO (by reducing
PAP) has been used as criterion to select candidates for cardiac
transplantation. A great interest for iNO has been suggested in
treatment of right heart failure after insertion of left ventricular
assist device, cardiogenic shock due to right ventricular myocar-
dial infarction and pulmonary ischemia-reperfusion injury as
early graft failure after lung transplantation.
iNO in adults with acute respiratory distress syndrome and
chronic obstructive pulmonary disease
In clinical studies, iNO has been shown to produce selec-
tive pulmonary vascular relaxation improving oxygenation.
Nevertheless, iNO treatment does not improve mortality rate,
duration of mechanical ventilation and numbers of days alive; so
if iNO administration improves or not severe acute respiratory
distress syndrome (ARDS), is not been defined. Severe chronic
obstructive pulmonary disease (COPD) is often complicated by
PPHN. In the latter condition hypoxemia is due to mismatching
of ventilation and perfusion, while in ARDS is due to intra- and
extrapulmonary right-to-left shunting. Breathing NO in COPD
can reduce oxygenation by increased mismatch V/P. In vivo study
demonstrated that inhalation of oxygen-NO mix can reduce PAP
and ameliorate right ventricular performance. Further studies are
necessary to validate this clinical practice [24].

4. 50 M. C. Muraca et al.
The Journal of Maternal-Fetal and Neonatal Medicine
Conclusions
Large placebo controlled trials have revealed that nitric oxide
decreases the risk of death or the need for ECMO in term and
near-term infants with PPHN. These results have led the US FDA
to approve iNO as a therapy. Term infants with PPHN, either as
a primary cause or secondary to other disease processes, respond
to iNO with improvement in oxygenation indices and a decreased
need for ECMO. ECMO is not available in all NICU so, infants
with progressive hypoxic respiratory failure, at high risk of death,
should be cared in centers with the expertise and experience to
provide multiple modes of ventilatory support and rescue thera-
pies (use of surfactant, high frequency oscillatory ventilation
(HFOV), iNO) or be transferred in a timely manner to such an
institution. The use of iNO in transport stabilization must be
developed. iNO therapy should be given using the indications,
dosing, administration, and monitoring guidelines outlined on
the product label. An echocardiogram to rule out CHD is recom-
mended. iNO should be initiated in centres with easy access to
ECMO and a comprehensive long-term medical and neurodevel-
opmental follow-up.
Infants with CDH are the exception to this finding, with little
clinical benefit observed with iNO treatment. More studies are
necessary to compare the efficacy of associated drugs (iNO,
pulmonary vasorelaxants) in presurgical stabilization and long
term follow-up.
Although respiratory disease in preterm infants has a compo-
nent of increased pulmonary vascular resistance, little benefit of
iNO administration has been observed in premature infants either
early in their course or later as a treatment to prevent the evolution
of chronic lung disease. Combined evidence of iNO treatment in
premature infants of 34 weeks’ gestation has shown equivocal
effects on pulmonary outcomes, survival, and neurodevelop-
mental outcomes. Despite these equivocal results, the off-label
use of iNO has increased substantially but iNO administration is
very expensive (up to $3000/day). On the basis of assessment of
currently available data, hospitals, clinicians and the pharmaceu-
tical industry should avoid marketing iNO for premature infants
of 34 weeks’ gestation.
Acknowledgements
The authors wish to acknowledge the contributions of Europe
Against Infant Brain Injury (EURAIBI) ONLUS.
Declaration of interest: The authors report no conflicts of
interests.
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