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OBJECTIVES
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Introduction
Early reports of the use of inhaled nitric oxide (iNO) in term newborns who had persistent pulmonary hypertension showed both acute and sustained improvement in oxygenation. Subsequently, randomized controlled trials of iNO in term newborns confirmed that this selective pulmonary vasodilator improves oxygenation and reduces the need for extracorporeal membrane oxygenation (ECMO). Results of a more recent randomized controlled trial of iNO in term newborns corroborate the findings of previous studies. These studies should provide sufficient evidence of the safety and efficacy of iNO to support regulatory approval of this therapy for persistent pulmonary hypertension of the newborn (PPHN). However, less is known about the potential role of iNO in preterm newborns. In this review, we summarize the key findings of clinical trials in the term newborn and the current status of iNO in the preterm newborn.
iNO in Term Newborns
After the publication of pilot trials with iNO, which documented marked improvement in oxygenation in term newborns who had PPHN, several randomized, controlled trials were conducted and demonstrated further the efficacy of iNO in PPHN. For example, these studies reported acute improvement in oxygenation after 30 minutes of iNO treatment. iNO reduced the need for ECMO, and lung recruitment strategies augmented the response to iNO when PPHN complicated the course of patients who had parenchymal lung disease. However, none of the studies was designed to evaluate the efficacy of the initial dose employed, and there remains some confusion about the appropriate starting dose for term newborns who have PPHN because of the lack of appropriate dose-response studies.
APPROPRIATE DOSES
The first published experience of
iNO treatment in term newborns
reported initial doses ranging from
6 to 20 ppm to 80 ppm. The
rationale for doses used in these clinical
trials was based on concentrations
that had been found to be effective
in animal experiments by the same
investigators. Brief (30 min)
inhalation of NO at 80 ppm improved
oxygenation in patients who had
PPHN, but the response was not
sustained in some patients after NO
was discontinued. Rapid
improvement in oxygenation in neonates
who had severe PPHN also was
demonstrated, but this was achieved
at lower doses (20 ppm)
administered for 4 hours, and decreasing the
iNO dose to 6 ppm for the duration
of treatment provided sustained
improvement in oxygenation. Other
studies documented the relative
effectiveness of low-dose iNO in
improving oxygenation in patients
who had severe PPHN. Thus, acute
improvement in oxygenation during
treatment does not appear to vary
with doses of iNO ranging from 5 to
80 ppm.
These laboratory and clinical studies established the boundaries of iNO dosing protocols for subsequent randomized, clinical trials in newborns. Increasing the dose to 40 ppm generally does not improve oxygenation among patients who do not respond to the lower dose of 20 ppm. The initial dose in the Neonatal Inhaled Nitric Oxide Study (NINOS) was 20 ppm, but the dose was increased to 80 ppm if the improvement in Pao2 was less than 20 torr. In this study, only 3 of 53 infants (6%) who had little response to 20 ppm had an increase in Pao2 of greater than 20 torr when treated with 80 ppm iNO. Whether a progressive increase in Pao2 would have occurred with continued exposure to 20 ppm could not be determined with this study design. Others initiated treatment with 80 ppm NO and subsequently weaned the iNO concentration if oxygenation improved, which precluded an evaluation of the effects of lower initial iNO doses. These studies did not evaluate individual doses systematically in a method that could be interpreted. However, a recent randomized, controlled, dose-response trial in term newborns who had hypoxemic respiratory failure evaluated the effects of sustained exposure to different doses of iNO in different treatment groups. Patients were randomized to treatment with either 0 (placebo), 5, 20, or 80 ppm NO. Each iNO dose improved oxygenation compared with placebo, but there was no difference in responses among treatment groups. However, at 80 ppm, methemoglobinemia (>7%) occurred in 13 of 37 patients (35%), and high inspired NO2 concentrations were measured in 7 of 37 patients (19%). Thus, 80 ppm iNO was no more effective in improving oxygenation than 5 or 20 ppm, but it was associated with adverse effects. Unfortunately, this trial was limited by early termination due to slow enrollment and the exclusion of lung recruitment approaches to optimize iNO efficacy.
Available evidence supports the use of doses of iNO beginning at 20 ppm in term newborns who have PPHN. Although brief exposures to higher doses (40 to 80 ppm) appear to be safe, sustained treatment with 80 ppm NO increases the risk of methemoglobinemia. The lowest effective initial dose for iNO in term newborns who have PPHN has not been determined, but sustained improvement in oxygenation (after >4 h of treatment) has been demonstrated for doses of less than 10 ppm.
USE OF ECMO
Overall, clinical trials of iNO in
term newborns have demonstrated
an approximately 40% reduction in
the use of ECMO. However, not all
treated patients experience a
sustained improvement in oxygenation;
some still require treatment with
ECMO. With impending regulatory
approval, this raises an important
concern about the use of iNO in
centers that do not employ ECMO.
Published reports on the use of iNO in ECMO centers have not substantiated early concerns that iNO would affect outcome adversely by delaying use of ECMO. In one study, the median time from randomization to treatment with ECMO was 4.4 and 6.7 hours for the control and iNO groups, respectively. Although this difference was statistically significant, there were no apparent adverse consequences caused by the delay. Patients treated with iNO did not have longer ECMO courses, increased rates of intracranial hemorrhage, or other bleeding complications compared with the control group. Indeed, iNO treatment may play an important role in stabilizing patients before ECMO is initiated. iNO may attenuate pulmonary vasolability even without marked increases in Pao2, thus improving the chances that ECMO cannulation may proceed without progressive clinical deterioration.
The potential dissemination of iNO therapy to nonECMO centers, however, warrants a cautious approach. Whether the use of iNO for PPHN in nonECMO centers will cause undue delays in initiation of transport to an ECMO center, increase the risks of transport, or significantly delay ECMO cannot be determined from the currently available evidence. It is likely that promising new therapies for severe hypoxemic respiratory failure will not be limited to centers that provide all modes of rescue treatment. Although marked improvement in oxygenation occurs in many term newborns who have severe PPHN, sustained improvement may be compromised in some patients by the nature of the underlying disease that leads to progressive atelectasis or systemic hemodynamic disturbances caused by overwhelming sepsis. When the clinical course is complicated by progression in the severity of the cardiopulmonary disease, withdrawal of NO during transport to an ECMO center may lead to acute deterioration. In such cases, iNO may provide an important therapeutic bridge to assure stability during transport. When progressive deterioration in oxygenation occurs during iNO treatment in institutions that cannot offer more advanced rescue therapy, provisions must be in place to transport the patient to the ECMO center without interrupting iNO treatment.
iNO in Preterm Newborns
ENDOGENOUS NO
Another area of investigation that is
of vital clinical importance is iNO
therapy in preterm newborns who
have hypoxemic respiratory failure.
The role of endogenous NO
production in vasoregulation of the preterm
pulmonary circulation and the
effects of iNO in the preterm
newborn have received less attention
than in the term infant. In the
late-gestation ovine fetus, endogenous
NO modulates basal pulmonary
vascular tone and contributes to the
normal fall in pulmonary vascular
resistance (PVR) at birth. In
addition, iNO causes potent, selective,
and sustained pulmonary
vasodilation in the normal term newborn
lamb. In the preterm lamb at 78% of
term (115 d gestation or about
31 wk of human gestational age),
inhibition of endogenous NO
production increases fetal PVR. Further,
when endogenous NO production is
blocked during delivery of the
preterm lamb, the normal increase in
pulmonary blood flow associated
with mechanical ventilation and lung
inflation is attenuated markedly.
The preterm lamb is an excellent model of respiratory distress syndrome and has been studied extensively. Survival with exogenous surfactant treatment and mechanical ventilation at delivery varies, depending on the gestational age of the lamb and the type of surfactant administered. In very immature lambs (78% of term gestation), gas exchange worsens and PVR increases during mechanical ventilation beyond 60 to 90 minutes after birth, despite treatment with exogenous surfactant at delivery. Intermittent mandatory ventilation over 2 hours in the extremely preterm sheep fetus (115 d gestation, 78% of term) causes progressive worsening of gas exchange and increased PVR. After 2 hours of ventilation, brief NO treatment lowers PVR and improves gas exchange. Moreover, early and continuous treatment with iNO (20 ppm) causes sustained improvement in gas exchange and pulmonary hemodynamics over 3 hours of mechanical ventilation. Lung recruitment strategies employing high-frequency oscillatory ventilation have been shown to augment the response to low-dose iNO in preterm lambs that have hyaline membrane disease, emphasizing the critical role of adequate lung inflation during inhalational vasodilator therapy.
In addition to its effects on pulmonary hemodynamics and gas exchange during inhalation, endogenous NO may regulate vascular permeability and neutrophil adhesion in the microcirculation. Moreover, in preterm lambs delivered at 78% of term, low-dose iNO (5 ppm) increases pulmonary blood flow and improves gas exchange without increasing pulmonary edema and decreases accumulation of lung neutrophils. In another recent study, lambs delivered at 130 days (90% of gestation) and mechanically ventilated for 5 hours with 20 ppm iNO showed no evidence of lung oxidative stress injury (lung malondialdehyde, reduced glutathione, glutathione reductase) compared with controls.
iNO THERAPY IN HUMANS
Preliminary studies in human
preterm neonates who had severe
hypoxemic respiratory failure
support the potential role of low-dose
iNO as adjuvant therapy. Low-dose
inhaled NO markedly improved
oxygenation in a preterm neonate who
had group B streptococcal sepsis
and severe pulmonary hypertension,
allowing reduction in ventilator
pressure and inspired oxygen
concentration and complete clinical
recovery. Preterm neonates who had
severe hypoxemia associated with
prolonged oligohydramnios and
suspected pulmonary hypoplasia
showed marked improvement in
response to iNO therapy. Five
patients survived in this trial, three
of whom had severe intracranial
hemorrhage (ICH). Another
dose-response study in preterm infants
concluded that 5 ppm of iNO was as
effective as 20 ppm in improving
oxygenation. In a small, unmasked,
randomized trial of iNO (20 ppm)
and dexamethasone treatment, no
differences were documented in
survival or incidence of chronic lung
disease (CLD) or ICH between
iNO-treated infants and controls. In yet
another dose-response study of iNO
in 11 preterm newborns, 5 ppm was
shown to be as effective as 20 ppm.
Seven (64%) of these infants had
ICH, and 5 (45%) had ICH of grade
3 to 4. However, when these results
were compared with the NICHD
Neonatal Network database (for
historical controls matched for severity
of illness), the incidence of ICH in
preterm newborns not treated with
iNO was identical (64%). These
observations illustrate the limitations
of determining toxicity without
appropriately designed clinical trials.
SAFETY AND EFFICACY
To begin to address the potential
safety and efficacy of iNO in
preterm newborns, we recently
conducted a randomized controlled trial
of iNO in preterm neonates who had
severe hypoxemic respiratory failure.
We hypothesized that low-dose iNO
(5 ppm) would improve survival in
affected preterm newborns who
were unresponsive to conventional
therapies, including surfactant, and
would not increase the incidence or
severity of ICH or CLD. We
randomized 80 preterm newborns
(gestational ages <34 wk) who had
severe hypoxemic respiratory failure
in 12 perinatal centers that provide
tertiary care. Forty-eight patients
were treated with iNO and 32
served as controls. Treatment
assignment was masked. The primary
outcome variable was survival to
discharge. Secondary outcome variables
included incidence and severity of
ICH and pulmonary hemorrhage,
duration of mechanical ventilation,
and incidence of CLD at 36 weeks’
postconceptional age. The groups
did not differ in baseline
characteristics or severity of
disease (Pao2/FiO2 = 42±18 mm
Hg for iNO;
42±16 mm Hg for
control; P=NS). iNO
improved
oxygenation acutely after
60 minutes of
treatment (Pao2/ FiO2 =
88±12 mm Hg for
iNO; 56±9 mm Hg
for control; P<0.05).
Survival to discharge
was 52% in the iNO
group and 47% in controls (P=NS).
Causes of death were related
primarily to extreme prematurity and were
similar between groups. Total
ventilator days for survivors was less for
the iNO group (P=0.046). In
contrast to uncontrolled pilot studies,
there was no difference in the
incidence of ICH between the control
and iNO-treated groups (Figure 
).
|
Thus, low-dose iNO resulted in acute improvement in oxygenation in preterm newborns who had severe hypoxemic respiratory failure without increasing the risk of bleeding complications, including ICH. Low-dose iNO may be effective as a lung-specific anti-inflammatory therapy to diminish lung neutrophil accumulation and the attendant inflammatory injury that contributes to the evolution of CLD. Sufficient evidence now may be available to warrant a controlled trial of low-dose iNO in preterm newborns who have less severe disease.
Summary
iNO improves oxygenation and decreases use of ECMO in term newborns who have PPHN. From the available information, a reasonable recommendation for the initial dose of iNO in the term infant is 20 ppm, with the dose reduced over time. Toxicity is apparent at 80 ppm, causing increases in methemoglobinemia and inspired NO2. High doses (>20 ppm) of iNO also may prolong bleeding time, but clinically significant increases in bleeding complications have not been reported in term newborns. Finally, there is increasing evidence for the potential role of low-dose iNO (5 ppm) in preterm newborns who have hypoxemic respiratory failure. This therapy causes acute improvement in oxygenation and may prove to be useful as a lung-specific anti-inflammatory treatment. However, clinical application currently should be limited to controlled trials that target outcomes of both safety and efficacy.
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