Keywords hypoxemic respiratory failure - noninvasive ventilation
Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of failed circulatory
adaptation at birth, characterized by high pulmonary vascular resistance causing extrapulmonary
left-to-right shunting of blood across the ductus arteriosus and/or foramen ovale.[1 ] Selective pulmonary vasodilatation with inhaled nitric oxide (iNO) has been proven
to improve oxygenation in term newborns with severe hypoxemic respiratory failure
(HRF) and PPHN.[2 ]
[3 ] Randomized controlled trials have demonstrated that iNO significantly decreased
the need for extracorporeal membrane oxygenation in newborns greater than 34 weeks'
gestational age with HRF.[4 ]
[5 ] Traditionally, iNO has been delivered to intubated and mechanically ventilated babies
when they continue to be hypoxemic despite administration of high levels of inspired
oxygen. Infants with PPHN suffer from long-term morbidity such as chronic lung disease,
neurological morbidity, and sensorineural deafness.[6 ] Some of these long-term consequences may be secondary to mechanical ventilation.
The use of iNO administered by a noninvasive method like nasal cannula has been only
anecdotally described, usually during the weaning process after the neonate has been
mechanically ventilated.[7 ] We report a case of idiopathic PPHN treated successfully with iNO delivered through
a nasal cannula, avoiding mechanical ventilation.
Case Report
A female infant weighing 2994 g was born at 39 weeks' gestation by spontaneous vaginal
delivery to a 16-year-old primigravida. Her antenatal history was unremarkable. There
was no history of any medication intake and no history of infections. There were no
inherited disorders reported in the family and no history of alcohol, drugs, or cigarette
smoking. The baby was born after rupture of membranes for 6 hours through meconium-stained
amniotic fluid with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. She
was vigorous at birth, received routine care at delivery, and was transferred to the
well baby nursery.
She remained asymptomatic for the next 36 hours, when during a feed she was noted
to be gray and tachypneic with a respiratory rate of 70/min. Her oxygen saturations
were noted to be 79 to 80% with a loud systolic murmur heard over the left heart border,
which had not been previously documented. She had an arterial blood gas with a pH
of 7.38, Paco2 of 44 mm Hg and a partial pressure of oxygen (Po2 ) of 47 mm Hg on 40% oxygen with an A-a gradient of 182 mm Hg. A hyperoxia test in
100% oxygen raised her Po2 to 372 mm Hg.
A chest X-ray showed clear lung fields with no significant abnormality ([Fig. 1 ]). An echocardiogram revealed moderate tricuspid regurgitation (estimated right ventricular
systolic pressure ~90 mm Hg; [Fig. 2 ]). Pulmonary venous return appeared normal to the left atrium without any evidence
of obstruction. The ductus arteriosus was not visualized. The baby was maintaining
oxygen saturations of 90% in room air, but was tachypneic with respiratory rates of
70 to 80/min. Intermittent periods of desaturation were observed requiring escalation
of inspired oxygen concentration to 100%. Oxygen saturations continued to drop below
90% periodically, despite receiving 2 L/min of 100% oxygen by nasal cannula. She was
transferred to the neonatal intensive care unit for further management.
Figure 1 Chest radiograph showing clear lung fields without any evidence of parenchymal lung
disease suggestive of idiopathic persistent pulmonary hypertension of the newborn
or “black lung disease.”
Figure 2 Echocardiography revealing a tricuspid regurgitation jet indicative of moderate pulmonary
hypertension in the upper frames. On inhaled nitric oxide, the right ventricular pressures
are seen to decrease in the lower frames.
In the intensive care unit, umbilical arterial and venous lines were placed for serial
blood gas and central venous pressure monitoring. iNO was started at 20 ppm through
a nasal cannula with 2 L/min flow. The inspired oxygen was weaned down to 40% after
initiation of iNO. Her first blood gas after iNO was started revealed a pH of 7.39
with a Po2 of 68 mm Hg and a pCO2 of 44 mm Hg on 40% oxygen by nasal cannula. Episodes of oxygen desaturation were
not observed during therapy with iNO.
Repeat echocardiogram after 24 hours of iNO therapy did not reveal tricuspid regurgitation.
Thereafter, iNO was weaned by 5 ppm every 4 hours per unit protocol for PPHN. After
the first wean from 20 to 15 ppm, the infant experienced some tachypnea and desaturation,
for which she was placed back on iNO 20 ppm for another 24 hours. Following this period,
she tolerated the iNO wean better and was off nitric oxide by day 4 of life. Repeat
echocardiogram done prior to discharge and after being off iNO for 24 hours showed
trace tricuspid regurgitation (estimated right ventricular systolic pressure 25 to
30 mm Hg). No patent ductus arteriosus was visualized, and there was good left ventricular
function. She was discharged home with close cardiology follow-up. Repeat echocardiogram
1 month after discharge revealed no tricuspid regurgitation and no PDA, with normal
cardiac function. The baby herself was asymptomatic in room air and growing well.
The etiology of pulmonary hypertension resulting in tricuspid regurgitation in this
baby was not clear but could be secondary to antenatal ductal closure resulting in
PPHN from vascular remodeling.[8 ]
Discussion
Barotrauma and volutrauma are often associated with prolonged mechanical ventilation
in newborn infants.[9 ]
[10 ] In this case report, we describe an infant with idiopathic PPHN successfully treated
with iNO, avoiding the hazards of mechanical ventilation. To our knowledge, this is
the first report of using iNO by nasal cannula as primary therapy for PPHN in the
immediate newborn period. Noninvasive methods of delivering iNO have been anecdotally
described in the literature. The fact that iNO can be delivered effectively by continuous
flow nasal cannulae was first demonstrated in a young infant with primary pulmonary
hypertension, who was treated with nasal nitric oxide for several weeks until approved
for enrollment into the long-term intravenous prostacyclin therapy program.[11 ] iNO via a nasopharyngeal tube was used in a 145-day-old infant with a severely hypoplastic
lung and end-stage pulmonary hypertension, in whom clinical improvement was maintained
for 7 days.[12 ] Use of pulsed nasal delivery of nitric oxide was described in adults with primary
pulmonary hypertension in the home setting.[13 ] Premature infants received iNO therapy through continuous positive airway pressure
and nasal cannula in the weaning phase in the Nitric Oxide to Prevent Chronic Lung
Disease (NO-CLD) trial for prevention of bronchopulmonary dysplasia without any negative
consequences.[14 ] Noninvasive delivery of iNO therapy has also been reported for late pulmonary hypertension
in newborn infants with congenital diaphragmatic hernia. In a case series, patients
who had suprasystemic pulmonary hypertension when iNO was discontinued before extubation
were treated with iNO through a nasal cannula. In the same study, nasopharyngeal nitric
oxide concentrations were 5.4 ± 0.5 ppm and 2.4 ± 0.4 ppm with iNO measured proximally
in the delivery device at 10 and 5 ppm, respectively.[7 ] In another case series, the tracheal concentration of nitric oxide was measured
using a chemiluminescence device during pulsed nasal nitric oxide delivery at 20,
40, and 60 mL/breath and found to range between 28 and 38 ppm.[15 ]
The feasibility of nitric oxide administration by oxygen hood in neonatal pulmonary
hypertension has been studied in piglets.[16 ] It was found that nitric oxide decreased (>50%) pulmonary artery pressure and vascular
resistance in both hypoxia- and Group B streptococcus–induced pulmonary hypertension,
with minimal effects on systemic arterial pressure and cardiac output.
A masked randomized controlled pilot trial using iNO via oxygen hood was conducted
in >34-weeks gestational age infants with high A–a gradient (400 to 600 mm Hg) with
the primary outcome measure being partial pressure of oxygen in the alveoli an hour
after starting study gas. This study did not complete enrollment but the authors concluded
that administration of iNO by oxygen hood is feasible, but required larger controlled
trials.[17 ]
Our patient had symptomatic pulmonary hypertension as demonstrated by her labile hypoxemia.
Echocardiogram supported this diagnosis and ruled out structural heart disease. With
adequate respiratory drive, no evidence of parenchymal lung disease on the chest radiograph,
and no signs of respiratory distress except for mild tachypnea, we felt she did not
warrant intubation and mechanical ventilation, which is associated with chronic lung
injury. iNO was delivered through the INOmax DS (Ikaria Inc., Hampton, NJ) with the
circuit as shown in the product manual. Though we did not measure environmental nitric
oxide levels, previous studies have shown negligible leakage of iNO with noninvasive
methods of delivery.[12 ]
[16 ]
[17 ]
We conclude that in newborn infants presenting with hypoxic repiratory failure with
hypoxemia without hypercarbia, respiratory distress, or evidence of parenchymal lung
disease, therapy with iNO using a nasal cannula may reduce exposure to high levels
of inspired oxygen and avoid mechanical ventilation. Randomized and double blinded
trials evaluating this therapeutic modality are warranted.
