Escolar Documentos
Profissional Documentos
Cultura Documentos
E-Mail karger@karger.com
Belfast BT12 6BB (UK)
www.karger.com/neo
E-Mail david.sweet@belfasttrust.hscni.net
sure and titration of oxygen, should be implemented from grams are rarely seen today due to early surfactant ther-
soon after birth. Surfactant replacement therapy is a crucial apy and early continuous positive airway pressure
part of the management of RDS, and newer protocols for sur- (CPAP). Definitions based on blood gas analysis and in-
factant administration are aimed at avoiding exposure to spired oxygen concentrations are also increasingly re-
mechanical ventilation, and there is more evidence of differ- dundant as clinicians have moved towards a more prag-
ences among various surfactants in clinical use. Newer meth- matic approach of giving surfactant therapy based on
ods of maintaining babies on non-invasive respiratory sup- clinical assessment of work of breathing and inspired ox-
port have been developed and offer potential for greater ygen requirement very early in the clinical course of the
comfort and less chronic lung disease. As technology for de- disease. Knowing how many babies have genuine RDS is
livering mechanical ventilation improves, the risk of causing therefore difficult. Of the 4,142 babies from Europe for
lung injury should decrease although minimizing the time whom data were submitted to the Vermont Oxford Net-
spent on mechanical ventilation using caffeine and if neces- work during 2015, RDS was coded for about 80% of ba-
sary postnatal steroids are also important considerations. bies born at 28 weeks gestation, increasing to 95% at 24
Protocols for optimizing the general care of infants with RDS weeks gestation [5]. However, recent large clinical trials
are also essential with good temperature control, careful flu- show that when given early CPAP, babies of 2629 weeks
id and nutritional management, maintenance of perfusion gestation can be managed without intubation or surfac-
and judicious use of antibiotics all being important determi- tant about 50% of the time, and the high reported inci-
nants of best outcome. 2016 S. Karger AG, Basel dence may reflect practice where babies are being coded
as having RDS because they were treated with prophylac-
tic or early surfactant.
The aim of the management of RDS is to provide in-
Introduction terventions that maximize survival whilst minimizing po-
tential adverse effects, including the risk of BPD. Many
Respiratory distress syndrome (RDS) remains a sig- strategies and therapies for prevention and treatment of
nificant problem for preterm babies although its manage- RDS are still being tested in clinical trials, and many new
ment has evolved gradually over the years, resulting in studies are incorporated into updated systematic reviews.
improved survival for the smallest infants but with pos- These guidelines update the previous three guidelines af-
sible increasing rates of bronchopulmonary dysplasia ter critical examination of the most up-to-date evidence
(BPD) at least in part due to the reduced use of postnatal available in early 2016. We have employed a similar for-
steroids [1]. Since 2006, a group of neonatologists from mat of summarizing the relevant issues requiring consid-
various European countries have met on a 3-yearly basis eration followed by evidence-based recommendations
to review the most up-to-date literature and to agree on supported by a score using the GRADE system to reflect
consensus recommendations for the optimal manage- the authors views on the strength of evidence supporting
ment of preterm babies with, or at risk of, RDS in order each of the recommendations [6]. Quality of evidence
to try and achieve the best outcomes for neonates in Eu- and strength of recommendations are summarized in ta-
rope. The European Consensus Guidelines for the Man- ble1.
agement of RDS were first published in 2007, have been
updated in 2010 and 2013 and are endorsed by the Euro-
pean Association of Perinatal Medicine [24]. The guide- Prenatal Care
lines have been translated into several languages, includ-
ing Chinese, and although primarily intended for use in There are no generally effective means to improve the
Europe, they contain recommendations that can poten- outcome of infants by preventing the common causes of
tially be used anywhere, provided clinicians have access either spontaneous or elective preterm births. However,
to resources needed to fulfil the standards present in in pregnant women at risk of spontaneous preterm birth,
modern neonatal intensive care units (NICU). due either to previous preterm birth or where a short cer-
Although primarily a disorder of surfactant deficiency vix has been identified on ultrasound examination, use of
resulting in pulmonary insufficiency from soon after progesterone has been associated with clinical benefits to
birth, the classical pattern of RDS has changed as treat- the infant including reduced preterm delivery rates and
ments have evolved over the years. Classical RDS radio- reduced perinatal mortality [7]. However, the findings
graphic appearances of ground glass with air broncho- may not be generally applicable to all modes of adminis-
158.232.240.113 - 9/26/2016 8:31:19 PM
DOI: 10.1159/000448985
HINARI Guatemala
Downloaded by:
Table 1. Representations of quality of evidence and strength of (RCTs) in which corticosteroids were given in both arms
recommendations of the trial [16]. Given their limited value, only drugs that
are safe for the mother should be considered, i.e. oxytocin
Quality of evidence
High quality A antagonists or Ca channel blockers [17]. Both drugs have
Moderate quality B similar efficacy and perinatal outcome; the former has the
Low quality C fewest maternal side effects.
Very low quality D Prenatal corticosteroids given to mothers with antici-
Strength of recommendation pated preterm delivery improve survival, reduce the risk
Strong recommendation for using intervention 1
Weak recommendation for using intervention 2 of RDS, NEC and intraventricular haemorrhage, and a
single course does not appear to be associated with any
significant maternal or short-term fetal adverse effects.
The beneficial effects of antenatal steroids were similar in
studies conducted in the 1970s as in those conducted
tration [8], and there are no data to suggest a longer-term more recently implying that they remain beneficial in the
benefit (or harm) on infant and childhood outcomes [9]. presence of modern neonatal care [18]. Prenatal cortico-
Cervical cerclage may also reduce preterm birth in at-risk steroid therapy is recommended in all pregnancies with
pregnancies, but it is not clear whether it improves peri- threatened preterm labour before 34 weeks gestation
natal outcome [10]. Adequate spacing between pregnan- where active care of the newborn is anticipated. Although
cies may reduce the risk of recurrent preterm delivery; a there are limited RCT data in babies <26 weeks gestation
Caesarean delivery is likely to increase the risk of sponta- or very immature twins, observational studies support
neous preterm delivery in a subsequent pregnancy. the concept that antenatal corticosteroids also reduce
Interventions to prevent RDS and improve outcome mortality in these infants [19, 20]. In pregnancies be-
can also begin before birth even if delivery cannot be pre- tween 34 and 36 weeks gestation, prenatal steroids will
vented. There is often warning of impending preterm de- also reduce the risk of short-term respiratory morbidity
livery, and interventions can be considered that might but not mortality, and there is a paucity of data on longer-
prolong gestation or reduce the risk of an adverse out- term follow-up [21]. When given before elective Caesar-
come by preparing the fetus, or enabling transfer to a ean section (CS) at 3739 weeks, they reduce the risk of
centre with more experience of dealing with problems of admission to the NICU, although the number needed to
prematurity. Cervical length measurement, in combina- treat is >20 [22]. Follow-up data on term babies exposed
tion with fetal fibronectin testing, can help to determine to antenatal steroids are limited.
which women are at low risk of delivery within 7 days, The optimal treatment to delivery interval is more
and perhaps allow a more judicious use of antenatal treat- than 24 h and less than 7 days after the start of steroid
ments [11]. Extremely preterm babies at risk of RDS treatment; beyond 14 days the benefits are diminished.
should be born in centres where appropriate skills are There is a continuing debate as to whether steroids should
available, as long-term health outcomes are better if they be repeated 1 or 2 weeks after the first course for women
receive their initial neonatal care in tertiary units [12]. In with threatened preterm labour. Such repeat courses do
cases of prenatal prelabour rupture of membranes, anti- not reduce the risk of neonatal death, but reduce RDS and
biotics can delay preterm delivery and reduce neonatal other short-term health problems, although birth weight
morbidity including the need for surfactant, although co- is reduced and long-term beneficial effects are lacking
amoxiclav should be avoided because of an association [23]. The WHO recommends that a single repeat course
with an increased risk of necrotizing enterocolitis (NEC) of steroids may be considered if preterm birth does not
[13]. Magnesium sulphate given to women with immi- occur within 7 days after the initial course and subsequent
nent preterm delivery marginally reduces the incidence assessment demonstrates that there is a high risk of pre-
of cerebral palsy [14], although a more recent longer- term birth in the next 7 days [24]. It is unlikely that repeat
term follow-up of an Australian cohort showed no differ- courses given after 32 weeks gestation improve outcome,
ences by school age [15]. Tocolytic drugs can be used in and recent long-term follow-up studies show no benefit
the short term to delay birth and allow safe transfer to a by school age in terms of reduction in death or disability
perinatal centre or to enable prenatal corticosteroids time if repeat courses are used [25].
to take effect. However, no beneficial effects of tocolytic A recent RCT from low- to medium-income countries
drugs have been shown in randomized controlled trials showed a higher neonatal mortality and maternal infec-
158.232.240.113 - 9/26/2016 8:31:19 PM
DOI: 10.1159/000448985
HINARI Guatemala
Downloaded by:
oxidative stress [37]. Protocols to achieve normal transi- 4 Intubation should be reserved for babies who have not re-
tional saturations measured by pulse oximetry at the right sponded to positive pressure ventilation via face mask (A1).
Babies who require intubation for stabilization should be giv-
wrist usually result in extremely low-birth-weight infants en surfactant (B1).
requiring around 3040% oxygen by about 10 min of age 5 Plastic bags or occlusive wrapping under radiant warmers
[38, 39]. Starting low and working up is better than start- should be used during stabilization in the delivery suite for
ing high and working down in terms of reducing oxida- babies <28 weeks gestation to reduce the risk of hypothermia
tive stress, although starting with 21% may be too low for (A1).
the most immature babies who may need at least 30%
oxygen, and further studies are under way to resolve this
issue [40]. Measuring heart rate by auscultation or cord Surfactant Therapy
palpation may not be accurate, and although ECG in the
delivery room offers a more rapid practical alternative to Surfactant therapy plays an important role in the man-
pulse oximetry for measuring heart rate, it is not widely agement of babies with RDS. By 2013 it was accepted that
available and may not offer any meaningful advantage in surfactant prophylaxis, in the current era of prenatal ste-
terms of improving outcome. The need to provide effec- roid use, was no longer indicated for babies receiving sta-
tive measurable CPAP from birth makes the T piece de- bilization using non-invasive respiratory support, and a
vice a better choice than a self-inflating anaesthetic bag strategy of initiation of CPAP from birth with early selec-
[41]. Routine suctioning is not needed before CPAP is tive surfactant administration for babies showing signs of
applied [42]. CPAP during stabilization can be delivered RDS was recommended, with the caveat that if the baby
either by face mask or a short nasal prong [43]. For spon- needed intubation for stabilization, surfactant should be
taneously breathing preterm babies, provision of CPAP given [4, 46]. The overall aim was to avoid mechanical
alone is optimal, and routine use of positive pressure ventilation (MV) where possible, or to reduce its dura-
breaths should be discouraged because of the risk of lung tion, whilst administering surfactant as early as possible
injury [44]. Gentle positive pressure ventilation should be in the course of RDS if it was deemed necessary. To this
provided for babies who remain apnoeic or bradycardic, end the INSURE (intubate-surfactant-extubate to CPAP)
and there is no apparent advantage of a sustained infla- technique was recommended with suggested protocols
tion over intermittent positive pressure breaths [45]. The for surfactant administration when babies showed signs
Sustained Aeration of Infants Lungs trial has been of RDS and needed more than 30% inspired oxygen to
launched and will hopefully more fully resolve this issue. maintain saturations in the normal range. Since the 2013
Only a minority of babies should require intubation for guideline update there have been further studies aimed at
stabilization. If intubation is required, the correct place- optimizing surfactant use, by avoiding potential exposure
ment of the endotracheal tube can be quickly verified to lung injury using less invasive methods of administra-
clinically by auscultation and using a colorimetric CO2 tion, and avoiding positive pressure ventilation through
detection device before administering surfactant which an endotracheal tube.
can be done prior to radiographic confirmation of RDS
in most circumstances. Surfactant Administration Methods
Surfactant administration is a skill that requires an ex-
Recommendations perienced clinical team comfortable with neonatal intu-
1 If possible delay clamping the umbilical cord for at least 60 s bation and MV if needed. Until recently the vast majority
to promote placentofetal transfusion (B1). Cord milking is a of clinical trials of surfactant used bolus administration
reasonable alternative if delayed cord clamping is not possi- via an endotracheal tube with a short period of manual
ble (B2). ventilation or MV to distribute the drug followed either
2 Oxygen for resuscitation should be controlled using a blend-
er. An initial concentration of 30% oxygen is appropriate for by continued MV or immediate (or early) extubation to
babies <28 weeks gestation, and 2130% for those of 2831 CPAP when spontaneous breathing had resumed if the
weeks, and adjustments up or down should be guided by INSURE method was used. INSURE was recommended
pulse oximetry from birth (B2). in the 2013 guideline on the basis that it reduced lung in-
3 In spontaneously breathing babies, stabilize with CPAP of at jury [47]; however, in the original studies sedation for in-
least 6 cm H2O via mask or nasal prongs (A1). Gentle posi-
tive pressure lung inflations using about 2025 cm H2O peak tubation was considered optional, and this was an area for
inspiratory pressure should be used for persistently apnoeic debate. Since then there have been studies to determine if
or bradycardic infants (B1). surfactant administration without endotracheal intuba-
158.232.240.113 - 9/26/2016 8:31:19 PM
tion results in improved outcomes, on the basis that tants are better than older synthetic (protein-free) prepa-
avoidance of any positive pressure ventilation may be rations, containing only phospholipids, at reducing pul-
beneficial. Two similar methods of administering surfac- monary air leaks and mortality [55]. Lucinactant is a syn-
tant via a fine catheter without traditional intubation thetic surfactant that contains sinapultide, a protein
have been studied. The first, developed in Germany and analogue mimicking surfactant protein-B (SP-B) activity.
now used widely in parts of Europe, uses a fine flexible It works better than the protein-free synthetic surfac-
catheter positioned in the trachea whilst the baby is kept tants, but is not yet proven to be better than animal-de-
on CPAP, using laryngoscopy and Magills forceps [48], rived surfactants and is not available in Europe [56]. Syn-
also known as LISA (less invasive surfactant administra- thetic surfactants containing both SP-B and SP-C ana-
tion). The second, developed in Australia, uses a more logues are also currently under evaluation in clinical trials
rigid thin vascular catheter that is stiff enough to be posi- [57]. Comparisons among animal-derived surfactants
tioned in the trachea under direct laryngoscopy without have also shown differences in clinical effect. Overall
forceps whilst the baby is kept on CPAP [49], also known there is a survival advantage when a 200 mg/kg dose of
as MIST (minimally invasive surfactant treatment). With poractant alfa is compared with 100 mg/kg of beractant
both methods the aim is to maintain spontaneous breath- or 100 mg/kg poractant alfa to treat RDS but it is unclear
ing on CPAP whilst surfactant is gradually administered whether this is a dose effect or related to differences in the
over several minutes using a syringe without resorting to surfactant preparations [58].
routine bagging. Both of these methods have been com-
pared to traditional intubation for surfactant administra- When to Treat with Surfactant?
tion followed by MV. Large cohort studies from the Ger- Where possible babies at risk of RDS should be started
man neonatal network with experience of this method on CPAP from birth, and where possible maintained on
were encouraging, reporting reduced use of MV and less CPAP without resorting to intubation. If RDS develops,
BPD [50]. A randomized non-blinded clinical trial of ex- and surfactant is needed, the earlier in the course of the
tremely preterm infants between 23 and 27 weeks gesta- disease surfactant is given, the better the outcome, in
tion showed no significant increase in survival without terms of reducing air leaks [59], or maximizing the chance
BPD in those treated with LISA although these infants of successful avoidance of MV if the INSURE technique
required less ventilation, had fewer pneumothoraces and is used [60]. However, prophylactic INSURE does not
a reduction in severe intraventricular haemorrhage. confer any advantage over initiation of CPAP alone [61].
However, nearly 75% of the intervention group eventu- The previous guideline recommendation was that surfac-
ally needed MV, and the rate of desaturations was sig- tant should be administered when FiO2 >0.30 for very im-
nificantly higher in this group [51]. Although direct com- mature babies and >0.40 for more mature infants, based
parison with INSURE reported improved outcomes in on thresholds used in trials comparing earlier versus later
one study [52], reanalysis of the data could not reproduce surfactant from an era when CPAP was not in widespread
statistical significance when included in a meta-analysis, use. Recent observational studies have confirmed that
and therefore to date this is still uncertain [53]. Nebuliza- FiO2 >0.30 by 2 h of age on CPAP is predictive of CPAP
tion to deliver surfactant has not yet reached a stage where failure by 6 h of age, and that those who fail CPAP have a
it can be recommended for routine clinical use [54]. poorer outcome [62]. This strengthens the argument for
interventions that reduce CPAP failure, such as early sur-
Surfactant Preparations factant given by minimally invasive methods, to avoid
Surfactants currently available in Europe are shown in lung injury. Methods to measure the presence or absence
table2. Animal-derived (formerly called natural) surfac- of endogenous surfactant, such as lamellar body count in
158.232.240.113 - 9/26/2016 8:31:19 PM
DOI: 10.1159/000448985
HINARI Guatemala
Downloaded by:
gastric aspirate, may help in deciding whom to treat [63]. in a prospective meta-analysis to give greater power to
However, methods that require laboratory expertise detect relatively small but important differences in out-
around the clock are unlikely to be widely adopted and a comes such as mortality [67]. Each trial was designed to
simple bedside test that can be used within the NICU is assess effects of saturation targeting in a lower range (85
needed. 89%) compared to a higher range (9195%) with blinding
There may be a need for further doses of surfactant. provided by oximeters which were offset to read higher
Randomized trials in the era before non-invasive ventila- or lower than the actual saturation within the target range.
tion was used widely showed that multiple doses reduced The SUPPORT trial from the USA, the first to be com-
the risk of air leaks [64] but this may not be true in the era pleted, showed the low saturation target group had a halv-
of early CPAP. Using a larger dose of 200 mg/kg porac- ing of ROP in survivors, but a worrying 4% increase in
tant alfa for the first dose will reduce the need for redosing mortality [68]. An interim meta-analysis combining these
[58]. Multiple INSURE has also been successfully em- data and all accrued at that time from the UK and Aus-
ployed and does not appear to worsen outcomes [65]. tralian BOOST-II trials was undertaken at the request of
Predicting who is likely to fail INSURE using clinical cri- the data safety-monitoring committee. This confirmed
teria and blood gases may help define a population that the excess mortality when targeting lower saturations,
would be reasonable to maintain on MV [66]. and further enrolment was stopped in the UK and Aus-
tralia/New Zealand [69]. In the meantime the Canadian
Recommendations COT trial was published reporting no significant differ-
1 Babies with RDS should be given a natural surfactant prepa-
ration (A1). ences in death or significant neurodisability, nor any sig-
2 A policy of early rescue surfactant should be standard (A1) nificant difference in ROP rates [70]. The outcomes from
but there are occasions when surfactant should be adminis- a combined analysis of the UK and Australia/New Zea-
tered in the delivery suite, such as those who require intuba- land BOOST-II trials have recently been published show-
tion for stabilization (B1). ing increased mortality in the low-saturation target group
3 Babies with RDS should be given rescue surfactant early in
the course of the disease. A suggested protocol would be to [71]. Meta-analysis of all available data in 2014 has fur-
treat babies 26 weeks gestation when FiO2 requirements ther added to uncertainty around ideal saturation targets.
>0.30 and babies >26 weeks when FiO2 requirements >0.40 Combining the data from 5 studies showed no difference
(B2). in death or disability at 24 months, no difference in mor-
4 Poractant alfa in an initial dose of 200 mg/kg is better than tality at 24 months but an increase in mortality before
100 mg/kg of poractant alfa or beractant for rescue therapy
(A1). hospital discharge in the restricted oxygen group [72].
5 INSURE should be considered for infants who are failing on Rates of ROP were similar in the two groups, although
CPAP (A2). there was an excess of NEC in the lower saturation group
6 LISA or MIST may be used as alternatives to INSURE for [72]. In 2016 the most up-to-date NeOProM meta-anal-
spontaneously breathing infants (B2). ysis confirmed that the lower target range (8589%) was
7 A second and sometimes a third dose of surfactant should be
administered if there is evidence of ongoing RDS such as per- associated with a significant increased risk of death but
sistent oxygen requirement and need for MV (A1). there was no difference between the 2 target ranges in
terms of disability at 1824 months [73]. Also, the lower
target range did not reduce BPD or severe visual impair-
ment but it did increase the risk of NEC requiring sur-
Oxygen Supplementation beyond Stabilization gery or causing death [73]. Current best evidence suggests
that it is reasonable to recommend aiming for saturations
For the last decade there has been an enormous effort between 90 and 94% rather than lower, although there is
to determine optimal saturation targets for preterm in- still a high level of uncertainty where ideal saturation tar-
fants, addressing the balance between avoiding negative gets lie.
effects of excess oxygen exposure such as retinopathy of The ability to maintain saturations within the pre-
prematurity (ROP) and potential negative effects of pro- defined target may also be important. There is a tension
longed low-grade hypoxia such as increased mortality, between narrower alarm limits, which increase alarm fre-
NEC or adverse neurodevelopmental outcome. The NeO- quency, nurse fatigue and potential wider fluctuations in
ProM collaboration was established to enable the results saturation and wider limits which may expose infants to
of 5 large-scale randomized clinical trials with similar potentially longer periods of time outside the desired
study design from different parts of the world to be used range [74]. Even in the best units many babies spend
158.232.240.113 - 9/26/2016 8:31:19 PM
DOI: 10.1159/000448985
HINARI Guatemala
Downloaded by:
carbon dioxide washout of the nasopharyngeal space; ance after lung fluid clearance or surfactant administra-
however, with higher flow rates there is also an element tion. Excessively high tidal volumes injure the lung and
of unquantified additional CPAP. Flow rates of 4.08.0 lead to hypocarbia which can subsequently cause brain
l/min are typically used, with weaning of flow rate deter- injury such as periventricular leukomalacia or intraven-
mined clinically by FiO2 levels remaining low and judge- tricular haemorrhage [94, 95]. In contrast, inadequately
ment of work of breathing. HF is also being studied as a low tidal volumes, which can occur after a decrease in
primary mode of respiratory support in the delivery room lung compliance, cause uneven distribution of tidal vol-
[91], and the results of large trials comparing HF with umes, increase work of breathing, agitation of the infant
CPAP are awaited [92]. and hypercarbia. VTV enables clinicians to ventilate with
less variable tidal volumes and real-time weaning of pres-
Recommendations sure as lung compliance improves. There are different
1 CPAP should be started from birth in all babies at risk of
RDS, such as those <30 weeks gestation who do not need ways of VTV regulation, such as inspiratory pressure,
intubation for stabilization (A1). flow or time adjustment, but better tidal volume stability
2 The system delivering CPAP is of little importance; however, is a final result of all these ventilator-driven algorithms.
the interface should be short binasal prongs or a mask, and a VTV compared to PLV may reduce BPD or death and
starting pressure of about 68 cm H2O should be applied intraventricular haemorrhage, and shorten duration of
(A2). CPAP pressure can then be individualized depending
on clinical condition, oxygenation and perfusion (D2). MV [96, 97]. Both an initial set tidal volume of about
3 CPAP with early rescue surfactant should be considered the 5 ml/kg in VTV and an estimated peak inspiratory pres-
optimal management for babies with RDS (A1). sure according to observation of chest movement in PLV
4 Synchronized NIPPV, if delivered through a ventilator rath- may need to be adjusted according to the babys own res-
er than a bilevel CPAP device, can reduce extubation failure, piratory efforts and gas exchange assessment. The re-
but may not confer long-term advantages such as reduction
in BPD (B2). quired tidal volume may need to increase with increasing
5 HF may be used as an alternative to CPAP for some babies postnatal age if the baby remains ventilated [98]. An
during the weaning phase (B2). open lung is achieved by setting adequate PEEP, and this
must be adjusted according to lung biophysical proper-
ties [99]. To determine optimum PEEP on conventional
Mechanical Ventilation Strategies ventilation, each incremental change of PEEP should be
evaluated by responses in FiO2 and CO2 levels. Lung com-
Despite best intentions to manage preterm babies on pliance is very dynamic during the management of RDS,
non-invasive respiratory support to protect their lungs, particularly following surfactant therapy, and for an indi-
about half of extremely preterm babies with RDS will fail vidual baby rapid ventilator responses may be needed.
and need support with MV through an endotracheal tube When high pressures are needed to achieve adequate
[93]. The aim of MV is to provide acceptable blood gas lung inflation, high-frequency oscillatory ventilation
exchange whilst minimizing the risk of lung injury, hypo- (HFOV) may be a reasonable alternative to MV. HFOV
carbia and circulatory disturbance. The principle of MV allows gas exchange with very low tidal volumes delivered
is to recruit atelectatic lung by inflation and optimize lung at very fast rates in lungs held open at optimal inflation
volume for an even distribution of tidal volumes at pres- by a continuous distending pressure. The optimum con-
sures set to prevent atelectasis and overinflation with tinuous distending pressure on HFOV is about 12 cm
minimal oxygen requirement. Overinflation increases the H2O above the closing pressure identified by deteriora-
risk of air leaks such as pneumothorax and pulmonary tion of oxygenation during stepwise reductions in airway
interstitial emphysema. However, ventilation at too low a pressure after full lung recruitment [100]. A recently up-
pressure risks areas of lung becoming repeatedly atelec- dated meta-analysis of RCTs comparing HFOV with con-
tatic during expiration, which can generate inflamma- ventional PLV shows a small inconsistent reduction in
tion. Modern neonatal ventilators offer various modes, BPD in the HFOV group; however, this benefit is coun-
with pressure-limited ventilation (PLV) and volume-tar- teracted by increased air leaks in those on HFOV [101].
geted ventilation (VTV) being the most common. Al- Although most trials reporting neurodevelopmental out-
though pressure-limited modes are relatively simple to come have not identified any differences, a recent long-
manage and allow ventilation even during the presence of term pulmonary follow-up of one RCT demonstrated
a large endotracheal tube leak, tidal volumes may increase better small airway function at 1114 years of age in in-
dangerously during rapid improvement of lung compli- fants originally managed with HFOV [102]. Whatever
158.232.240.113 - 9/26/2016 8:31:19 PM
DOI: 10.1159/000448985
HINARI Guatemala
Downloaded by:
dose hydrocortisone also has the potential to reduce BPD, anticipated there will be need for regular blood gas analy-
but again long-term follow-up data are needed before this ses. Transcutaneous oxygen and CO2 monitoring has also
therapy can be routinely recommended [119]. Inhaled been used to access continuous information for trending
budesonide seems an obvious logical alternative to sys- but can cause skin injury [123]. Methods of monitoring
temic steroids and recently a large RCT confirmed that cerebral oxygenation are also available with potential to
prophylactic inhaled budesonide reduces both persistent guide clinicians about optimal cerebral blood flow but no
ductus arteriosus (PDA) and BPD [120]. There was a clear clinical benefit has yet been identified [124]. Access
trend toward increased mortality with treatment, and to laboratory support is necessary to enable close moni-
long-term developmental follow-up is not yet available. toring of serum electrolytes and haematological values
The addition of budesonide to natural surfactant prepa- ideally using microsampling techniques. Blood pressure
rations may also decrease lung inflammation in ventilat- should be recorded via indwelling arterial lines or inter-
ed preterm babies and reduce the risk of BPD, although mittently using approved oscillometric devices. Around-
this will need further verification by randomized multi- the-clock access to radiology services and portable ultra-
centre trials [121]. sound is also essential as these are often used to confirm
RDS diagnosis, exclude air leaks and confirm correct
Recommendations placement of endotracheal tubes and central lines.
1 After stabilization, MV should be used in babies with RDS
when other methods of respiratory support have failed (A1).
Duration of MV should be minimized (B2). Temperature Control
2 Targeted tidal volume ventilation should be employed as this Maintaining normal body temperature during stabili-
shortens the duration of ventilation and reduces BPD and zation and after admission is important for babies with
intraventricular haemorrhage (A1). RDS. The most recent International Liaison Committee
3 Avoid hypocarbia (A1) as well as severe hypercarbia (C2) as
these are associated with an increased risk of brain injury. on Resuscitation guidelines for resuscitation recom-
When weaning from MV, it is reasonable to tolerate a modest mend maintaining body temperature between 36.5 and
degree of hypercarbia, provided the pH remains above 7.22 37.5 C, and suggest that to do this effectively in preterm
Monitoring and Supportive Care [128]. For the smallest babies humidity of 6080% should
be used initially and reduced as skin integrity improves,
To achieve best outcomes for preterm babies with RDS as maintaining high humidity may promote bacterial or
they should have optimal supportive care, with monitor- fungal growth. WHO guidelines promote the use of kan-
ing physiological variables and appropriate responses. garoo mother care in stable low-birth-weight babies as a
The ability to maintain body temperature from birth is means of maintaining temperature and reducing mortal-
extremely important. Pulse oximetry and possibly ECG ity in lower income settings, and increasingly kangaroo
monitoring from birth provide rapid information of re- mother care is being used to maintain temperature to
sponses to stabilization [122]. In the NICU there should maximize maternal-infant bonding, even in babies on
be access to continuous pulse oximetry, ECG monitoring MV [129, 130].
as well as monitoring PaCO2 levels. Detection of exhaled
CO2 can ensure correct placement of endotracheal tubes, Recommendation
and continuous measurement of end-tidal CO2 also gives 1 Maintain core temperature between 36.5 and 37.5 C at all
DOI: 10.1159/000448985
HINARI Guatemala
Downloaded by:
Table 3. Summary of recommendations
Prenatal care Preterm babies at risk of RDS should be born in centres where appropriate care, including MV, is available
Judicious antenatal assessment should include risk of preterm delivery and need for maternal corticosteroids if
the risk is moderate or high. Tocolytics can be used to allow time for steroids to take effect or for safe transfer
where appropriate
Delivery room Aim to delay cord clamping at birth by at least 1 min, or cut the cord long and milk towards the baby after birth
stabilization Stabilize the baby in a plastic bag under a radiant warmer to prevent heat loss
Gently support breathing using CPAP if possible, and, if inflations are needed, avoid excessive tidal volumes.
ECG and pulse oximetry can help guide heart rate response to stabilization. Start with about 21 30% oxygen and
titrate up or down as needed
Intubation at birth should be considered only for those not responding to the above, although early intubation
and surfactant may be required for babies who demonstrate early signs of severe RDS such as chest retractions
and high oxygen requirements
Respiratory An animal-derived (natural) surfactant should be used and given as early as possible in the course of RDS. For
support and very immature infants, a treatment threshold of FiO2 0.30 0.40 on CPAP seems reasonable. Repeat doses of
surfactant surfactant may be required if there is ongoing evidence of RDS
Babies can often be extubated to CPAP or NIPPV immediately following surfactant, and judgement needs to be
made if an individual baby will tolerate this. Consider minimally invasive surfactant (LISA or MIST) as an
alternative to INSURE if your unit has appropriate expertise
For those who require MV, aim to ventilate for as short a time as possible, avoiding hyperoxia, hypocarbia and
volutrauma. This may be best achieved with VTV and saturation alarm limits set at 89 and 95%
Caffeine therapy should be used routinely to minimize the need for ventilation. Babies should be maintained on
non-invasive respiratory support in preference to MV if possible. Beyond 1 2 weeks, steroids should be
considered to facilitate extubation if the baby remains ventilated
In preterm babies receiving oxygen, the saturation target should be between 90 and 94%. To achieve this,
suggested alarm limits should be 89 and 95%
Supportive Maintain body temperature at 36.5 37.5 C at all times
care Start parenteral nutrition immediately with amino acids and lipids with initial fluid volumes about 70 80 ml/kg/
day for most babies and restrict sodium during the early transitional period
Enteral feeding with mothers milk should also be started on day 1 if the baby is stable
Antibiotics should be used judiciously and stopped early when sepsis is ruled out
Blood pressure should be monitored regularly, aiming to maintain normal tissue perfusion, if necessary using
inotropes. Hb should be maintained at acceptable levels
Protocols should be in place for monitoring pain and discomfort and consideration given for non-
pharmacological methods of minimizing procedural pain and judicious use of opiates for more invasive
procedures
to its ability to increase contractility and decrease after- these slightly more restrictive values [154]. However,
load [150]. Studies assessing different thresholds for in- long-term follow-up has shown some better cognitive
tervention with dopamine to determine if inotrope ther- outcomes in those with more liberal Hb thresholds [155],
apy influences long-term outcome are ongoing [151]. and further trials are ongoing to resolve this issue [156].
Epinephrine and hydrocortisone can be used in refrac- PDA may provide clinical problems for very preterm
tory hypotension when dopamine and dobutamine have babies with RDS in terms of low blood pressure, poor tis-
failed although there is little new evidence on safety or sue perfusion, pulmonary oedema and difficulty weaning
efficacy [152, 153]. from MV. As all infants start life with an open ductus ar-
Maintaining a reasonable haemoglobin (Hb) concen- teriosus, it is difficult to make recommendations for when
tration is also important. Randomized trials comparing to treat it. Surgical ligation of PDA is associated with
targeting more restrictive versus more liberal Hb concen- worse long-term neurodevelopmental outcome, and al-
trations (about 12 g/dl lower) result in less need for though it is not clear whether this is due to the PDA or its
blood transfusion without affecting hospital outcomes, treatment, surgery should only be considered after medi-
and suggested Hb thresholds for transfusion are based on cal therapy has failed [157]. Permissive tolerance of PDA
158.232.240.113 - 9/26/2016 8:31:19 PM
DOI: 10.1159/000448985
HINARI Guatemala
Downloaded by:
Acknowledgements Disclosure Statement
A European panel of experts was convened under the auspices Henry L. Halliday and Christian P. Speer are consultants to
of the European Association of Perinatal Medicine to update evi- Chiesi Farmaceutici, Parma, the manufacturer of a leading animal-
dence-based guidelines on the management of RDS. The guide- derived surfactant preparation used to treat RDS and a caffeine
lines were prepared using evidence-based methods as summarized product for treatment of apnoea of prematurity. Henry L. Halliday
in table1. We are grateful to Roger Soll and Eric Shinwell for their and Christian P. Speer are joint Chief Editors of Neonatology.
helpful comments on the final draft of these guidelines.
References
1 Stoll BJ, Hansen NI, Bell EF, Walsh MC, Car- cebo-controlled trial on the effect of vaginal Research Network: Association of antenatal
lo WA, Shankaran S, et al; Eunice Kennedy micronized progesterone. Ultrasound Obstet corticosteroids with mortality, morbidity,
Shriver National Institute of Child Health and Gynecol 2011;38:272280. and neurodevelopmental outcomes in ex-
Human Development Neonatal Research 10 Alfirevic Z, Stampalija T, Roberts D, Jorgensen tremely preterm multiple gestation infants.
Network: Trends in care practices, morbidity, AL: Cervical stitch (cerclage) for preventing JAMA Pediatr 2016;170:593601.
and mortality of extremely preterm neonates, preterm birth in singleton pregnancy. Coch- 21 Gyamfi-Bannerman C, Thom EA, Blackwell
19932012. JAMA 2015;314:10391051. rane Database Syst Rev 2012;4: CD008991. SC, Tita AT, Reddy UM, Saade GR, et al: An-
2 Sweet D, Bevilacqua G, Carnielli V, Greisen 11 Van Baaren GJ, Vis JY, Wilms FF, Oudijk tenatal betamethasone for women at risk for
G, Plavka R, Saugstad OD, Simeoni U, et al; MA, Kwee A, Porath MM, et al: Predictive late preterm delivery. N Engl J Med 2016;374:
Working Group on Prematurity of the World value of cervical length measurement and fi- 13111320.
Association of Perinatal Medicine, European bronectin testing in threatened preterm labor. 22 Sotiriadis A, Makrydimas G, Papatheodorou
Association of Perinatal Medicine: European Obstet Gynecol 2014;123:11851192. S, Ioannidis JP: Corticosteroids for prevent-
consensus guidelines on the management of 12 Rautava L, Eskelinen J, Hkkinen U, Lehtonen ing neonatal respiratory morbidity after elec-
neonatal respiratory distress syndrome. J L; PERFECT Preterm Infant Study Group: tive caesarean section at term. Cochrane Da-
Perinat Med 2007;35:175186. 5-year morbidity among very preterm infants tabase Syst Rev 2009;4:CD006614.
3 Sweet DG, Carnielli V, Greisen G, Hallman in relation to level of hospital care. JAMA Pe- 23 Crowther CA, McKinlay CJD, Middleton P,
M, Ozek E, Plavka R, Saugstad OD, et al; Eu- diatr 2013;167:4046. Harding JE: Repeat doses of prenatal corti-
ropean Association of Perinatal Medicine: 13 Kenyon S, Boulvain M, Neilson JP: Antibiot- costeroids for women at risk of preterm
European consensus guidelines on the man- ics for preterm rupture of membranes. Coch- birth for improving neonatal health out-
agement of neonatal respiratory distress syn- rane Database Syst Rev 2013;12:CD001058. comes. Cochrane Database Syst Rev 2015;
drome in preterm infants 2010 update. Neo- 14 Doyle LW, Crowther CA, Middleton P, Mar- 7:CD003935.
natology 2010;97:402417. ret S, Rouse D: Magnesium sulphate for wom- 24 World Health Organization:WHO Recom-
4 Sweet DG, Carnielli V, Greisen G, Hallman en at risk of preterm birth for neuroprotection mendations on Interventions to Improve Pre-
M, Ozek E, Plavka R, Saugstad OD, et al; Eu- of the fetus. Cochrane Database Syst Rev term Birth Outcomes. Geneva, WHO, 2015.
ropean Association of Perinatal Medicine: 2009;1:CD004661. 25 Asztalos EV, Murphy KE, Willan AR, Mat-
European consensus guidelines on the man- 15 Darlow B, Austin N, French N, Campbell C, thews SG, Ohlsson A, Saigal S, et al: Multiple
agement of neonatal respiratory distress syn- Carse E, Hayes M, et al: School-age outcomes courses of antenatal corticosteroids for pre-
drome in preterm infants 2013 update. Neo- of very preterm infants after antenatal treat- term birth study: outcomes in children at 5
natology 2013;103:353368. ment with magnesium sulfate vs placebo. years of age (MACS-5). JAMA Pediatr 2013;
5 https://nightingale.vtoxford.org/reports.asp. JAMA 2014;312:11051113. 167:11021110.
6 Guyatt GH, Oxman AD, Kunz R, Falck-Ytter 16 Haas DM, Caldwell DM, Kirkpatrick P, Mc- 26 Althabe F, Belizn JM, McClure EM, Heming-
Y, Vist GE, Liberati A, Schnemann, HJ; Intosh JJ, Welton NJ: Tocolytic therapy for way-Foday J, Berrueta M, Mazzoni A, et al: A
GRADE Working Group: Going from evi- preterm delivery: systematic review and net- population-based, multifaceted strategy to
dence to recommendations. BMJ 2008; 336: work meta-analysis. BMJ 2012;345:e6226. implement antenatal corticosteroid treat-
10491051. 17 Tocolysis for women in preterm labour. ment versus standard care for the reduction of
7 Dodd JM, Jones L, Flenady V, Cincotta R, Green-top guideline No 1b, February 2011. neonatal mortality due to preterm birth in
Crowther CA: Prenatal administration of Royal College of Obstetricians and Gynaeco- low-income and middle-income countries:
progesterone for preventing preterm birth in logists. https://www.rcog.org.uk/globalas- the ACT cluster-randomised trial. Lancet
women considered to be at risk of preterm sets/documents/guidelines/gtg_1b.pdf. 2015;385:629639.
birth. Cochrane Database Syst Rev 2013; 18 Roberts D, Dalziel S: Antenatal corticoste- 27 American College of Obstetricians and Gyne-
7:CD004947. roids for accelerating fetal lung maturation cologists: ACOG committee opinion No 559:
8 Norman JE, Marlow N, Messow CM, Shen- for women at risk of preterm birth. Cochrane Cesarean delivery on maternal request. Ob-
nan A, Bennett PR, Thornton S, et al; Database Syst Rev 2006;3:CD004454. stet Gynecol 2013;121:904907.
OPPTIMUM study group: Vaginal progester- 19 Manktelow BN, Lal MK, Field DJ, Sinha SK: 28 Wyllie J, Bruinenberg J, Roehr CC, Rdiger
one prophylaxis for preterm birth (the Antenatal corticosteroids and neonatal out- M, Trevisanuto D, Urlesberger B: European
OPPTIMUM study): multicentre, random- comes according to gestational age: a cohort Resuscitation Council guidelines for resusci-
ised, double-blind trial. Lancet 2016; 387: study. Arch Dis Child Fetal Neonatal Ed 2010; tation 2015. Section 7: resuscitation and sup-
21062116. 95:F95F98. port of transition of babies at birth. Resuscita-
9 Rode L, Klein K, Nicolaides KH, Krampl-Bet- 20 Boghossian NS, McDonald SA, Bell EF, Carlo tion 2015;95:249263.
telheim E, Tabor A; PREDICT Group: Pre- WA, Brumbaugh JE, Stoll BJ, et al; Eunice 29 Saugstad OD: Delivery room management of
vention of preterm delivery in twin gestations Kennedy Shriver National Institute of Child term and preterm newly born infants. Neona-
(PREDICT): a multicenter, randomized, pla- Health and Human Development Neonatal tology 2015;107:365371.
158.232.240.113 - 9/26/2016 8:31:19 PM
DOI: 10.1159/000448985
HINARI Guatemala
Downloaded by:
69 BOOST II United Kingdom Collaborative respiratory distress syndrome: continuous 94 Erickson SJ, Grauaug A, Gurrin L, Swamina-
Group; BOOST II Australia Collaborative positive airway pressure and nasal intermit- than M: Hypocarbia in the ventilated pre-
Group; BOOST II New Zealand Collaborative tent positive pressure ventilation. Semin Fetal term infant and its effect on intraventricular
Group; Stenson BJ, Tarnow-Mordi WO, Dar- Neonatal Med 2009;14:1420. haemorrhage and bronchopulmonary dys-
low BA, Simes J, Juszczak E, Askie L, et al: Ox- 82 De Paoli AG, Davis PG, Faber B, Morley CJ: plasia. J Paediatr Child Health 2002;38:560
ygen saturation and outcomes in preterm in- Devices and pressure sources for administra- 562.
fants. N Engl J Med 2013;368:20942104. tion of nasal continuous positive airway pres- 95 Ambalavanan N, Carlo WA, Wrage LA, Das
70 Schmidt B, Whyte RK, Asztalos EV, Mod- sure (NCPAP) in preterm neonates. Co- A, Laughon M, Cotten CM, et al; SUPPORT
demann D, Poets C, Rabi Y, et al; Canadian chrane Database Syst Rev 2002;3:CD002977. Study Group of the NICHD Neonatal Re-
Oxygen Trial (COT) Group: Effects of target- 83 Kieran EA, Twomey AR, Molloy EJ, Murphy search Network: PaCO2 in surfactant, posi-
ing higher vs lower arterial oxygen satura- JF, ODonnell CP: Randomized trial of prongs tive pressure, and oxygenation randomised
tions on death or disability in extremely pre- or mask for nasal continuous positive airway trial (SUPPORT). Arch Dis Child Fetal Neo-
term infants: a randomized clinical trial. pressure in preterm infants. Pediatrics 2012; natal Ed 2015;100:F145F149.
JAMA 2013;309:21112120. 130:e1170e1176. 96 Peng W, Zhu H, Shi H, Liu E: Volume-tar-
71 BOOST-II Australia and United Kingdom 84 Lampland AL, Plumm B, Worwa C, Meyers P, geted ventilation is more suitable than pres-
Collaborative Groups; Tarnow-Mordi W, Mammel MC: Bi-level CPAP does not im- sure-limited ventilation for preterm infants:
Stenson B, Kirby A, Juszczak E, Donoghoe M, prove gas exchange when compared with a systematic review and meta-analysis. Arch
Deshpande S, et al: Outcomes of two trials of conventional CPAP for the treatment of neo- Dis Child Fetal Neonatal Ed 2014; 99:F158
oxygen-saturation targets in preterm infants. nates recovering from respiratory distress F165.
N Engl J Med 2016;374:749760. syndrome. Arch Dis Child Fetal Neonatal Ed 97 Wheeler K, Klingenberg C, McCallion N,
72 Saugstad OD, Aune D: Optimal oxygenation 2015;100:F31F34. Morley CJ, Davis PG: Volume-targeted ver-
of extremely low birth weight infants: a meta- 85 Lemyre B, Davis PG, de Paoli AG, Kirpalani sus pressure-limited ventilation in the neo-
analysis and systematic review of the oxygen H: Nasal intermittent positive pressure venti- nate. Cochrane Database Syst Rev 2010;
saturation target studies. Neonatology 2014; lation (NIPPV) versus nasal continuous posi- 11:CD003666.
105: 5563. tive airway pressure (NCPAP) for preterm 98 Keszler M, Nassabeh-Montazami S, Abuba-
73 Stenson BJ: Oxygen saturation targets for ex- neonates after extubation. Cochrane Data- kar K: Evolution of tidal volume require-
tremely preterm infants after the NeOProM base Syst Rev 2014;9:CD003212. ment during the first 3 weeks of life in infants
trials. Neonatology 2016;109:352358. 86 Dumpa V, Katz K, Northrup V, Bhandari V: <800 g ventilated with volume guarantee.
74 Sola A, Golombek SG, Montes Bueno MT, SNIPPV versus NIPPV: does synchronization Arch Dis Child Fetal Neonatal Ed 2009;
Lemus-Varela L, Zuluaga C, Domnguez F, et matter? J Perinatol 2012;32:438442. 94:F279F282.
al: Safe oxygen saturation targeting and mon- 87 Bancalari E, Claure N: The evidence for non- 99 Rimensberger PC, Cox PN, Frndova H, Bry-
itoring in preterm infants: can we avoid hy- invasive ventilation in the preterm infant. an AC: The open lung during small tidal vol-
poxia and hyperoxia? Acta Paediatr 2014;103: Arch Dis Child Fetal Neonatal Ed 2013; ume ventilation: concepts of recruitment
10091018. 98:F98F102. and optimal positive end-expiratory pres-
75 Van Zanten HA, Tan RN, van den Hoogen A, 88 Kirpalani H, Millar D, Lemyre B, Yoder BA, sure. Crit Care Med 1999;27:19461952.
Lopriore E, te Pas AB: Compliance in oxygen Chiu A, Roberts RS; NIPPV Study Group: A 100 De Jaegere A, van Veenendaal MB, Michiels
saturation targeting in preterm infants: a sys- trial comparing noninvasive ventilation strat- A, van Kaam AH: Lung recruitment using
tematic review. Eur J Pediatr 2015;174:1561 egies in preterm infants. N Engl J Med 2013; oxygenation during open lung high-fre-
1572. 369:611620. quency ventilation in preterm infants. Am J
76 Lim K, Wheeler KI, Gale TJ, Jackson HD, 89 Millar D, Lemyre B, Kirpalani H, Chiu A, Yo- Respir Crit Care Med 2006;174:639645.
Kihlstrand JF, Sand C, et al: Oxygen satura- der BA, Roberts RS: A comparison of bilevel 101 Cools F, Offringa M, Askie LM: Elective high
tion targeting in preterm infants receiving and ventilator-delivered non-invasive respi- frequency oscillatory ventilation versus con-
continuous positive airway pressure. J Pediatr ratory support. Arch Dis Child Fetal Neonatal ventional ventilation for acute pulmonary
2014;164:730736. Ed 2016;101:2125. dysfunction in preterm infants. Cochrane
77 Poets CF, Roberts RS, Schmidt B, Whyte RK, 90 Wilkinson D, Andersen C, ODonnell CP, de Database Syst Rev 2015;3:CD000104.
Asztalos EV, Bader D, et al: Association be- Paoli AG, Manley BJ: High flow nasal cannula 102 Zivanovic S, Peacock J, Alcazar-Paris M, Lo
tween intermittent hypoxemia or bradycardia for respiratory support in preterm infants. JW, Lunt A, Marlow N, Calvert S, Gree-
and late death or disability in extremely pre- Cochrane Database Syst Rev 2016;2:CD006405. nough A; United Kingdom Oscillation
term infants. JAMA 2015;314:595603. 91 Reynolds P, Leontiadi S, Lawson T, Otunla T, Study Group: Late outcomes of a random-
78 Van Kaam AH, Hummler HD, Wilinska M, Ejiwumi O, Holland N: Stabilisation of pre- ized trial of high-frequency oscillation in
Swietlinski J, Lal MK, te Pas AB, et al: Auto- mature infants in the delivery room with nasal neonates. N Engl J Med 2014; 370: 1121
mated versus manual oxygen control with dif- high flow. Arch Dis Child Fetal Neonatal Ed 1130.
ferent saturation targets and modes of respi- 2016;101:F284F287. 103 Manley BJ, Doyle LW, Owen LS, Davis PG:
ratory support in preterm infants. J Pediatr 92 Roberts CT, Owen LS, Manley BJ, Donath Extubating extremely preterm infants: pre-
2015;167:545550. SM, Davis PG: A multicentre, randomised dictors of success and outcomes following
79 Davis PG, Henderson-Smart DJ: Nasal con- controlled, non-inferiority trial, comparing failure. J Pediatr 2016;173:4549.
tinuous positive airway pressure immediately high flow therapy with nasal continuous pos- 104 Danan C, Durrmeyer X, Brochard L, Dec-
after extubation for preventing morbidity in itive airway pressure as primary support for obert F, Benani M, Dassieu G: A random-
preterm infants. Cochrane Database Syst Rev preterm infants with respiratory distress (the ized trial of delayed extubation for the re-
2003;2:CD000143. HIPSTER trial): study protocol. BMJ Open duction of reintubation in extremely pre-
80 Rojas-Reyes MX, Morley CJ, Soll R: Prophy- 2015;5:e008483. term infants. Pediatr Pulmonol 2008; 43:
lactic versus selective use of surfactant in pre- 93 SUPPORT Study Group of the Eunice Kennedy 117124.
venting morbidity and mortality in preterm Shriver NICHD Neonatal Research Network; 105 Buzzella B, Claure N, DUgard C, Bancalari
infants. Cochrane Database Syst Rev 2012; Finer NN, Carlo WA, Walsh MC, Rich W, E: A randomized controlled trial of two nasal
3:CD000510. Gantz MG, Laptook AR, Yoder BA, et al: Early continuous positive airway pressure levels
81 Davis PG, Morley CJ, Owen LS: Non-invasive CPAP versus surfactant in extremely preterm after extubation in preterm infants. J Pediatr
respiratory support of preterm neonates with infants. N Engl J Med 2010;362:19701979. 2014;164:4651.
158.232.240.113 - 9/26/2016 8:31:19 PM
DOI: 10.1159/000448985
HINARI Guatemala
Downloaded by:
147 Batton B, Li L, Newman NS, Das A, Watter- 156 https://www.nichd.nih.gov/about/Docu- 167 Stevens B, Yamada J, Lee GY, Ohlsson A: Su-
berg KL, Yoder BA, et al; Eunice Kennedy ments/TOP_Protocol.pdf. crose for analgesia in newborn infants un-
Shriver National Institute of Child Health 157 Weisz DE, More K, McNamara PJ, Shah PS: dergoing painful procedures. Cochrane Da-
and Human Development Neonatal Re- PDA ligation and health outcomes: a meta- tabase Syst Rev 2013;1:CD001069.
search Network: Use of antihypotensive analysis. Pediatrics 2014;133:e1024e1046. 168 Tan K, Lai NM, Sharma A: Surfactant for
therapies in extremely preterm infants. Pe- 158 Heuchan AM, Clyman RI: Managing the bacterial pneumonia in late preterm and
diatrics 2013;131:e1865e1873. patent ductus arteriosus: current treatment term infants. Cochrane Database Syst Rev
148 Roehr CC, te Pas AB, Dold SK, Breindahl M, options. Arch Dis Child Fetal Neonatal Ed 2012;2:CD008155.
Blennow M, Rdiger M, Gupta S: Investigat- 2014;99:F431F436. 169 Vento G, Tana M, Tirone C, Aurilia C, Lio
ing the European perspective of neonatal 159 Ohlsson A, Walia R, Shah SS: Ibuprofen for A, Perelli S, Ricci C, Romagnoli C: Effective-
point-of-care echocardiography in the neo- the treatment of patent ductus arteriosus in ness of treatment with surfactant in prema-
natal intensive care unit a pilot study. Eur preterm or low birth weight (or both) in- ture infants with respiratory failure and pul-
J Pediatr 2013;172:907911. fants. Cochrane Database Syst Rev 2015; monary infection. Acta Biomed 2012; 83
149 Subhedar NV, Shaw NJ: Dopamine versus 2:CD003481. (suppl 1):3336.
dobutamine for hypotensive preterm in- 160 Ohlsson A, Shah PS: Paracetamol (acet- 170 Aziz A, Ohlsson A: Surfactant for pulmo-
fants. Cochrane Database Syst Rev 2003; aminophen) for patent ductus arteriosus in nary haemorrhage in neonates. Cochrane
3:CD001242. preterm or low-birth-weight infants. Coch- Database Syst Rev 2012;7:CD005254.
150 Ruoss JL, McPherson C, DiNardo J: Inotro- rane Database Syst Rev 2015;3:CD010061. 171 Bozda , Dilli D, Gkmen T, Dilmen U:
pe and vasopressor support in neonates. 161 Kluckow M, Jeffery M, Gill A, Evans N: A Comparison of two natural surfactants for
Neoreviews 2015;16:e351e361. randomised placebo-controlled trial of early pulmonary hemorrhage in very low-birth-
151 Dempsey EM, Barrington KJ, Marlow N, treatment of the patent ductus arteriosus. weight infants: a randomized controlled tri-
ODonnell CP, Miletin J, Naulaers G, et al; Arch Dis Child Fetal Neonatal Ed 2014; al. Am J Perinatol 2015;32:211218.
HIP Consortium: Management of Hypoten- 99:F99F104. 172 Askie LM, Ballard RA, Cutter GR, Dani C,
sion in Preterm infants (The HIP Trial): a 162 https://www.npeu.ox.ac.uk/baby-oscar/ Elbourne D, Field D, Hascoet JM, et al; Me-
randomised controlled trial of hypotension protocol. ta-Analysis of Preterm Patients on Inhaled
management in extremely low gestational 163 Hummel P, Lawlor-Klean P, Weiss MG: Va- Nitric Oxide Collaboration: Inhaled nitric
age newborns. Neonatology 2014; 105: 275 lidity and reliability of the N-PASS assess- oxide in preterm infants: an individual-pa-
281. ment tool with acute pain. J Perinatol 2010; tient data meta-analysis of randomized tri-
152 Paradisis M, Osborn DA: Adrenaline for 30:474478. als. Pediatrics 2011;128:729739.
prevention of morbidity and mortality in 164 Durrmeyer X, Dahan S, Delorme P, Blary S, 173 Breatnach CR, Flanagan F, James A, Corco-
preterm infants with cardiovascular com- Dassieu G, Caeymaex L, Carbajal R: Assess- ran JD, Franklin O, El-Khuffash A: The use
promise. Cochrane Database Syst Rev 2004; ment of atropine-sufentanil-atracurium an- of inhaled nitric oxide in a tertiary neonatal
1:CD003958. aesthesia for endotracheal intubation: an ob- intensive care unit. Ir Med J 2015; 108: 275
153 Ibrahim H, Sinha IP, Subhedar NV: Cortico- servational study in very premature infants. 278.
steroids for treating hypotension in preterm BMC Pediatr 2014;14:120. 174 Ellsworth MA, Harris MN, Carey WA,
infants. Cochrane Database Syst Rev 2011; 165 Dekker J, Lopriore E, Rijken M, Rijntjes-Ja- Spitzer AR, Clark RH: Off-label use of in-
12:CD003662. cobs E, Smits-Wintjens V, te Pas A: Sedation haled nitric oxide after release of NIH con-
154 Whyte R, Kirpalani H: Low versus high hae- during minimally invasive surfactant thera- sensus statement. Pediatrics 2015; 135: 643
moglobin concentration threshold for blood py in preterm infants. Neonatology 2016; 648.
transfusion for preventing morbidity and 109:308313. 175 Shah DM, Kluckow M: Early functional
mortality in very low birth weight infants. 166 Bell R, de Waal K, Zanini R: Opioids for echocardiogram and inhaled nitric oxide:
Cochrane Database Syst Rev 2011; 11: neonates receiving mechanical ventilation: a usefulness in managing neonates born fol-
CD000512. systematic review and meta-analysis. Arch lowing extreme preterm premature rupture
155 Whyte RK, Kirpalani H, Asztalos EV, An- Dis Child Fetal Neonatal Ed 2010; 95:F241 of membranes (PPROM). J Paediatr Child
dersen C, Blajchman M, Heddle N, et al; F251. Health 2011;47:340345.
PINTOS Study Group: Neurodevelopmen- 176 Cheng DR, Peart S, Tan K, Sehgal A: Nitric
tal outcome of extremely low birth weight therapy in preterm infants: rationalised ap-
infants randomly assigned to restrictive or proach based on functional neonatal echo-
liberal hemoglobin thresholds for blood cardiography. Acta Paediatr 2016; 105: 165
transfusion. Pediatrics 2009;123:207213. 171.