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Pediatrics International (2004) 46, 10–14

Original Article

Nitric oxide inhalation therapy in very low-birthweight infants with

hypoplastic lung due to oligohydramnios

NAOKI UGA, TETSUYA ISHII, YASUHIRO KAWASE, HIROKO ARAI AND HIROSHI TADA

Division of Neonatology, Perinatal Center, Toho University School of Medicine, Tokyo, Japan

Abstract Background

: Although nitric oxide inhalation (iNO) therapy improves arterial oxygenation and reduces the

rate of extracorporeal membrane oxygenation in term neonates, the efficacy of this therapy in premature

infants is controversial. The objective of the present study was to determine whether iNO therapy improves the

survival of very low-birthweight infants with pulmonary hypoplasia due to prolonged rupture of membrane.

Methods

: A retrospective comparative study of very low-birthweight infants with pulmonary hypoplasia due

to oligohydramnios who had or had not been treated with iNO therapy, was performed (iNO-treated group,

eight infants; control group, 10 infants). A neonate was considered to have pulmonary hypoplasia due to

oligohydramnios if the following conditions were satisfied: (i) artificial surfactant treatment did not improve

the respiratory distress; (ii) prolonged rupture of membrane (PROM) continued for more than 5 days witholigohydramnios; and (iii) sufficient arterial oxygenation did not occur even after giving 100% oxygen, and

more than 8 cm H

2

O of mean airway pressure was needed to maintain arterial oxygenation.

Results

: Nitric oxide inhalation improved arterial oxygenation rapidly and consistently in all eight infants with

pulmonary hypoplasia. All eight iNO-treated infants survived longer than 28 days, while five of the 10 control

infants died within 24 h of birth (

P

< 0.05). Before starting iNO, seven of the eight treated infants had shown

persistent pulmonary hypertension, which was confirmed by echocardiography. No iNO-treated infant had

IVH greater than grade 1, while one control infant had grade 2 IVH. All six long-term survivors in the iNO-

treated group are developing normally, while only two of the control infants are developing normally as of

February 2002.

Conclusions

: The majority of the infants with pulmonary hypoplasia due to oligohydramnios had persistent

pulmonary hypertension. iNO improved the arterial oxygenation and significantly improved the survival rate.

A controlled study to determine whether iNO therapy improves the survival rate of preterm infants withpulmonary hypoplasia due to oligohydramnios is necessary.

Key words nitric oxide inhalation therapy, oligohydramnios, persistent pulmonary hypertension of newborn, pulmonary

hypoplasia, very low-birthweight infant.

Prolonged rupture of membrane sometimes causes severe

oligohydramnios, which impedes normal pulmonary develop-

ment and causes pulmonary hypoplasia to some degree. The

precise mechanisms of pulmonary hypoplasia due to

oligohydramnios are not clear but the restricted fetal respir-

atory movement in utero

is thought to be the common

mechanism in Potter syndrome, diaphragmatic hernia, orhydropse fetalis with massive pleural fluid. The treatment

of choice is vigorous respiratory pressure support, but the

majority of infants with pulmonary hypoplasia succumb to

death in the early neonatal period. It has been reported that

persistent pulmonary hypertension accompanies severe respir-

atory distress in very low-birthweight infants.

1

Nitric oxide

inhalation (iNO) therapy was reported to reduce pulmonary

arterial resistance and to improve pulmonary failure due to

persistent pulmonary hypertension.

2

However, its outcome is

unclear. We found that iNO therapy dramatically improvedrespiratory failure due to pulmonary hypoplasia in very low-

birthweight infants. Most of them recovered from the respir-

atory failure and survived. Pulmonary hypertension aggravates

the hypoxia in pulmonary hypoplasia, and iNO can improve

not only the pulmonary function, but also the outcome of this

serious disease. We report the results of iNO therapy in eight

very low-birthweight infants with pulmonary hypoplasia, and

compared these infants with those who had hypoplastic lung

due to oligohydramnios and who did not receive iNO

Correspondence: Naoki Uga MD, Division of Neonatology, PerinatalCenter, Toho University School of Medicine, 6-11-1 Omori-nishi,Otaku, Tokyo 143-8540, Japan. Email: [email protected]

Received 13 May 2002; revised 28 December 2002; accepted7 July 2003.

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iNO therapy in infants 11

therapy. This is a secondary publication using the same cases

that were published in Acta Neonatolgica Japonica

.

3

Methods

Since January 1999, we have treated very low-birthweight

neonates with iNO if the neonate was considered to have

pulmonary hypoplasia due to oligohydramnios. The diagnosis

was made if following criteria were all satisfied: (i) artificial

surfactant treatment did not improve the respiratory distress;

(ii) prolonged rupture of membrane continued for more than

5 days with oligohydramnios; and (iii) sufficient arterial

oxygenation did not occur even after giving 100% oxygen,

and more than 8 cm H

2

O of mean airway pressure was

needed to maintain arterial oxygenation. Eight very low-

birthweight neonates were considered to have pulmonary

hypoplasia and were treated with iNO. The control patientssatisfied the same criteria but they were not treated with iNO.

Immediately after birth all the infants were resuscitated

with positive ventilation with 100% oxygen. No infant

responded to artificial pulmonary surfactant treatment. Even

though antibiotics were given to all patients, none of them

showed high C-reactive protein values, or positive blood culture.

Mean blood pressure within 3 h after birth were 28.7 ±

1.7 in

iNO-treated group, and 27.3 ±

4.5 in the control group.

The starting concentration of NO gas ranged between 40

and 30 p.p.m. iNO therapy was continued more than 24 h.

The concentration of iNO was reduced during the therapy

according to respiratory improvement. One thousand p.p.m.of NO gas was added to the respiratory circuit to obtain the

intended concentration of iNO, which was confirmed by an

electrical sensor in the efferent circuit from the patient.

Before starting the iNO therapy, it was confirmed that seven

of the eight iNO-treated infants had persistent pulmonary

hypertension by echocardiography. The gestational age, birth-

weight and duration of PROM (days) of the iNO-treated/

control infants (mean ±

SD) were 27.2 ±

2.2/25.8 ±

2.4 weeks,

996 ±

254/809 ±

316 g, and 21.4 ±

20.6/26.6 ±

9.8 days,

respectively (

P

= 0.22, 0.19, 0.49). Two groups were com-

pared in terms of survival, intraventricular hemorrhage, and

bronchopulmonary dysplasia. Fisher’s exact test was used to

analyze the difference of survival rates, intraventricular

hemorrhage, and bronchopulmonary dysplasia. Student’s

t

-test was used to analyze the effects of iNO therapy on

respiratory conditions.

Results

The characteristics of the very low-birthweight infants who

had or had not been treated with iNO therapy are shown in

Table 1. The gestational age and birthweight of the infants

indicated that iNO-treated infants were slightly more mature

than the control infants, although the differences were not

significant. In Table 2 the effects of iNO on survival and

clinical conditions of both groups are shown. The meanairway pressure, oxygenation index and alveolar arterial

oxygen difference immediately before starting iNO in the

iNO-treated group were worse than in the control infants that

had been measured at the corresponding time as in the

iNO-treated group. In the iNO-treated group, the arterial

oxygenation 2 h after commencing iNO therapy was signifi-

cantly higher than that measured before iNO therapy was

started (

P

< 0.001), although the arterial oxygenation of the

iNO-treated group 2 h after the treatment and the control

group at the corresponding time, did not differ significantly.

All eight iNO-treated infants survived more than 28 days,

while five of the 10 control infants died within 24 h of birth(survival rate at 7 days of birth, P

< 0.05). Before starting

iNO therapy, seven of the eight infants in the iNO-treated

group had shown persistent pulmonary hypertension, which

was confirmed by echocardiography, with tricuspid valve

regurgitation and/or a right-to-left shunt in the ductus

arteriosus or foramen ovale. Although one iNO-treated infant

could not be examined by echocardiography before the iNO

therapy, a rapid response to the iNO suggested that the infant

had persistent pulmonary hypertension.

Table 1

Characteristics of the very low-birthweight neonates

iNO-treated group Control group

P

value

No. patients 8 10Gestation (weeks)Mean ±

SD 27.2 ± 2.2 25.8 ± 2.4 0.22

†

Range 24–30 24–30

Birth weight (g)Mean ±

SD 996 ± 294 809 ± 316 0.19

†

Range 570–1317 426–1453Rupture of membrane (days) 21.4 ± 20.6 26.6 ± 9.8 0.49

†

Mean ±

SD 5–60 8–39

†

Analyzed by t

-test. iNO, nitric oxide inhalation.

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12 N Uga et al

.

The iNO-treated infants and control infants did not have

serious intraventricular hemorrhage (IVH). No iNO-treated

infant had IVH greater than grade 1, and only one control

infant had grade 2 IVH. All six long-term survivors in the

iNO-treated group are developing normally, while only

two of the control infants are developing normally as of

February 2002.

Discussion

Nitric oxide is a short-lived highly reactive molecule, cleaved

from its precursor, arginine. NO generated in the endotheliumenters the adjacent vascular smooth muscle where it binds to

the heme component of guanylate cyclase, which induces

synthesis of cyclic guanosine monophosphate which is a key

modulator of vascular smooth muscle tone. Exogenous NO

inhaled into the alveolus diffuses to the pulmonary vascular

smooth muscle cell stimulating this soluble guanylate cyclase.

In contrast with other vasodilators, inhaled NO has virtually

no effect on systemic vascular tone because of rapid binding

and deactivation by reduced hemoglobin within the vascular

space.

Pulmonary hypoplasia is associated with either a restriction

of lung growth or the absence of fetal breathing. Pulmonaryhypoplasia often occurs in premature infants with oligo-

hydramnios due to prolonged rupture of the membrane for

more than 5 days. Severe pulmonary hypoplasia is character-

ized by a decrease in lung size and cell number together with

narrow airways, a retardation of epithelial differentiation

and surfactant deficiency. Pulmonary hypertension persists

inevitably because of severe hypoxemia. Mortality is very

high. Thibeault et al

. reported that 20 out of 76 premature

infants less than 35 weeks’ gestation with prolonged rupture

of membrane of more than 5 days had pulmonary hypoplasia

and 18 of the 20 patients died.

4

McIntosh and Harrison

studied 117 infants of less than 37 weeks’ gestation who had

prolonged rupture of membrane of more than 99 h.

5

Among

the 117 cases, 11 cases died and were considered to have

pulmonary hypoplasia. The median age of death was 20 h

(range 12–48 h). Early death because of respiratory failure

is relatively common. For the present study, we selected 18

very low-birthweight infants who had prolonged ruptured

membrane for more than 5 days and oligohydramnios recorded

in the obstetric charts, and who had severe respiratory failure

without respiratory distress syndrome or pneumonia. All 18

infants had pulmonary hypoplasia. Five of the 10 control

infants died within 24 h of age because of hypoxia. No infantdied of asphyxia. These infants probably would have

survived had respiratory failure been cured by such treatment

as iNO to attain sufficient arterial oxygenation. The eight

infants who had been treated with iNO had respiratory failure

as severe as that in the 10 control infants, and it was thought

that the eight infants would die before the iNO therapy was

commenced. Because two of the eight infants had air leak,

we considered that a greater increase in pressure would

further damage the lungs without any benefit. iNO improved

the arterial oxygenation rapidly and consistently in all eight

infants. The iNO therapy alleviated the pulmonary hyper-

tension which was confirmed by echocardiography beforeand after the therapy. We believe the improvement of

oxygenation is a result of reduced right to left cardiac shunt

and increased pulmonary blood flow which was brought by

the reduced pulmonary pressure. The treated infants all

survived more than 28 days, but one case died at 30 days of

age due to sepsis, and one case died at 330 days of age due

to respiratory failure of bronchopulmonary dysplasia. iNO

therapy was successful in all of the infants with pulmonary

hypoplasia due to oligohydramnios.

Table 2

Effects of nitric oxide inhalation (iNO) on survival, and clinical conditions

iNO-treated group Control group P value

Survived more than7 days 8 5 <0.05

‡

28 days 8 5 <0.05

‡

Mean airway pressure

§

12.6 ± 2.8 10.9 ± 1 0.11

†

Oxygenation index

§

28.8 ± 18.3 13.9 ± 10.2 0.06

†

Oxygenation index

¶

6.7 ± 3.7* 12.2 ± 9.7 0.167

†

Alveolar arterial oxygen

§

621.8 ± 43.0 539.3 ± 63.5 <0.05

†

Air leak 2 1 NS

‡

IVH1–2 1 2 NS

‡

3–4 0 0 NS

‡

Bronchopulmonary dysplasia 6 3 NS

‡

IVH, intraventricular hemorrhage; NS, not significant. †

Analyzed by t

-test. ‡

Fisher’s exact test. §

Figures represents values immediatelybefore iNO was started in treated group, and worst value among those measured at a comparable time in control group. ¶

Value 2 h after theiNO treatment. *P

< 0.001, before and after the iNO treatment in the iNO-treated group.

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iNO therapy in infants 13

Subhedar et al

. reported the results of a randomized

study of 42 infants below 32 weeks’ gestation who were

recruited for iNO or early dexamethasone treatment at 96 h

of age if deemed to be at high risk for developing chronic

lung disease.

6

No significant difference in developing

chronic lung disease nor survival was noted between the

iNO group and the control group. It is very likely thatinfants with pulmonary hypoplasia were excluded because

of early death. Two other randomized studies have assessed

the use of iNO in preterm infants. The Franco-Belgium

collaborative NO trial group reported the results of a

randomized controlled study, and they found that low-dose

iNO improved the oxygenation index and reduced the

mechanical ventilation time only in near-term neonates.

7

They concluded that iNO does not significantly benefit

preterm neonates. In 1999, Kinsella reported a multi-center

randomized controlled trial of iNO in premature neonates

with severe hypoxemic respiratory failure.

8

Forty-eight

iNO-treated infants and 32 control infants less than 33

weeks’ gestation were included in that study. iNO signifi-

cantly improved the oxygenation index after 60 min.

However, in both studies iNO did not significantly improve

the survival rate. In Kinsella’s study, the mean age of

enrolment was 30 h in the study group and 27 h in the

control group. In our cases iNO was given earlier

(11.5 ±

11.6 h of age) than those reports. Therefore, the

majority of infants with severe respiratory failure might

have been excluded, or irreversible hypoxic damage might

have already occurred when iNO was commenced. A

randomized study to clarify the effect of iNO on early death

in very low-birthweight infants with pulmonary hypoplasia

of oligohydramnios is necessary.In 1988, McIntosh proposed dry lung syndrome as the

condition where an infant with severe respiratory distress as

seen in pulmonary hypoplasia due to oligohydramnios after

prolonged rupture of membrane, shows dramatic improvement

after very high initial ventilation.

9

We are not aware of how

many cases of dry lung syndrome were among our cases. As

Losa and Kind reported, some cases in their study might

have improved by giving a much higher positive pressure.

10

However, we could not administer higher pressure because it

was felt that increasing pressure would generate a pulmonary

air leak. It is very difficult to differentiate between dry lung

syndrome and pulmonary hypoplasia if pulmonary recruitmentcannot be attained by high positive pressure. We feel that

pulmonary hypoplasia due to oligohydramnios is an extreme

type of dry lung syndrome. Pulmonary hypoplasia due to

oligohydramnios in very low-birthweight infants is not fatal

if the pulmonary hypertension is ameliorated. However, this

does not mean that high positive pressure is not necessary if

iNO is given. Both iNO therapy and high positive pressure to

recruit the alveoli are needed to treat infants with pulmonary

hypoplasia.

Nitric oxide is known to suppress the adhesion and

aggregation of platelets.

11

Hogman et al

. reported that when

healthy adults were treated with 30 p.p.m. of iNO for 15 min,

the bleeding time increased by 33 ±

5%.

12

Cheung et al

.

reported that iNO treated very low-birthweight infants with

severe respiratory failure of unidentified causes.

2

Fourteen of

the 24 cases in their study died. Only three cases developednormally. They warned of the possibility of worsening IVH

after treatment with iNO. However, no randomized study has

found that iNO therapy increases the rate of intracranial

hemorrhage in premature infants.

6,7

Among the cases in the

present study, IVH was not a serious problem. Only one

control infant had grade 2 IVH, and no infant in the iNO-

treated group had IVH above grade 1. It seems that iNO

therapy does not aggravate the IVH in neonates with

pulmonary hypoplasia due to oligohydramnios. iNO therapy

was successful in treating all eight cases, but two died after

the neonatal period. The six other iNO-treated infants had no

abnormalities on cranial sonography and are developing

normally.

Clark et al

. reported that low-dose iNO therapy reduces

the extent of extracorporeal membrane oxygenation in

neonates with hypoxemic respiratory failure and pulmonary

hypertension.

13

Chronic lung disease developed less often in

the iNO-treated group. Short-term side-effects were not

observed. Methemoglobinemia was observed in only those

patients treated with 80 p.p.m. NO. We used 40–30 p.p.m.

NO at the start of the iNO therapy and the therapy was given

for 24 h. Methemoglobinemia of more than 2% did not occur

in any of the iNO-treated infants. We conclude that iNO can

treat severe respiratory failure due to oligohydramnios with

pulmonary hypertension without any serious side-effects.A prospective randomized study is urgently needed to

confirm the efficacy of iNO therapy given at an early age in

very low-birthweight infants with hypoplastic pulmonary

disease due to oligohydramnios.

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: 319–23.2 Cheung PY, Peliowski A, Robertson CM. The outcome of very

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