Surfactant therapy via brief tracheal catheterization in preterm infants with or at risk of respiratory distress syndrome

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Surfactant therapy via brief tracheal catheterization in

preterm infants with or at risk of respiratory distress

syndrome (Protocol)

Wheeler KI, Abdel-Latif ME, Davis PG, De Paoli AG, Dargaville PA

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The CochraneLibrary 2015, Issue 4

http://www.thecochranelibrary.com

Surfactant therapy via brief tracheal catheterization in preterm infants with or at risk of respiratory distress syndrome (Protocol)

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iSurfactant therapy via brief tracheal catheterization in preterm infants with or at risk of respiratory distress syndrome (Protocol)


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[Intervention Protocol]

Surfactant therapy via brief tracheal catheterization inpreterm infants with or at risk of respiratory distresssyndrome

Kevin I Wheeler1,2,3, Mohamed E Abdel-Latif4, Peter G Davis5, Antonio G De Paoli1, Peter A Dargaville1,6

1Department of Paediatrics, Royal Hobart Hospital, Hobart, Australia. 2Department of Neonatal Medicine, Royal Children’s Hospital

Melbourne, Parkville, Australia. 3Murdoch Childrens Research Institute, Hobart, Australia. 4Department of Neonatology, Australian

National University Medical School, Woden, Australia. 5The University of Melbourne, Melbourne, Australia. 6Menzies Institute for

Medical Research, University of Tasmania, Hobart, Australia

Contact address: Kevin I Wheeler, Department of Paediatrics, Royal Hobart Hospital, Hobart, Australia. [email protected].

Editorial group: Cochrane Neonatal Group.

Publication status and date: New, published in Issue 4, 2015.

Citation: Wheeler KI, Abdel-Latif ME, Davis PG, De Paoli AG, Dargaville PA. Surfactant therapy via brief tracheal catheterization

in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2015, Issue 4. Art. No.:

CD011672. DOI: 10.1002/14651858.CD011672.


A B S T R A C T

This is the protocol for a review and there is no abstract. The objectives are as follows:

In non-intubated preterm infants with, or at risk of, RDS to compare surfactant administration via brief tracheal catheterization with:

1. continuation of non-invasive respiratory support (CPAP) or high flow nasal cannulae (HFNC) without surfactant

administration;

2. intubation and surfactant administration through an ETT with or without intent to remove the ETT immediately after the

procedure;

Additionally:

• to compare different methods of surfactant administration via brief tracheal catheterization with each other.

B A C K G R O U N D

Description of the condition

Respiratory distress syndrome (RDS) and its complications are

major contributors to morbidity and mortality in preterm infants.

Recognition that surfactant deficiency is an important cause of

RDS (Avery 1959) ultimately led to the development of surfac-

tant replacement therapy for RDS (Jobe 1993). Administration of

exogenous surfactant is known to reduce mortality and the risk of

air leak, and has become a mainstay of therapy in preterm infants

with RDS (Suresh 2005; Sweet 2013).

1Surfactant therapy via brief tracheal catheterization in preterm infants with or at risk of respiratory distress syndrome (Protocol)


mailto:[email protected]

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In recent years, techniques of non-invasive respiratory support

have increasingly been used in the management of preterm infants

with respiratory dysfunction (Berger 2013; Soll 2013). Three large

randomised controlled trials have found that applying nasal con-

tinuous positive airway pressure (CPAP) from birth is at least as

effective as intubation and ventilation in infants < 30 weeks ges-

tation (Morley 2008; Dunn 2010; Finer 2010). Applying CPAP

from the outset in an unselected population of preterm infants

does, however, run the risk of under-treating those with significant

RDS, for whom CPAP may fail to provide adequate respiratory

support. The absence of an endotracheal tube means the usual

portal for exogenous surfactant administration is unavailable. The

risks and consequences of CPAP failure under these circumstances

are now being appreciated (Ammari 2005; Dargaville 2013). Such

infants, once intubated, receive surfactant at a later than ideal

time and have an increased risk of adverse outcomes compared

to like-gestation infants managed on CPAP alone (Ammari 2005;

Dargaville 2013).

One approach to resolution of the CPAP-surfactant dilemma has

been to briefly intubate infants on CPAP to administer surfactant,

followed by rapid extubation back to CPAP (Victorin 1990; Verder

1994; Stevens 2007a; Stevens 2007b). This technique has been

found to have benefits over continuation of CPAP, but most often

it requires sedating pre-medication and extubation may thus be

delayed due to respiratory suppression.

Numerous investigators have sought a more practical solution to

the problem of administering surfactant to infants on non-in-

vasive respiratory support. Several techniques of minimally-inva-

sive surfactant therapy have been described and are the subject

of other reviews, including surfactant administration by aerosoli-

sation (Abdel-Latif 2012), pharyngeal deposition (Abdel-Latif

2011a) and through a laryngeal mask (Abdel-Latif 2011b). The

subject of this review is the administration of surfactant by brief

tracheal catheterization (Kribs 2007; Dargaville 2011), which has

not previously been systematically reviewed.

Description of the intervention

Surfactant administration via brief tracheal catheterization encom-

passes any method in which a catheter, expected to be narrower

than a standard endotracheal tube (ETT), is passed through the

vocal cords to allow surfactant instillation. Variation may be en-

countered in i) the premedication used, ii) the means of laryn-

goscopy, iii) the type of catheter, iv) the method of guiding the

catheter through the vocal cords, v) the approach to surfactant de-

livery (bolus versus infusion, rapid versus slow), vi) the surfactant

preparation, viii) the surfactant dose, and viii) the approach to

respiratory management before, during and after the technique,

including the type of non-invasive respiratory support being used.

It is expected that the infant will be spontaneously breathing at

least to some degree throughout such that positive pressure infla-

tions would not be required for surfactant dispersal from the tra-

chea. Unlike an ETT, the catheter itself is unsuitable for delivering

positive pressure inflations.

How the intervention might work

In infants with RDS managed with non-invasive respiratory sup-

port, administering surfactant directly into the trachea using a

minimally-invasive approach has the potential to overcome in-

tra-alveolar surfactant deficiency and replenish the endogenous

surfactant pool. Progressive respiratory deterioration culminat-

ing in CPAP failure may thus be avoided, and along with it

the known associated adverse outcomes. Non-randomised stud-

ies have demonstrated that methods of surfactant administration

by tracheal catheterization are feasible (Kribs 2007; Kribs 2009;

Kribs 2010; Dargaville 2011; Dargaville 2013) and appear to be

safe (Porath 2011; Aguar 2014), and that a reduction in the need

for subsequent ventilation or supplemental oxygen, or both, may

be achievable. These short term clinical benefits have the potential

to lead to improvements in longer term clinical outcomes.

Why it is important to do this review

Surfactant administration via brief tracheal catheterization is a

promising, feasible therapy which is leading to practice change in

many sites around the world. It is therefore important to assess

whether this treatment is safe and clinically effective. This area

of clinical practice has not been subject to a previous systematic

review.

O B J E C T I V E S

In non-intubated preterm infants with, or at risk of, RDS to com-

pare surfactant administration via brief tracheal catheterization

with:

1. continuation of non-invasive respiratory support (CPAP) or

high flow nasal cannulae (HFNC) without surfactant

administration;

2. intubation and surfactant administration through an ETT

with or without intent to remove the ETT immediately after the

procedure;

Additionally:

• to compare different methods of surfactant administration

via brief tracheal catheterization with each other.



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M E T H O D S

Criteria for considering studies for this review

Types of studies

Parallel interventional trials, randomised or quasi-randomised, re-

gardless of the unit of allocation (individual or cluster).

Types of participants

Preterm infants (< 37 weeks) with or without signs of RDS.

Types of interventions

Methods of surfactant administration via brief tracheal catheteri-

zation:

• tracheal catheterization using a flexible tube and Magill’s

forceps (e.g. Kribs 2007);

• tracheal catheterization using a semi-rigid catheter without

Magill’s forceps (e.g. Dargaville 2011);

• variations or modifications of these two methods, including

the use of video-laryngoscopy for catheter placement.

Where appropriate, trials of the different methods will be analysed

as subgroups.

Trials using any surfactant formulation, including animal-derived

and synthetic surfactants (with or without surfactant protein ac-

tivity) will be eligible.

Comparison groups

Trials will be included which compare surfactant administration

by brief tracheal catheterization with the following.

• Continuation of non-invasive respiratory support without

surfactant administration. Trials will be eligible if enrolled

infants in the comparison group are managed using non-invasive

respiratory support and do not routinely receive surfactant:

◦ within this comparison category, trials of CPAP or

HFNC will be analysed as subgroups if appropriate.

• Intubation and surfactant administration through an ETT.

Trials will be eligible if enrolled infants in the comparison group

are intubated and receive surfactant delivered by conventional

means with positive pressure ventilation. This includes trials

with or without the intent to remove the ETT immediately after

surfactant delivery (Haberman 2002):

• ◦ within this comparison category, trials with or without

the intent to remove the ETT immediately will be analysed as

subgroups if appropriate.

• Studies comparing different tracheal catheterization

techniques with each other will be included, for example studies

comparing use of a rigid versus flexible catheter.

Trials within different comparison categories will not be combined

in a meta-analysis.

Types of outcome measures

Primary outcomes

• Incidence of combined outcome of death or

bronchpulmonary dysplasia (BPD) at 36 weeks postmenstrual

age. BPD is defined in the secondary outcomes.

Secondary outcomes

Measures of safety of the surfactant administration procedure

These will be compared with data from intubation episodes in

control infants or, where relevant, between different methods of

tracheal catheterization.

• Incidence and duration of bradycardia (heart rate < 100

bpm) during the dosing procedure.

• Incidence and duration of hypoxaemia (peripheral capillary

oxygen saturation (SpO2) < 80%) during the dosing procedure.

• Incidence of discontinuation of the intervention.

• Incidence of intratracheal surfactant received post-

intervention (and number of doses).

• Incidence of dosing failure (e.g. failure to catheterize the

trachea using the method).

• Incidence of need for facemask intermittent positive

pressure ventilation (IPPV) for apnoea or hypopnoea during the

procedure.

• Incidence of need for immediate intubation (within 15

minutes of surfactant administration).

• Incidence of need for early intubation (within one hour of

surfactant administration).

Outcomes during initial period of respiratory support

• Incidence of need for mechanical ventilation within first 72

hours.

• Incidence of need for mechanical ventilation at any time.

• Duration of mechanical ventilation (days; in survivors).

• Duration of any respiratory support (mechanical

ventilation, CPAP, HFNC) (days; in survivors).

• Duration of oxygen therapy (days; in survivors).

• Incidence of air leak requiring drainage.

• Use of postnatal corticosteroid as a prophylactic or rescue

treatment for chronic lung disease (CLD).

• Use of diuretic therapy as a prophylactic or rescue treatment

for CLD.



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Outcomes during initial period of hospitalisation

• Incidence of neonatal death (all causes) during the first 28

days.

• Incidence of death (all causes) prior to discharge.

• Incidence of BPD (Northway 1967) at 36 weeks, using two

definitions:

◦ clinical definition (BPD(C)): need for oxygen or

respiratory support at 36 weeks (Shennan 1988, modified);

◦ physiological definition (BPD(P)): as above but

supplemented by a room-air challenge for infants with

borderline oxygen requirements (Walsh 2004).

• Duration of hospitalisation (days; in survivors).

• Incidence of any intraventricular haemorrhage (IVH any)

(Papile 1978).

• Incidence of Papile grade 3 or 4 IVH (IVH ≥ 3) (Papile

1978).

• Incidence of cystic periventricular leukomalacia (PVL).

• Incidence of patent ductus arteriosus (PDA) requiring

medical therapy.

• Incidence of PDA requiring surgical therapy.

• Incidence of necrotising enterocolitis (NEC); Modified Bell

stage ≥ 2 (Bell 1978; Walsh 1988).

• Incidence of retinopathy of prematurity (ROP); stage 3 or

greater (ROP3+).

• Incidence of major morbidity (any of IVH ≥ 3, PVL, ROP

≥ 3, BPD) (Schmidt 2003).

• Incidence of death or major morbidity.

• Time to regain birth weight (days, in survivors).

Post-discharge outcomes

• Discharged home with oxygen.

• Number of re-admissions within first year (any cause).

• Number of re-admissions within first year (respiratory).

• Incidence of parent-reported wheeze in first two years.

• Incidence of bronchodilator use in first two years.

• Neurodevelopmental outcome at more than one year

postconceptional age.

Search methods for identification of studies

The standard search strategy of the Cochrane Neonatal Review

Group will be used, as outlined in the Cochrane Library. No lan-

guage restrictions will be applied.

Electronic searches

Two review authors will independently perform electronic

database searches for randomised and quasi-randomised studies

(1990 to current) using the following tools.

• MEDLINE, using MeSH headings: infant, newborn;

pulmonary surfactant.

• EMBASE.

• CINAHL.

• Google Scholar.

• Conference abstracts: Pediatric Academic Societies (PAS)

(American Pediatric Society, Society for Pediatric Research).

• Conference abstracts: European Academy of Pediatic

Societies (EAPS), European Society for Paediatric Research

(ESPR).

• Conference abstracts: the Perinatal Society of Australia and

New Zealand (PSANZ).

Searching other resources

The search strategy will include communication with expert infor-

mants and searches of bibliographies of reviews and trials for refer-

ences to other trials, as well as searches of previous reviews includ-

ing cross-references, abstracts and conferences and symposia pro-

ceedings (as above) from 1990 to current. For unpublished trials,

the contact investigator will be contacted to request information.

Unpublished studies and studies reported only as abstracts will

be considered as eligible for review if final trial data are reported,

not an interim analysis. The corresponding authors of identified

trials will be contacted for additional information when further

data about their studies are required. Clinical trial registries will

be searched for ongoing or recently completed trials (Australia

and New Zealand Clinical Trials Register (ANZCTR); clinicaltri-

als.gov; controlled-trials.com; who.int/ictrp).

Data collection and analysis

Standard methods of The Cochrane Collaboration and the

Cochrane Neonatal Review Group (CNRG: http://neona-

tal.cochrane.org/en/index.html) will be used. Two authors will in-

dependently conduct searches, assess study eligibility and extract

study results and risk of bias. Discrepancies will be resolved by

discussion and consensus.

Selection of studies

Authors will independently review the titles and abstracts of po-

tentially relevant studies against the inclusion and exclusion cri-

teria. Authors will independently assess titles and the abstracts of

studies identified by the search strategy for eligibility for inclusion

in this review. Full-text versions of studies will be obtained for

closer examination of eligibility or when inadequate information

is provided in the abstract.

Data extraction and management

The review authors will independently extract data from the full-

text articles using a specifically designed spreadsheet to manage the

information. Discrepancies will be resolved through discussion or,



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if required, by consulting a review arbiter. Data will be entered into

Review Manager software (Revman 5.3) and checked for accuracy.

When information regarding any of the above is missing or unclear,

attempts will be made to contact the authors of the original reports

to clarify and provide further details.

Assessment of risk of bias in included studies

The standardised review methods of the Cochrane Neonatal Re-

view Group (CNRG) will be used to assess the methodological

quality of included studies. Review authors will independently as-

sess study quality and risk of bias using the following criteria, as

documented in the Cochrane Handbook for Systematic Reviews ofInterventions (Higgins 2011).

For each trial, the following domains will be evaluated and entered

in the ’Risk of bias’ table. Each domain will be judged as being

at ’low risk’ of bias, ’high risk’ of bias or ’unclear’ risk of bias (for

lack of information or uncertainty over the potential for bias).

1. Selection bias

◦ Random sequence generation: we will describe the

method used to generate the allocation sequence in sufficient

detail to allow an assessment of whether it should produce

comparable groups.

◦ Allocation concealment: we will describe the method

used to conceal the allocation sequence in sufficient detail to

determine whether intervention allocation could have been

foreseen in advance of, or during, enrolment.

2. Performance bias

◦ Blinding of participants and personnel: we will

describe all measures used, if any, to blind study participants and

personnel from knowledge of which intervention a participant

received. We will provide any information relating to whether

the intended blinding was effective.

3. Detection bias

◦ Blinding of outcome assessment: we will describe all

measures used, if any, to blind outcome assessors from

knowledge of which intervention a participant received. We will

provide any information relating to whether the intended

blinding was effective.

4. Attrition bias

◦ Incomplete outcome data: we will describe the

completeness of outcome data for each main outcome, including

attrition and exclusions from the analysis. We will state whether

attrition and exclusions were reported, the numbers in each

intervention group (compared with total randomised

participants), reasons for attrition and exclusions where reported,

and any re-inclusions in analyses performed by the review

authors.

5. Reporting bias

◦ Selective reporting: we will state how the possibility of

selective outcome reporting was examined by the review authors,

and what was found.

6. Other bias

◦ We will state any important concerns about bias not

addressed in the other domains.

Measures of treatment effect

The results of included studies will be analysed using the statis-

tical package Review Manager (RevMan) software (Revman 5.3).

The standard method of the CNRG will be used, using a fixed-

effect model for meta-analysis. In assessing the treatment effects

for dichotomous data and categorical data, the risk ratio or the

risk difference will be reported respectively, along with the 95%

confidence interval. If the risk difference (RD) is statistically sig-

nificant, the number needed to treat for an additional beneficial

outcome (NNTB) and the number needed to treat for an addi-

tional harmful outcome (NNTH) (1/RD) will be calculated. For

outcomes measured on a continuous scale the mean difference,

along with the 95% confidence interval, will be reported.

Unit of analysis issues

Cluster-randomised and individually randomised trials will be

combined in a single meta-analysis using the generic inverse vari-

ance method.

Dealing with missing data

The authors of all published studies will be contacted to request

study protocols, raw data or if further clarifications are required. In

the case of missing data, the number of participants with missing

data will be described in the results section and in the ’Character-

istics of included studies’ table. Where possible, an intention-to-

treat (ITT) meta-analysis will be performed using reconstructed

denominators. The implications of missing data will be discussed

in the review.

Assessment of heterogeneity

RevMan (Revman 5.3) will be used to assess the heterogeneity of

treatment effects between trials. Two formal statistical approaches

will be used.

• The Chi2 test for homogeneity: the presence of statistical

heterogeneity will be assessed using the Chi2 test for

homogeneity (P < 0.1). Because this test has low power when the

number of studies included in the meta-analysis is small, the level

of significance will be set at 10% probability (Higgins 2011).

• The I2 statistic, to ensure that pooling of data is valid: the

impact of statistical heterogeneity will be quantified by using the

I2 statistic, available in RevMan, which describes the percentage

of total variation across studies due to heterogeneity rather than

sampling error. The degree of heterogeneity will be graded as

follows: 25%, no heterogeneity; 25% to 49%, low heterogeneity;



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50% to 74%, moderate heterogeneity; and > 75%, high

heterogeneity.

When evidence of apparent or statistical heterogeneity is noted, the

source of the heterogeneity will be assessed by using sensitivity and

subgroup analyses to look for evidence of bias or methodological

differences between trials.

Assessment of reporting biases

Attempts will be made to obtain the study protocols of all included

studies, and to compare outcomes reported in the protocol versus

those reported in the findings for each of the included studies.

Reporting and publication bias will be investigated by examining

the degree of asymmetry of a funnel plot if 10 or more trials are

identified. If reporting bias is suspected (see selective reporting

bias above), attempts will be made to contact the study authors

to ask them to provide missing outcome data. When this is not

possible, and the missing data are thought to introduce serious

bias, the impact of including such studies in the overall assessment

of results will be examined by performing a sensitivity analysis.

Data synthesis

Meta-analyses will be performed using the standard methods of the

Cochrane Handbook for Systematic Reviews of Interventions. A fixed-

effect model be used. Where studies are statistically heterogenous,

study characteristics including study design and quality will be

examined. If appropriate, subset meta-analysis will be performed

by including only the trials with higher methodological rigour.

Trials with different comparison groups (see Types of

interventions) will not be combined during meta-analysis.

Subgroup analysis and investigation of heterogeneity

Trials with different techniques for tracheal catheterization will be

included in the meta-analysis as subgroups where appropriate (see

Types of interventions).

If appropriate, the following subgroup analyses will be performed:

• gestational age (≤ 28 weeks (extremely preterm), 29 to ≤

32 weeks (very preterm), ≥ 33 weeks (preterm));

• prophylactic surfactant administration via brief tracheal

catheterization trials (intervention performed within 15 minutes

of birth in infants with or at risk of RDS), and rescue trials

(intervention performed beyond 15 minutes);

• use of sedating premedication in the tracheal

catheterization group;

• surfactant type (animal-derived, synthetic).

Sensitivity analysis

Methodological heterogeneity will be explored through the use of

sensitivity analysis. Studies will be assessed as low risk of bias if

sequence generation and allocation concealment are adequate and

losses are less than 10% with ITT analysis.

A C K N O W L E D G E M E N T S

As part of the pre-publication editorial process, this protocol has

been commented on by three peers (an editor and two referees

who are external to the editorial team) and the Group’s Statistical

Adviser.

The Cochrane Neonatal Review Group has been funded in part

with Federal funds from the U.S. Department of Health and

Human Services, National Institutes of Health, Eunice Kennedy

Shriver National Institute of Child Health and Human Develop-

ment USA, under Contract No. HHSN267200603418C.

R E F E R E N C E S

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C O N T R I B U T I O N S O F A U T H O R S

The review was conceived by Peter Dargaville and Kevin Wheeler.

The protocol was developed by Kevin Wheeler and Peter Dargaville. Peter Davis also provided methodological input, and the authors

are grateful to the Cochrane Editorial Team for their feedback.

The manuscript was prepared in RevMan5 by the contact author (Kevin Wheeler). All authors provided feedback on the content of

the final manuscript.

D E C L A R A T I O N S O F I N T E R E S T

Dr Peter Dargaville is the Chief Investigator of the OPTIMIST trial, a multicentre randomised controlled trials of surfactant via

tracheal catheterization in preterm infants on CPAP. Chiesi Farmaceutici (Parma, Italy) is providing in-kind support for these trials. Dr

Dargaville has served as a consultant for Chiesi Farmaceutici and AbbVie Inc. Neither company is involved with the protocol, analysis,

manuscript preparation or publication processes of this review.



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S O U R C E S O F S U P P O R T

Internal sources

• No sources of support supplied

External sources

• Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health,

Department of Health and Human Services, USA.

Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver

National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human

Services, USA, under Contract No. HHSN275201100016C



Documents

Surfactant therapy via brief tracheal catheterization in preterm infants with or at risk of respiratory distress syndrome