Matching Ventilatory Support Strategies
to Respiratory Pathophysiology
Anne Greenough, MDa,*,
Steven M. Donn, MDb
aDivision of Asthma, Allergy and Lung Biology, King’s College London,
Children Nationwide Regional Neonatal Intensive Care Centre,
4th Floor, Golden Jubilee Wing, King’s College Hospital,
London SE5 9PJ, UK
bDepartment of Pediatrics, Division of Neonatal–Perinatal Medicine,
C.S. Mott Children’s Hospital, University of Michigan Health System,
1500 E. Medical Center Drive, Ann Arbor,
MI 48109-0254, USA
During the last two decades, new respiratory techniques have become
available to support the neonate. Although these have been actively
researched, many studies have only included prematurely born infants
who have acute respiratory distress. The newborn can suffer from various
diseases, each with a different pathophysiology and impact on lung function.
A term infant who has meconium aspiration syndrome may have over-
distended lungs with high airway resistance, whereas the surfactant-deficient
lungs of prematurely born infants are atelectatic and noncompliant. Thus,
the concept of ‘‘one size fits all’’ can no longer be an appropriate manage-
ment strategy, and the results of studies examining the efficacy of respiratory
support modes that have included only one type of lung disorder may not be
generalized to others.
In this review, the authors discuss respiratory strategies according to
pathophysiology and critically evaluate the evidence, because many of the
studies undertaken have lacked suitable or indeed any comparator controls,
and other randomized trials have been too small to robustly test a clinically
AG has received research grants and/or support to attend meetings from SLE Systems
UK, Draeger Medical, and F. Stephan Biomedical.
* Corresponding author.
E-mail address: firstname.lastname@example.org (A. Greenough).
0095-5108/07/$ - see front matter ? 2007 Elsevier Inc. All rights reserved.
Clin Perinatol 34 (2007) 35–53
Time-cycled, pressure-limited ventilation
Time-cycled, pressure-limited ventilation (intermittent positive pressure
ventilation [IPPV]) has been the most frequently used mode for the
newborn. During IPPV, inflations can be delivered at rates of 30 to 120 bpm;
when rates of 60 bpm or more are used, this is termed high-frequency
positive pressure ventilation (HFPPV). Inspiratory times between 0.3 and
0.5 seconds with a longer expiratory than inspiratory time (giving a physi-
ologic inspiratory/expiratory ratio) are generally used, because these are
similar to spontaneous respiratory times in the preterm infant and more
likely to promote a synchronous interaction and improved gas exchange
[1,2]. If, however, the infant has severe disease, an inspiratory time longer
than the expiratory time is sometimes used (reversed inspiratory/expiratory
ratio) to increase mean airway pressure (MAP) and oxygenation. Positive
end expiratory pressures (PEEP) of 3 to 6 cmH2O are generally employed,
but if the infant has severe disease, the PEEP can be raised as high as
12 cmH2O, again to increase MAP. The relative effectiveness of these
variations, except for comparing different rates (see later discussion),
have usually only been tested in physiologic studies with gas exchange
as the outcome.
Patient-triggered ventilation was reintroduced into neonatal intensive
care in the 1980s, initially as assist/control (A/C) (inflations triggered by ev-
ery spontaneous breath that exceed the critical trigger threshold) and syn-
chronized intermittent mandatory ventilation (SIMV) (only the preset
number of inflations are triggered regardless of the infant’s spontaneous re-
spiratory rate). Newer triggered modes, such as pressure support ventilation
(PSV) and proportional assist ventilation (PAV), are now available. During
PSV, not only the initiation (as with A/C and SIMV), but also the termina-
tion of ventilator inflation are determined by the infant’s spontaneous respi-
ratory efforts by using airway flow changes as an expiratory trigger. Inflation
is terminated when the inspiratory flow level reaches a certain percentage of
peak flow. For example, in PSV mode of the Draeger Babylog 8000 (Draeger
Medical, Luebeck, Germany), inflation is terminated when the flow is re-
duced to 15% of the maximum inspiratory flow, whereas PSV termination
criteria used with the VIP BIRD (Bird Products, Palm Springs, California)
are 5% to 25%, depending on the delivered tidal volume. This is referred
to as flow cycling. During PAV, the applied pressure is servo-controlled
throughout each spontaneous breath, and the frequency, timing, and rate
of lung inflation are controlled by the patient. The applied pressure increases
in proportion to the tidal volume and inspiratory flow generated by the pa-
tient. This can be enhanced to reduce the work of breathing .
GREENOUGH & DONN
volume; this ventilator modality will subsequently be referred to as volume-
changes in the infant’s respiratory compliance and/or efforts; this is achieved
by servo-controlled adjustments in the inflating pressure. The adjustments in
inflating pressure are made in response to differences in the preset and either
the exhaled or inhaled volume. There are different forms of VTV . During
volume-controlled or volume-support ventilation, the desired tidal volume is
selected and the duration of inflation depends on the time taken for the vol-
ume to be delivered, which is adjusted by changes in the inspiratory flow
rate. During Volume guarantee (Draeger Medical, Luebeck, Germany) ven-
tilation, a preset expiratory tidal volume is selected, but the preset inspiratory
time determines the duration of inflation, and the maximum pressure set by
the clinician limits the maximum peak inflation pressure. The desired tidal
volume, however, will not be delivered if the preset peak inspiratory pressure
ventilation, during which the pressure support for any inflation is aborted if
the measured inspired tidal volume exceeds a preset upper limit. During vol-
ume-controlled inflation, there is breath-by-breath servo-controlled flow,
which is constant during inspiration so that the required volume is delivered
over the set inspiratory time. Ventilator manufactures have used different
strategiesto achieve VTV.The SLE 5000(Specialised LaboratoryEquipment
Ltd., UK) and Bear Cub 750 psv (Viasys Healthcare, Palm Springs, Califor-
nia) deliver targeted tidal or volume-limited ventilation, the Draeger Babylog
8000 delivers volume guarantee ventilation, the VIP BIRD and Avea (Viasys
Healthcare, Palm Springs, California) deliver volume-controlled (or volume-
support) ventilation and the Stephanie paediatric ventilator (F. Stephan Bio-
volume guarantee (VG) levels between 4 and 6 mL/kg have been used, but
there is evidence to suggest that the VG level used may be critical to efficacy.
In one study , a VG level of 4 mL/kg with SIMV in the first 48 hours after
of the time. It seems likely that 6 mL/kg may be the most appropriate level. A
level of 6 but not 4.5 mL/kg reduced the duration of hypoxemic episodes
during SIMV in one study , and in another trial, 6 mL/kg compared with
4 or 5 mL/kg was associated with the lowest work of breathing . Both
VTV and VG are described in more detail in other articles in this issue.
Forms of high-frequency ventilation include high-frequency jet ventilation
(HFJV), high-frequency flow interruption (HFFI), and high-frequency
oscillatory ventilation (HFOV). HFJV is a modification of the technique
initially developed to provide respiratory support during bronchoscopy. A
high-pressure source is used to deliver short bursts of gas through a small-
bore injector cannula in a specially designed endotracheal tube, or alterna-
tively through a special proximal endotracheal tube adapter. The pulses are
superimposed on a constant flow (PEEP) provided by a tandem conventional
ventilator, which may also be used to deliver periodic sigh breaths. Frequen-
cies between 150 and 660/min are used with short (eg, 20 msec) inspiratory
times. During HFFI, small volumes of gas at high frequencies (up to 20 Hz)
are delivered. A high-pressure gas source, fed into a continuous positive
airway pressure (CPAP) circuit immediately opposite the endotracheal tube
connector, is interrupted. During HFOV, even smaller tidal volumes are
delivered at frequencies between 8 and 15 Hz. Various techniques are used
to generate HFOV and include a sine wave pump and a diaphragm driven
by a linear motor. The delivered volume is inversely related to frequency
with all oscillators , and hence frequencies between 5 and 10 Hz rather
than faster rates can be more effective in infants who have severe carbon
dioxide retention. Unlike other forms of respiratory support, HFOV has
an active expiratory as well as an active inspiratory phase. Certain oscillators
allow an inspiratory/expiratory ratio of up to 1:2 to reduce the likelihood of
gas trapping. Use of a 1:2 ratio is associated with lower volume delivery,
MAP, and poorer oxygenation) , and it has been demonstrated that even
underextreme conditions(high resistance andhigh compliance), gastrapping
did not occur with an inspiratory/expiratory ratioof 1:1 . HFOV has been
used with either a low-volume strategy in which the MAP is limited with the
aim of preventing damage from baro/voluotrauma, or a high-volume strat-
egy in which MAP is elevated to promote optimum alveolar recruitment
and expansion and avoid damage from atelectotrauma. Comparisons have
only been undertaken in animal models, but the evidence is compelling
that the high-volume strategy is less damaging to the lungs . In infants
who have severe respiratory failure, transfer to a high-volume HFOV
strategy results in increased MAP in an attempt to improve oxygenation.
Assessment of lung volume by ahelium gas dilution technique before transfer
to HFOV can predict the change in MAP necessary to optimize oxygenation
Noninvasive respiratory support
CPAP can be delivered by a headbox, facemask, nasaopharyngeal or
endotracheal tubes, single or dual nasal prongs, or a high-flow nasal cannula.
Nowadays, the first two methods are rarely used. Studies have demonstrated
that the method of CPAP delivery influences outcome. In one randomized
trial, use of binasal prongs versus a nasopharyngeal prong was associated
with a lower oxygen requirement and respiratory rate . Meta-analysis of
the results of two randomized trials evaluating CPAP following extubation
demonstrated that short binasal prongs were more effective at preventing re-
intubation than a single or nasopharyngeal prong (RR 0.59 (0.41–0.85)) .
GREENOUGH & DONN
In another study, however, the CPAP duration was shorter in very low birth
weight infants when a nasopharyngeal prong was used rather than binasal
prongs . During ‘‘bubble’’ CPAP, the pressure in the device is generated
byacontinuous flow ofgas withthe distalendplaced asetdepth under water.
noise superimposed on the transmitted pressure wave form during bubble
CPAP . However, in a randomized crossover trial of 26 infants with
a mean gestational age of 27 weeks, vigorous, high-amplitude bubbling com-
in any significant differences with regard to respiratory rate, pulse oximetry,
and transcutaneous carbon dioxide tensions .
It has been suggested that the chests of infants who receive bubble CPAP
by way of an endotracheal tube vibrate in a similar manner and frequency to
those who receive HFOV , and as a consequence it was hypothesized
that bubble CPAP might reduce the work of breathing and augment gas
exchange by facilitated diffusion. Lee and colleagues  were subsequently
able to demonstrate that despite reduction in minute ventilation and respi-
ratory rate on bubble CPAP compared with ventilator-derived CPAP in
intubated infants, blood gas parameters were maintained. Variable flow
CPAP is by way of nasal prongs or a modified nasal cannula, and the
work of breathing is lower. The positive effects may result from gas entra-
inment by the high-velocity jet flows. Lung overdistension, however, may
occur in infants who have mild disease if variable flow CPAP levels greater
than 6 cmH2O are used.
Although nasal CPAP is considered by many as a gentler form of respira-
tory support , it does have adverse effects including nasal trauma. In some
studies, this has been reported to be common; 20% of infants supported on
dual prongs were affected in one series  and 32% in another . It had
but randomized studies have demonstrated no significant differences in the
incidence of trauma between binasal prongs and nasopharyngeal tube ,
or binasal prongs and facemask . The only significant relationship to
trauma in one series was CPAP duration .
Continuous negative distending pressure (CNEP) is an alternative way of
providing distending pressure. The infant’s body is placed in a negative pres-
sure box from which the head protrudes, and CNEP of -4 to -10 cmH2O
is applied .
Extracorporeal membrane oxygenation
Extracorporeal membrane oxygenation (ECMO) is a form of cardiopul-
monary bypass in which the circulation is diverted from the body and
pumped through a silicon membrane oxygenator. Cannulation for ECMO
is either venoarterial or venovenous. During venoarterial ECMO, total
bypass can be achieved and the level of respiratory support can be reduced
to limit further trauma to the lungs. In venovenous ECMO, total cardiopul-
monary bypass is not achieved and the infant must have reasonable myocar-
dial function. ECMO has traditionally been used in term or near-term
infants to treat reversible respiratory failure, when it is felt that the risk of
death exceeds 80% and all other therapies have failed.
Inhaled nitric oxide
Inhaled nitric oxide (iNO), administered directly to the airway, is a selec-
tive pulmonary vasodilator used to treat hypoxemic respiratory failure asso-
ciated with pulmonary hypertension of the newborn. Studies in term infants
have demonstrated that levels of 5 ppm are equally as effective as higher
doses [22,23]. In addition, four dose–response studies have demonstrated
that the maximum beneficial effect is seen at levels of less than 30 ppm,
and increases of up to 80 to 100 ppm did not result in further improvements
in oxygenation . Side effects are more likely at higher doses. Nitric oxide
reacts with oxygen to form nitrogen dioxide (NO2), and the reaction rate is
proportional to the square of the nitric oxide concentration. NO2is toxic to
the lungs; humans inhaling 2 to 3 ppm for 3 to 5 hours had reductions in
antioxidant defenses and an increase in alveolar permeability. In addition,
reactive species such as peroxynitrite formed from NO2have the potential
to damage DNA, raising the possibility of mutagenic or carcinogenic effects.
Nitric oxide should only be administered where there is immediate access to
methemoglobin analysis. The nitrosylhemoglobin produced by nitric oxide
binding to hemoglobin is rapidly converted to methemoglobin, which is
then reduced by methemoglobin reductase in the erythrocytes. Premature
infants and those of certain ethnic origins have low levels of methemoglobin
reductase. It is important, therefore, to assess methemoglobin levels
immediately before and during iNO therapy.
Liquid ventilation is performed by filling the lungs with perfluorocar-
bons (PFC). PFC, compared with water, have a low surface tension and
a high solubility for respiratory gases. Liquid ventilation can be applied
as total liquid ventilation in which the oxygenated PFC are instilled into
the lung and the ventilator circuit is filled with PFC. The PFC are then
moved backward and forward from the circuit into the lungs. The alterna-
tive technique is partial liquid ventilation, during which the PFC are in-
stilled into the lungs at a volume equivalent to the expected functional
residual capacity and the infant’s endotracheal tube is connected to a con-
GREENOUGH & DONN
A square airway pressure wave form is often assumed during IPPV, but
ventilators may be unable to maintain such a wave form at fast rates and
short inflation times . Certain new neonatal ventilators allow the rise
time to peak pressure to be varied. Physiologic data suggest a rapid rather
than a slurred upstroke is more likely to provoke active expiration/asyn-
chrony . Asynchrony does occur in the population of premature infants
. Whether this is reduced by use of a slurred upstroke to positive pressure
inflation has to be appropriately tested. Delivered volume is compromised in
certain ventilators when rate is increased or inflation time reduced .
Many studies have shown differences in the performance of different types
of triggering systems. The most compelling evidence is from a study 
in which two different triggering systems were assessed using a single neona-
tal ventilator, thus any difference noted was from the triggering system
and not the ventilator. This study demonstrated that pressure triggering
compared with airflow triggering had a lower sensitivity and a longer trigger
delay (also referred to as response time), which could translate into a higher
air leak rate. In VTV, there are differences according to ventilator type in the
delivered peak pressure, inflation time, and MAP. These related to differ-
ences in the airway pressure wave forms delivered by the different ventilator
types: airway pressure wave forms vary from a square wave form with a pos-
itive pressure plateau; termination of the peak pressure once the preset
volume has been delivered (decelerating wave form); and a slurred upstroke
in the inflating pressure, with the delivered volume only being achieved at
the end of the preset inflation time . Various techniques have been
used to generate HFOV and this influences the airway pressure wave form
and the volume delivered . Despite using the same oscillatory settings,
volumes vary according to oscillator type, but, as the frequency is increased,
the volume delivered falls with all oscillators .
The newer generation of ventilators displays the delivered volume and
thus it is tempting to use these values to determine the most appropriate
level of volume delivery. Physiologic studies, however, have demonstrated
that the delivered volume may vary considerably even when infants have
blood gases within the ‘‘therapeutic’’ range, because their spontaneous respi-
ratory efforts may make a sizeable contribution to minute ventilation .
In addition, the monitors may be inaccurate. For example, in a physiologic
study examining the VIP BIRD ventilator, the actual volume delivery was
always significantly higher than the volume displayed by the ventilator
and incidentally lower than the preset level . The latter difference results
from compressible volume loss in the circuit and is also influenced by gas
leaks around the uncuffed endotracheal tubes used in neonates. Frequency
can affect the accuracy of the volumes displayed by oscillators . Compar-
ison of the displayed versus the measured volumes using a lung model and
a sine wave pump (which delivered a constant volume) demonstrated that
the SLE 5000 overread by 5%, but at 5 Hz the Draeger 8000 Plus and
Stephanie ventilators underread by 20%. Increasing the frequency from
5 to 15 Hz resulted in even greater discrepancy between the measured and
displayed volumes by the Stephanie oscillator. It is important then to check
arterial blood gases soon after changing frequency rather than rely on the
oscillator volume display, particularly because abrupt reductions in carbon
dioxide tension during HFOV can cause large changes in cerebral blood
flow velocity .
Acute respiratory distress in preterm infants
Time-cycled, pressure-limited ventilation
IPPV has been the most frequently used mode for the newborn. Meta-
analysis of the results of randomized trials demonstrated the risk for air
leaks was lower with HFPPV compared with slower rate IPPV (RR 0.69,
95% CI 0.51,0.93) . Faster rates reduce active expiration  and hence
may have reduced the risk of pneumothorax. The trials, however, were per-
formed before the routine use of antenatal corticosteroids and postnatal sur-
factant. Whether HFPPV compared with slow rate IPPV reduces the risk of
pneumothoraces in the present population of prematurely born infants has
not been appropriately tested.
Physiologic studies demonstrated benefits for either A/C or SIMV,
including less asynchrony, reduced cerebral blood flow fluctuations, and
lower work of breathing, but the comparator was often intermittent man-
datory ventilation. No significant differences in the rates of bronchopulmo-
nary dysplasia (BPD), severe intracranial hemorrhage (ICH), air leaks, and
mortality according to ventilation mode, however, were demonstrated in
the meta-analysis  of the results of randomized trials. Although the
meta-analysis did not demonstrate any significant excess of adverse effects
, in the largest trial  included in the meta-analysis, there was a trend
for more immature infants supported by A/C to have air leaks. It is pos-
sible that the results of the A/C arm of the trial were adversely affected by
using an airway pressure trigger in most infants on A/C . The meta-
analysis, however, did demonstrate that patient-triggered ventilation was
associated with a shorter duration of ventilation, but this was only seen
in infants recovering from rather than in the acute stages of respiratory
distress . In three trials, A/C has been compared with weaning by
SIMV in infants recovering from respiratory distress syndrome (RDS)
GREENOUGH & DONN
[38,39]. In all three trials, the infants were supported by a single ventilator
type, and weaning in the A/C arm was by pressure reduction only. The
method of weaning by SIMV, however, differed. In one trial, during
SIMV the peak inflating pressure was reduced and the rate decreased to
5 bpm before extubationdthis resulted in a significantly longer duration
of weaning. In the trial in which the SIMV rate was decreased to a mini-
mum of 20 bpm, the duration of weaning by SIMV and A/C was similar.
In these trials, spontaneous breaths were supported solely by PEEP
[38,39], and the likely explanation for the difference in the results of the
trials is that reduction in the number of breaths supported by mechanical
inflations below 20 per minute increases the work of breathing related to
overcoming the imposed work of breathing. In support of that hypothesis,
oxygen consumption has increased at low ventilator rates . SIMV has
also been an inferior weaning mode in randomized trials in adults. PSV
has been associated with a lower rate of asynchrony  and thus might
reduce air leaks, but this has not yet been tested in a randomized trial.
In a short-term study, PAV allowed adequate gas exchange at lower
MAPs than A/C and IMV in premature infants  and was associated
with a lower incidence of thoracoabdominal asynchrony and chest wall
distortion than CPAP .
Meta-analysis of the results of four randomized trials  demonstrated
VTV was associated with significant reductions in the duration of ventilation
and the rate of pneumothorax, but not death or BPD. The trials, however,
were small, including a total 178 infants. In two studies, volume-controlled
ventilation was examined and in the other two VG was studied. In addition,
the design of the two volume-controlled ventilation trials limits the general-
izability of their results. In one , IPPV was not delivered by a comparable
neonatal ventilator, and in the second , the airway pressure wave form on
the IPPV mode differed from that delivered by other neonatal ventilators in
that there was no positive pressure plateau . A further randomized trial
comparing volume-controlled ventilation to time-cycled, pressure-limited
ventilation using the VIP BIRD has recently been published . Among
infants weighing between 600 and 1500 g and gestational ages 24 to 31 weeks
and have RDS, those on volume-controlled ventilation reached predeter-
mined success criteria faster; the difference reached statistical significance
in babies weighing less than 1000 g. There were, however, no significant
differences in the duration of ventilation or occurrence of complications.
However, all respiratory-related deaths in the first week of life occurred ex-
clusively in the IPPV group. During VG, adequate gas exchange is achieved
at lower MAPs , because the baby makes a greater contribution to minute
ventilation . Results of randomized trials have suggested that addition of
VG to A/C allows more rapid improvement in oxygenation, particularly in
infants who have a birth weight of less than 1000 g . In another random-
ized study, a VG level of 4 mL/kg with SIMV rather than SIMV alone was
more effective with regard to maintaining desirable carbon dioxide tensions
in infants greater than 25 weeks of gestational age, but was ineffective in
more immature infants . Volume targeting may be more effective when
used with A/C rather than SIMV, as evidenced by a lower work of breathing
Whether the use of VG in combination with PSV improves outcomes
remains controversial, particularly with regard to the effect on lung inflam-
mation [51,52]. In one study, the only advantage of using VG with PSV was
less blood gas monitoring , but in another, the MAP was higher than
during SIMV without VG .
In one randomized study, use of HFJV was associated with a reduction in
the incidence of BPD at 36 weeks and less need for home oxygen , but
a second trial  was halted for safety reasons, because infants exposed
to HFJV had higher rates of severe ICH (41% versus 22%) and periventric-
ular leukomalacia (PVL) (31% versus 6%). There have been at least 11 trials
in which infants have been randomized to receive HFOV or standard venti-
lation techniques in the first 24 hours after birth. Meta-analysis of their re-
sults  demonstrated that HFOV had no significant effect on mortality,
only a modest reduction in BPD in survivors at term, but no statistically sig-
nificant effect on short-term neurologic abnormality, ICH, or PVL. The 3
most recently reported randomized trials included in the meta-analysis
yielded different results. Moriette and colleagues  reported that HFOV
was associated with a trend toward an increase in severe ICH; the type of
oscillator used in their trial has not been used in any of the other random-
ized studies. Courtney and colleagues  reported that HFOV reduced the
combined outcome of BPD and death, but the randomized comparator
group was supported solely by SIMV, which may have put them at a disad-
vantage because the work of breathing is increased at low SIMV rates .
In the third trial  (United Kingdom Oscillation, UKOS trial), 799 infants
below 29 weeks of gestation were randomized within 1 hour of birth to
HFOV or standard ventilation techniques, and no benefits or disadvantages
of HFOV were noted. In addition, the follow-up assessments of the UKOS
survivors also demonstrated no significant differences in the results of lung
function measurements at 1 year of age  or respiratory or neurodevelop-
mental outcome at 2 years of corrected age .
Noninvasive respiratory support
CPAP is now used in many centers in preference to early intubation and
IPPV [18,62–64]. In nonrandomized trials, its use has been associated with
GREENOUGH & DONN
a reduction in the requirement for mechanical ventilation and the incidence
of BPD. Yet, meta-analysis of two published randomized trials examining
whether prophylactic CPAP commenced soon after birth reduced the use
of mechanical ventilation, and the incidence of BPD demonstrated no signif-
icant differences in any of the outcomes . In addition, in a randomized
study including 230 infants of gestational ages 29 to 31 weeks, prophylactic
CPAP (instituted within 30 minutes of birth) was not found more efficacious
than rescue CPAP, applied when the inspired oxygen requirement was
greater than 40%, with regard to need for surfactant treatment or mechan-
ical ventilation . In another randomized study , however, infants who
developed RDS and were given surfactant and subsequently randomized
to immediate extubation and nasal CPAP required a shorter duration of
oxygen therapy, nasal CPAP, and mechanical ventilation than those
randomized to remain on mechanical ventilation. Meta-analysis of the
results of postextubation randomized trials has demonstrated that CPAP
significantly reduced the need for additional respiratory support [RR 0.62
(0.49–0.77)], but not the need for endotracheal intubation [RR 0.93
(0.72–1.19)] or supplemental oxygen requirement at 28 days [RR 1.00
The evidence for benefit of nasal ventilation modes, including IPPV,
SIMV, or HFOV delivered by nasal prongs is from either anecdotal studies
or from trials with only short-term outcomes, and it remains uncertain
whether they have significant adverse outcomes [69–71]. Randomized trials
comparing nasal IPPV with CPAP in infants who have apnea of prematurity
have yielded conflicting results. One trial  showed no differences,
whereas the other  concluded that nasal IPPV was associated with
a reduction in apnea frequency. Meta-analysis of the results of the two trials
demonstrated no significant differences in carbon dioxide elimination at the
end of the 4- to 6-hour study period.
Early studies  demonstrated CNEP was associated with improve-
ments in oxygenation in infants who have severe RDS. In a randomized trial
, use of CNEP (-4 to–6 cmH2O) was associated with a lower duration of
oxygen therapy (18.3 versus 33.6 days), but there were trends toward
increases in mortality and cranial ultrasound abnormalities in the CNEP
Severe lung disease
High-frequency oscillatory ventilation
There have been two randomized trials of HFOV in infants who have
severe respiratory failure. In term infants , although HFOV was
a more effective rescue therapy than IPPV, there were no significant differ-
ences in the requirement for ECMO or duration of ventilator or oxygen
dependency between the two groups. In preterm infants, use of HFOV
was associated with a significant reduction in new pulmonary air leaks (RR
0.73, 95% CI 0.55–0.96), but a significant increase in ICH (RR 1.77, 95%
CI 1.06–2.96) . High-volume strategy HFOV is not a successful form of
rescue support in all babies who have severe respiratory disease, and failure
to improve oxygenation after 6 hours of a high-volume strategy identifies
those babies most likely to die  or survive with disability . An initial
improvement in oxygenation in response to HFOV, however, does not
guarantee a normal neurodevelopmental outcome at 2 years in prematurely
born infants .
Extracorporeal membrane oxygenation
Two early trials performed in the United States using adaptive experi-
mental designs demonstrated the efficacy of neonatal ECMO in severe respi-
ratory failure. In a multicenter United Kingdom randomized trial of 185
infants who had an oxygenation index greater than 40, ECMO compared
with conventional ventilation was associated with a 50% reduction in
mortality in infants who had persistent pulmonary hypertension of the new-
born (PPHN) or meconium aspiration syndrome (MAS). The ELSO data
highlight that ECMO survival figures vary according to diagnosis with sur-
vival rates of 90% for infants who have MAS, 76% for larger infants who
have RDS, and only 50% for infants who have congenital diaphragmatic
Inhaled nitric oxide
Meta-analysis of the results of randomized trials has demonstrated that
iNO reduces the need for ECMO or death in infants born at or near
term, but the positive effect is on ECMO requirement . Meta-analysis
 of the results of seven trials in premature infants demonstrated that
iNO had short-term positive effects on oxygenation, but no significant
effects on mortality, BPD, or ICH. In one study , however, iNO was as-
sociated with a significant reduction in the combined outcome of death and
BPD (RR 0.76, 0.60–0.97) and in grade 3 and 4 IVH (RR 0.51, 0.27–0.97);
subanalysis demonstrated the advantages were seen in the infants who had
mild disease. In contrast, in infants who had severe respiratory failure, the
use of iNO was associated with prolongation of intensive care and increased
cost of care without clear beneficial effects . Recently, two positive iNO
studies have been reported; both suggest that prolonged therapy with iNO
may be more efficacious. In one , although overall there was no reduc-
tion in death or BPD, in infants with birth weights between 1000 and
1250 g, low-dose (5 ppm) iNO reduced the incidence of BPD by 50% and
in this cohort was associated with a lower rate of the combined outcome
of ICH, PVL, and ventriculomegaly. In that trial, iNO was given for 21
days or until extubation. In the second trial , iNO was associated with
GREENOUGH & DONN
a significant increase in survival without BPD (43.9% versus 36.8%); the
minimum treatment exposure was 24 days. The infants who received iNO
were discharged sooner and received supplemental oxygen for a shorter
time. Posthoc analysis demonstrated that the positive effects were seen in
infants enrolled at 7 to 14 days but not at 15 to 21 days and were restricted
to infants who had less-severe lung disease.
There are limited data on liquid ventilation. In a nonrandomized, un-
blinded study, premature infants who had severe RDS in whom conventional
ventilation had failed were treated with partial liquid ventilation for up to 96
hours; they experienced significant increases in their arterial oxygen tension
and dynamic compliance . Similarly, dynamic pulmonary compliance
significantly increased  in response to partial liquid ventilation in six
term infants who had respiratory failure who showed no improvement while
Pulmonary interstitial emphysema
Increasing the ventilator rate to 100 to 120 bpm on conventional ventila-
tion can reduce the number of infants who have pulmonary interstitial
emphysema (PIE) who develop pneumothorax, but the severity of their
PIE worsens . Oxygenation in infants who have severe PIE has been re-
ported in small nonrandomized series to improve when continuous negative
pressure is combined with intermittent mandatory ventilation or infants are
transferred from conventional ventilation to HFOV or HFJV. In random-
ized trials, however, high-frequency oscillatory was not of greater benefit
than positive pressure ventilation , but HFJV use was associated with
more rapid resolution of PIE . HFFI use has also been associated
with improvements in blood gases in babies who have PIE and radiologic
resolution of the PIE , but only in anecdotal studies.
Meconium aspiration syndrome
Oxygenation of infants who have severe MAS may improve if HFJV is
used in combination with surfactant . Similarly, HFOV has improved
oxygenation in infants who have severe MAS; the combination of HFOV
and iNO may be particularly efficacious . The most compelling evidence
is from a randomized trial in which ECMO improved the survival of infants
who had MAS with an oxygenation index greater than 40 by 50% . Data
from the ELSO registry highlight that approximately 94% of infants who
have MAS placed on ECMO survive, and other results suggest that this is
not associated with an increased risk of neurologic disability.
In uncontrolled studies, hyperventilation to achieve carbon dioxide
tensions of 20 to 25 torr and an elevation of pH resulted in improvements
in oxygenation , but such low CO2levels are associated with a 50% re-
duction in cerebral blood flow, and hypocarbia has been associated with
PVL in preterm infants . Moreover, the technique of hyperventilation
was described for primary pulmonary hypertension of the newborn,
whereby the pathophysiology was increased pulmonary vascular resistance
in the absence of pulmonary parenchymal disease. Applying this technique
to parenchymal lung diseases, especially MAS, may be dangerous. Even in
the early studies, hyperventilation was associated with an increase in air leak
and BPD . Both HFJV and HFOV anecdotally have improved oxygen-
ation in infants who have pulmonary hypertension, but no long-term bene-
fits have been investigated. In contrast, in a randomized trial, ECMO
improved survival in infants who have severe PPHN .
Congenital diaphragmatic hernia
Preoperative stabilization of infants who have CDH reduces mortality
[98,99]. Refractory hypoxemia on conventional ventilation anecdotally re-
sponds to HFJV and HFOV, but there are no proven long-term benefits
of either. Although ECMO is frequently considered for infants who have
CDH, in a randomized trial no benefit in survival was associated with
ECMO use . Inhaled nitric oxide does not reduce the need for ECMO
in infants who have CDH .
to minimize further trauma to the lungs. Conventional ventilator techniques
have been studied in infants developing BPD. Rates over 60 bpm have not
been demonstrated to offer advantages over lower rates , but increasing
the PEEP to 6 cmH2O can improve oxygenation without adversely affecting
carbon dioxide elimination . Patient-triggered ventilation and HFOV
have been used with short-term success in infants who have BPD, but the
evidence is anecdotal. Some studies have examined the efficacy of iNO in
infants who have BPD. In infants who have early BPD, a level of 20 ppm
was associated with improvements in oxygenation without inducing changes
in inflammatory markers or oxidative injury . In a nonrandomized study
of BPD infants , a positive rather than no response was associated with
a better long-term outcome; those who responded were ultimately weaned
from the ventilator, whereas the five nonresponders died or failed to be
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