Neonatal acute respiratory failure

Jeevarathi Gnanaratnem, MD, and Neil N. Finer, MD

Acute respiratory failure is the most common problem seen in
the preterm and term infants admitted to neonatal intensive
care units. In preterm infants, the most common cause of acute
respiratory failure is respiratory distress syndrome caused by
surfactant deficiency. Acute respiratory failure in term and near
term infants is usually a result of meconium aspiration
syndrome, sepsis, pulmonary hypoplasia, and primary
pulmonary hypertension of the newborn. The response to
various methods of treatment may vary, depending on the
severity of respiratory failure and the cause of the acute respi-
ratory failure. We reviewed the evidence for efficacy and
current utilization of newer treatment modalities, including
exogenous surfactant administration, high frequency ventila-
tion, inhaled nitric oxide therapy, antenatal steroids for the
prevention of respiratory distress syndrome, and use of post-
natal steroids for the prevention of chronic lung disease. Curr
Opin Pediatr 2000, 12:227–232 © 2000 Lippincott Williams & Wilkins, Inc.
Each year, approximately 75,000 newborn infants require
mechanical ventilation in the United States [1]. Respiratory
distress syndrome (RDS) is the most common cause of
acute respiratory failure in preterm infants. Persistent
pulmonary hypertension of newborn (PPHN), either with
or without parenchymal lung disease, can cause severe
hypoxemic respiratory failure in preterm and term infants.
New treatment methods have improved the survival rate of
infants with acute respiratory failure.
Respiratory failure in preterm infants
Respiratory distress syndrome, caused by surfactant
deficiency, is the most common cause of acute respira-tory
failure in preterm infants. Other causes include transient
tachypnea of newborn, pneumonia, sepsis, and pulmonary
hemorrhage. Antenatal steroids given for fetal lung
maturation and exogenous surfactant adminis-tration have
dramatically reduced the mortality of infants with RDS.

University of California San Diego, Division of Neonatology, San

Diego, California, USA
Antenatal steroids
Correspondence to Neil N. Finer, MD, University of California San Antenatal steroids have reduced the incidence and the
Diego, Division of Neonatology, 200 W. Arbor Drive, 8774, San Diego, severity of RDS in preterm infants. Liggins and Howie
CA 92103-8774, usa; e-mail: nfiner@ucsd.edu
[2] published the first study demonstrating the value of
antenatal steroids in 1972. They reported a decreased
Current Opinion in Pediatrics 1999, 12:227–232
mortality and morbidity in preterm infants whose mothers
Abbreviations received this treatment. Subsequently, many randomized
CDH congenital diaphragmatic hernia trials [3–5] have confirmed the benefit of prenatal steroids
CLD chronic lung disease in reducing mortality, decreasing the incidence of RDS and
CPAP continuous positive airway pressure
ECMO extracorporeal membrane oxygenation intraventricular hemorrhage (IVH), and improving long
HFV high frequency ventilation term neurodevelopment outcome of prematurely born
INO inhaled nitric oxide
IVH intraventricular hemorrhage neonates. The consensus development conference
NO nitric oxide statement on “Effect of Corticosteroids for Fetal
PaCO2 arterial carbon dioxide tension
PHC permissive hypercapnia Maturation on Perinatal Outcome” provides convincing
PPHN persistent pulmonary hypertension of newborn evidence for beneficial effects of antenatal steroids. More
RCT randomized controlled trials
RDS respiratory distress syndrome recently, antenatal steroids have been shown to reduce the
VLBW very low birth weight incidence of periventricular leukomalacia and
ventriculomegaly [6,7]. Currently, about 60% of women at
ISSN 1040–8703 © 2000 Lippincott Williams & Wilkins, Inc. risk for preterm delivery are receiving antenatal steroids.
Repeated weekly courses of antenatal steroids are now
being administered in certain high risk pregnancies such as
twins [8]. Case reports and animal studies [9] suggest
repeated courses of antenatal steroids are associated with
undesirable side effects including poor fetal growth, poor
brain cell differentiation [10], and an increased incidence
of neonatal sepsis [11]. An observa-tional study by French
et al. [12] suggests that repeated courses of antenatal
steroids are associated with poor

227
228 Emergency and critical care
weight and head circumference at birth. A retrospective
study done by Elimian et al. [13] shows that compared with
a single course, multiple courses of antenatal steroids
significantly reduce the incidence of RDS with no increase
in neonatal sepsis or reduced fetal growth. We are
concerned that although there are substantial benefits of
antenatal steroids in reducing respiratory morbidity and
mortality in preterm infants, the use of repeated courses of
this treatment may cause unwanted long term side effects.
Randomized controlled trials (RCTs) are required to
evaluate the safety and efficacy of repeated courses of
antenatal steroids.
Exogenous surfactant administration
Multiple RCTs of synthetic, modified animal, purified
animal, and human surfactants have shown that exoge-nous
surfactant is safe and effective in the treatment of RDS. A
significant number of studies [14–16] have compared
synthetic and natural surfactants. Although there were some
differences in the short term response, long term outcome
after treatment with different surfac-tants did not differ.
Incidences of necrotizing enterocolitis, IVH, sepsis, patent
ductus arteriosus, and chronic lung disease (CLD) are not
affected by surfactant replacement therapy. Exogenous
surfactant administration does not appear to have any effect
on the long term growth and neurologic or developmental
outcomes [17].
Prophylactic use of surfactant has been shown to reduce the
occurrence of pneumothoraces, pulmonary intersti-tial
emphysema, and mortality in preterm infants [18]. Kendig
et al. [19] showed that prophylactic surfactant can be safely
and effectively administered at 10 to 15 minutes of age
with no difference between neonatal outcomes for infants
treated with a bolus of surfactant immediately after birth.
Postnatal steroid therapy
Postnatal steroid therapy is being widely used in mechani-
cally ventilated preterm infants to reduce inflammation and
prevent CLD. Studies [20–23] evaluating the effects of
postnatal steroids revealed that systemic steroid admin-
istered before 14 days improved gas exchange and lung
mechanics, shortened the need for mechanical ventilation,
and reduced the incidence of CLD and death at 28 days or
36 weeks of postconceptional age in neonates who were
ventilator dependent. Currently, as many as 50% of
extremely low birth weight infants are likely to receive this
medication during their neonatal stay [24,25].
Significant short term adverse effects include gastroin-
testinal hemorrhage, intestinal perforation, nosocomial
sepsis, meningitis, hyperglycemia, and hypertension [26–
29]. In addition, and of potentially greater concern,
poorer somatic growth [30], neuromotor dysfunction, and
developmental delay have been recently reported. Yeh et
al. [31] reported that infants who received neona-tal
dexamethasone had a higher incidence of neuromo-tor
dysfunction and lower psychomotor developmental index
scores. O’Shea et al. [32] and Shinwell et al. [33] reported
that the incidence of cerebral palsy was signifi-cantly
higher in their infants who were treated with
dexamethasone, and another recent report [34] demon-
strated a significantly higher incidence of periventricular
leukomalacia in neonates treated with steroids.
Watterberg et al. [35•] reported that early treatment with
low dose hydrocortisone in very low birth weight (VLBW)
infants increases the likelihood of survival without CLD.
Although the use of lower dose hydrocortisone may be
safer, the long term neurodevelopmental effects of low
dose hydrocortisone remain to be evaluated.
We believe that the beneficial effects of early use of potent
steroids may be more than offset by the early adverse
events and the increased risks of abnormal
neurodevelopmental outcome. There needs to be a serious
re-evaluation of the role of postnatal steroids in premature
infants at risk for CLD, and further informa-tion provided
regarding the outcomes of infants who have received such
treatment before postnatal steroids becomes an accepted
intervention.
High frequency ventilation in preterm infants
There has been an increasing trend toward the use of high
frequency ventilation (HFV) for the VLBW infant. Data
from the Vermont Oxford Network [24] demon-strate that
more than 50% or more of infants weighing less than 700 g
receive HFV. Infants treated with HFV often require a
longer period of mechanical ventilation than infants who
are not so treated. The multicenter study by Gertsman et al.
[36] included only 21 infants whose birth weight was less
than 1000 g. They noted a reduction in duration of
mechanical ventilation for infants who received HFV,
compared with infants treated with conventional
ventilation, from 53.7 days to 24.7 days, both very long
durations. In the most recent study from Europe, Thome et
al. [37•] showed that HFV was not associated with less
lung injury in preterm infants, compared with intermittent
positive pressure ventilation (IPPV), and there was no
difference in the incidence of IVH in these infants. In their
study, air leaks occurred in 31% and 42%, CLD in 23%
and 25%, and grade 3 to 4 IVH in 13% and 14% of infants
treated with IPPV and HFV, respectively. A meta-analysis
of elective HFV in preterm infants with RDS suggests that
although HFV reduces CLD, it seems to increase the risk of
IVH [38]. The increasing trend toward early use of HFV in
VLBW infants, without clear evidence of its beneficial
effects, is of significant concern.

Early continuous positive airway
pressure and permissive hypercapnia
A survey of eight neonatal units done in the United States
in 1987 demonstrated that one unit, Columbia Presbyterian
Medical Center (New York, NY, USA), had the lowest rate
of bronchopulmonary dysplasia [39]. This unit instituted
early nasal continuous positive airway pressure (CPAP),
avoided hyperventilation, and accepted high arterial carbon
dioxide tension (PaCO2). Subsequent studies from Europe
have also suggested that it is possible to avoid intubating a
significant number of VLBW infants, through the use of
early CPAP, and by the acceptance of higher levels of
PaCO2. For infants who develop respiratory distress,
intubation with surfactant treatment, followed by
extubation, has resulted in excellent outcomes with a
lowered incidence of CLD and no increased morbidity.
Jonsson et al. [40] reported on the experience from
Stockholm for all infants who weighed less than 1501 g
from 1988 to 1993, and reported that 59% of all infants
studied could be treated with either oxygen or CPAP alone.
Gittermann et al. [41] reported that early CPAP was
associated with a significantly lower frequency of
intubation, mortality, and a trend toward shorter duration of
intubation. The first attempt to prospectively evaluate the
use of early CPAP and short-term intubation for surfactant
adminis-tration was conducted by Verder et al. [42]. In this
study, they showed that a single dose of surfactant reduced
the need for mechanical ventilation. In a more recent multi-
center study, Verder et al. [43••] reported that nasal CPAP,
in combination with early treatment with surfac-tant,
significantly improved oxygenation and reduced the
subsequent need for mechanical ventilation in infants born
at less than 30 weeks gestation with RDS.
Permissive hypercapnia (PHC), in which higher levels of
PaCO2 are accepted to prevent lung injury, has been shown
to be effective in adult RDS [44]. All early extu-bation
studies in VLBW babies done in Europe have accepted
higher levels of PaCO2 (55–60 mmHg). The only
randomized trial of PHC in preterm infants done by
Mariani et al. [45••] reported that the total number of days
on assisted ventilation was 2.5 in the PHC group and 9.5 in
the normocapneic group. The use of early CPAP and PHC
appears to be safe and should promote earlier extubation of
VLBW infants. In addition, this approach may prevent
unnecessary intubation, and mechanical ventilation for a
significant proportion of these infants.
Inhaled nitric oxide in preterm infants
Nitric oxide (NO) is released by the vascular endothe-lium,
and it diffuses to the underlying vascular smooth muscle,
causing vasodilatation. When given as an inhala-tion, NO
acts as a selective pulmonary vascular relaxant.
Neonatal acute respiratory failure Gnanaratnem and Finer 229
Nitric oxide is known to inhibit platelet adhesion and
aggregation. Prolonged bleeding time secondary to inhi-
bition of platelet function has been reported in adults
receiving inhaled nitric oxide (INO). The effect of INO on
platelet function and bleeding time is of significant concern
in preterm infants at risk for IVH.
There are few published randomized trials of INO therapy
in preterm infants. Kinsella et al. [46••–49] reported that
low dose INO improves oxygenation but not survival of
preterm infants with acute respiratory failure. They also
reported that low dose INO treatment does not increase the
risk of IVH in preterm infants with acute respiratory
failure. These trials do not provide convincing evidence for
the efficacy of INO in the treat-ment of premature infants
with hypoxic respiratory failure. The possibility of
increased risk of IVH, associ-ated with INO therapy should
introduce a note of caution in using this treatment in
preterm infants. The safety and efficacy of INO in
premature infants requires validation by further
randomized trials.
Respiratory failure in term and near term
infants
Approximately 35,000 near term and term infants in the
United States require mechanical ventilation each year,
secondary to hypoxic respiratory failure [1]. Near term and
term infants have a higher mortality compared to preterm
infants with acute respiratory failure.
Persistent pulmonary hypertension of
the newborn
Persistent pulmonary hypertension of the newborn (PPHN)
is associated with increased pulmonary vascular resistance.
This leads to right-to-left shunting at either the foramen
ovale or the ductus arteriosus levels, or both, in addition to
ventilation perfusion mismatching. Both of these will result
in systemic desaturation.
Numerous treatments have been described to reduce
pulmonary hypertension, beginning with the use of tola-
zoline by Goetzman et al. [50], and followed by the advent
of hyperventilation as described by Drummond et al. [51].
Walsh-Sukys et al. [52•] recently reviewed the
management of PPHN and reported on the different
therapies utilized before widespread use of INO. However,
none of these therapies has been reported to improve
survival in near term or term infants with hypoxic
respiratory failure, as tested by prospective controlled
trials.
Inhaled nitric oxide in near term infants with
acute respiratory failure
Higenbottam et al. [53] initially showed the ability of INO
to selectively reduce pulmonary hypertension in adults
without effect on the systemic vascular resistance
230 Emergency and critical care
[54]. Subsequently, Roberts et al. [55] and Kinsella et al.
[56] demonstrated that INO rapidly produced a signifi-cant,
and, in some cases, a sustained improvement in oxygen
saturation in near term neonates with PPHN. From the
results of RCTs that have been completed in term and near
term infants, it is evident that death or need for
extracorporeal membrane oxygenation (ECMO) was
significantly reduced by treatment with INO in these
infants [57]. Follow-up studies have demonstrated that INO
is not associated with increased neurodevelop-mental
abnormalities [58•]. As a result, INO was approved by the
Food and Drug Administration in December 1999 for use in
near term and term infants with hypoxic respiratory failure.
High frequency ventilation in near term
infants with acute respiratory failure
Only two prospective randomized studies [59,60] have
compared HFV with conventional ventilation in near term
infants with acute respiratory failure. Neither of these
studies showed a reduction in mortality or the need for
ECMO. High frequency ventilation, using a high volume
strategy, can be used as an effective rescue therapy for
some of these infants.
Surfactant in the treatment of acute
respiratory failure in near term infants
Exogenous surfactant administration has been shown to
improve the oxygenation in near term infants with acute
hypoxic respiratory failure. An RCT by Lotze et al. [61]
showed that exogenous surfactant administration signifi-
cantly decreases the need for ECMO in term infants with
severe respiratory failure. In a previous study, Lotze et al.
[62] reported that multiple doses of surfac-tant
administration in near term infants who were receiving
ECMO decreased their time on ECMO.
Findlay et al. [63] demonstrated that surfactant replace-
ment therapy improves oxygenation, and reduces the air
leaks, the need for ECMO, and hospitalization time in
meconium aspiration syndrome. Animal studies [64] and
two pilot studies [65,66] suggest that surfactant lavage may
be a safe and effective method of treatment for meconium
aspiration syndrome.
A retrospective study done by Pandit et al. [67] in preterm
and term infants suggests that exogenous surfac-tant
administration improves oxygenation in infants with
pulmonary hemorrhage. Exogenous surfactant may be an
effective intervention in term and near term infants with
acute hypoxemic respiratory failure and is more effective
when used earlier in the disease progression.
Extracorporeal membrane oxygenation
Extracorporeal membrane oxygenation is used to treat acute
respiratory failure when other modalities of treat-
ments have failed. Extracorporeal membrane oxygena-tion
had been shown to improve the survival in term and near
term infants with severe respiratory failure in at least two
small controlled clinical trials [68,69]. Subsequently, the
UK collaborative randomized trial of neonatal ECMO and
follow-up studies show that ECMO significantly reduced
the risk of death without an increase in severe disabilities.
In this study [70,71], 30 of 93 infants in the ECMO group
died, compared with 54 of 92 in the conventional care
group. Currently, the use of ECMO is decreasing because
of the effective-ness of the previously described treatments
such as INO and exogenous surfactant administration in
near term infants. Venovenous ECMO, which is less
frequently used, is preferred to venoarterial ECMO in acute
respi-ratory failure, as it avoids cannulation of the carotid
artery.
Congenital diaphragmatic hernia
Historically, acute respiratory failure secondary to
congenital diaphragmatic hernia (CDH) has had a poor
outcome, and, in RCTs [73], has been shown to have a poor
response to INO. Preoperative stabilization using
prophylactic surfactant, gentle ventilation, permissive
hypercarbia and hypoxia, HFV, and INO has been asso-
ciated with improved survival in infants with CDH
[74,75•]. Advances in fetal surgery have improved the
outcome of fetuses with CDH predicted to have poor
outcome. A very promising new approach, fetoscopically
performed tracheal occlusion, seems to improve the
outcome of fetuses with CDH [76]. Harrison et al. are
currently conducting a prospective randomized trial to
evaluate this innovative approach.
Conclusions
Recent advances in neonatology have substantially
improved the outcome of newborns with acute respira-tory
failure. The final decision regarding the introduction of any
new therapy into neonatal intensive care must be based on
the beneficial acute short term effects associ-ated with the
maximum preservation of neurodevelop-mental potential
for the infants for whom it is prescribed.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
• Of special interest
• Of outstanding interest
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232 Emergency and critical care
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