CD011878

Cochrane
Library
Cochrane Database of Systematic Reviews
Salbutamol for transient tachypnea of the newborn

(Review)
Moresco L, Bruschettini M, Macchi M, Calevo MG
Moresco L, Bruschettini M, Macchi M, Calevo MG.

Salbutamol for transient tachypnea of the newborn.
Cochrane Database of Systematic Reviews 2021, Issue 2. Art. No.:
CD011878. DOI: 10.1002/14651858.CD011878.pub3.
www.cochranelibrary.com
Salbutamol for transient tachypnea of the newborn (Review)

Copyright © 2021 The Cochrane Collaboration. Published by John Wiley
& Sons, Ltd.
Cochr Trusted
evidence.
Libr Informed Cochrane Database of Systematic
TABLEOF CONT
ENTS
ABSTRACT .................................................................................................................................................................................................
. 1
PLAIN LANGUAGE SUMMARY ....................................................................................................................................................................
2
SUMMARY OF FINDINGS ........................................................................................................................................................................... 3
BACKGROUND ...........................................................................................................................................................................................
5
OBJECTIVES ...............................................................................................................................................................................................
5
METHODS ..................................................................................................................................................................................................
6
RESULTS .....................................................................................................................................................................................................8
Figure 1. .............................................................................................................................................................................................. 9
Figure 2. .............................................................................................................................................................................................. 11
Figure 3. .............................................................................................................................................................................................. 12
Figure 4. .............................................................................................................................................................................................. 13
Figure 5. .............................................................................................................................................................................................. 14
Figure 6. .............................................................................................................................................................................................. 14
DISCUSSION.................................................................................................................................................................................................... 15
AUTHORS' CONCLUSIONS ........................................................................................................................................................................
15
ACKNOWLEDGEMENTS .............................................................................................................................................................................
16
REFERENCES .............................................................................................................................................................................................
17
CHARACTERISTICS OF STUDIES ...............................................................................................................................................................
19
DATA AND ANALYSES.................................................................................................................................................................................. 32
Analysis 1.1. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 1: Duration of oxygen therapy
...................... 33
Analysis 1.2. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 2: Need for continuous positive
airway pressure 33
(yes/no) ...............................................................................................................................................................................................
Analysis 1.3. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 3: Need for mechanical ventilation
(yes/no) .. 34
Analysis 1.4. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 4: Duration of hospital stay...........34
Analysis 1.5. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 5: Duration of tachypnea
.............................. 34
Analysis 1.6. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 6: Initiation of oral feeding
........................... 34
Analysis 1.7. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 7: Duration of respiratory support
(intermittent 35
positive pressure ventilation or continuous positive airway pressure)
.........................................................................................
ADDITIONAL TABLES ................................................................................................................................................................................. 35
APPENDICES ..............................................................................................................................................................................................
36
WHAT'S NEW................................................................................................................................................................................................... 39
HISTORY ..................................................................................................................................................................................................... 39
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................39
DECLARATIONS OF INTEREST ..................................................................................................................................................................
39
SOURCES OF SUPPORT ............................................................................................................................................................................
39
DIFFERENCES BETWEEN PROTOCOL AND REVIEW .................................................................................................................................
40
Copyright © 2021 The Cochrane Collaboration. Published by John

Cochr Trusted
evidence.
INDEX TERMS ............................................................................................................................................................................................ 40
Salbutamol for transient tachypnea of the newborn (Review) i

Cochr Trusted
evidence.
[Intervention Review]
Salbutamol for transient tachypnea of the newborn
Luca Moresco1, Matteo Bruschettini2,3, Marina Macchi4, Maria Grazia Calevo5
1Pediatric and Neonatology Unit, Ospedale San Paolo, Savona, Italy. 2Department of Clinical Sciences Lund,
Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden. 3Cochrane Sweden, Lund University, Skåne
University Hospital, Lund, Sweden. 4University of Milan, Milano, Italy. 5Epidemiology, Biostatistics Unit, IRCCS, Istituto
Giannina Gaslini, Genoa, Italy
Contact: Matteo Bruschettini, matteo.bruschettini@med.lu.se, matbrus@gmail.com.
Editorial group: Cochrane Neonatal Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue
2, 2021.
Citation: Moresco L, Bruschettini M, Macchi M, Calevo MG. Salbutamol for transient tachypnea of the newborn.
Cochrane Database of Systematic Reviews 2021, Issue 2. Art. No.: CD011878. DOI: 10.1002/14651858.CD011878.pub3.
Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Backgrou
nd
Transient tachypnea of the newborn is characterized by tachypnea and signs of respiratory distress. Transient
tachypnea typically appears within the first two hours of life in term and late preterm newborns. Although transient
tachypnea of the newborn is usually a self-limited condition, it is associated with wheezing syndromes in late
childhood. The rationale for the use of salbutamol (albuterol) for transient tachypnea of the newborn is based on
studies showing that β-agonists can accelerate the rate of alveolar fluid clearance. This review was originally
published in 2016 and updated in 2020.
Objectives
To assess whether salbutamol compared to placebo, no treatment or any other drugs administered to treat transient
tachypnea of the newborn, is effective and safe for infants born at 34 weeks’ gestational age with this diagnosis.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2020, Issue 4) in the Cochrane Library;
PubMed (1996 to April 2020), Embase (1980 to April 2020); and CINAHL (1982 to April 2020). We applied no language
restrictions. We searched the abstracts of the major congresses in the field (Perinatal Society of Australia New Zealand
and Pediatric Academic Societies) from 2000 to 2020 and clinical trial registries.
Selection criteria
Randomized controlled trials, quasi-randomized controlled trials and cluster trials comparing salbutamol versus
placebo or no treatment or any other drugs administered to infants born at 34 weeks' gestational age or more
and less than three days of age with transient tachypnea of the newborn.
Data collection and analysis

We used standard Cochrane methodology for data collection and analysis. The primary outcomes considered in this
review were duration of oxygen therapy, need for continuous positive airway pressure and need for mechanical
ventilation. We used the GRADE approach to assess the certainty of evidence.
Main results
Seven trials, which included 498 infants, met the inclusion criteria. All trials compared a nebulized dose of
Salbutamol for transient tachypnea of the newborn (Review) 1

Cochr Trusted
evidence.
salbutamol with normal saline. Four studies used one single dose of salbutamol; in two studies, three to four doses
were provided; in one study, additional doses were administered if needed. The certainty of the evidence was low for
duration of hospital stay and very low for the other outcomes. Among the primary outcomes of this review, four trials
(338 infants) reported the duration of oxygen therapy, (mean difference (MD) -19.24 hours,

Cochr Trusted
evidence.
95% confidence interval (CI) -23.76 to -14.72); one trial (46 infants) reported the need for continuous positive airway
pressure (risk ratio (RR) 0.73, 95% CI 0.38 to 1.39; risk difference (RD) -0.15, 95% CI -0.45 to 0.16), and three trials (254
infants) reported the need for mechanical
ventilation (RR 0.60, 95% CI 0.13 to 2.86; RD -0.01, 95% CI -0.05 to 0.03). Both duration of hospital stay (4 trials; 338 infants)
and duration
of respiratory support (2 trials, 228 infants) were shorter in the salbutamol group (MD -1.48, 95% CI -1.8 to -1.16; MD -9.24,
95% CI -14.24 to
-4.23, respectively). One trial (80 infants) reported duration of mechanical ventilation and pneumothorax but data
could not be extracted due to the reporting of these outcomes (type of units of effect measure and unclear number of
events, respectively). Five trials are ongoing.
Authors' conclusions
There was limited evidence to establish the benefits and harms of salbutamol in the management of transient
tachypnea of the newborn. We are uncertain whether salbutamol administration reduces the duration of oxygen
therapy, duration of tachypnea, need for continuous positive airway pressure and for mechanical ventilation.
Salbutamol may slightly reduce hospital stay. Five trials are ongoing. Given the limited and low certainty of the
evidence available, we could not determine whether salbutamol was safe or effective for the treatment of transient
tachypnea of the newborn.
PLAIN LANGUAGE SUMMARY
The use of salbutamol (albuterol) in the management of transient tachypnea of the newborn
Review question: does salbutamol reduce the duration of oxygen therapy and the need for respiratory support in
newborns with transient tachypnea?
Background: transient tachypnea (abnormally rapid breathing) of the newborn is characterized by high respiratory
rate (more than 60 breaths per minute) and signs of respiratory distress (difficulty in breathing); it typically
appears within the first two hours of life in infants born at or after 34 weeks' gestational age. Although transient
tachypnea of the newborn usually improves without treatment, it is associated with wheezing syndromes in late
childhood. The idea behind using salbutamol for transient tachypnea of the newborn is based on studies showing that
medicines called β-agonists, such as epinephrine (also known as adrenaline), can accelerate the rate of clearance of
fluid from small cavities (alveoli) within the lungs. This review reported and critically analyzed the available evidence
on the effectiveness of salbutamol in the management of transient tachypnea of the newborn.
Study characteristics: in medical literature searches complete to April 2020, we identified and included seven
clinical trials with 498 newborns comparing salbutamol with placebo. Six studies evaluated a single, nebulized (where
the medicine is given in a fine mist) dose of salbutamol, and one study evaluated two different dosages. We found five
additional trials that are still underway.
Key results: we are uncertain whether salbutamol administration reduces the duration of oxygen therapy, duration
of tachypnea, need for continuous positive airway pressure and for mechanical ventilation. Salbutamol may slightly
reduce hospital stay.
Certainty of evidence was low for the outcome, duration of hospital stay, and very low for duration of oxygen
therapy and of tachypnea, need for continuous positive airway pressure and for mechanical ventilation. Given the
limited and low certainty of the evidence available, we could not determine whether salbutamol was safe or effective
for the treatment of transient tachypnea of the newborn.

SUMMARY OF FINDINGS
Copyright
Summary of findings 1. Salbutamol versus placebo/no treatment for transient tachypnea of the newborn
Libr
Cochr
©
Salbutamol versus placebo/no treatment for transient tachypnea
2021 The Cochrane Collaboration. Published by John
of the newborn Patient or population: patients with transient
tachypnea of the newborn
Informed
evidence.
Trusted
Settings: neonatal units in Iran (4 trials), Korea (1 trial), Mexico (1 trial) and Turkey (1 trial); See Table 1.
Intervention: salbutamol versus placebo/no treatment
Outcomes Illustrative comparative risks* (95% CI) Relative No of Certainty of Comments

effect (95% Partici- the evidence
Assumed risk Corresponding risk CI) pants (GRADE)
(studies)
Control Salbutamol versus placebo/no
treatment
Duration of oxygen range 26 to 77 The mean duration of oxygen therapy 338 ⊕⊝⊝⊝
therapy (hours) (hours) in the intervention groups was (4 studies) very low 1,2,3
19.24 lower
(23.76 to 14.72 lower)
Need for continuous Study RR 0.73 46 ⊕⊝⊝⊝

positive airway (0.38 to 1.39) (1 study) very low 1,4
pressure (yes/no) population 389 per 1000
(203 to 741)
533 per 1000
Medium risk population
533 per 1000 389 per 1000
Cochrane Database of Systematic

(203 to 741)
Need for mechanical Study RR 0.6 254 ⊕⊝⊝⊝

ventilation (yes/no) (0.13 to 2.86) (3 studies) very low 1,4
population 25 15 per 1000
(3 to 71)
per 1000
Medium risk population
27 per 1000 16 per 1000

3
(4 to 77)
Duration of range 22-30 The mean duration of respiratory 228 ⊕⊝⊝⊝
respiratory support support (intermittent positive (2 studies) very low 1,4
(intermittent positive
pressure venti-
lation or continuous positive airway pressure;
pressure hours).or continuous positive airway pressure; hours). in the intervention groups was
ventilation
9.24 lower
Copyright
(14.24 to 4.23 lower)
Libr
Cochr
©
2021 The Cochrane Collaboration. Published by John
Duration of hospital stayrange 5-9 The mean duration of hospital stay (days) in the intervention
338 groups was⊕⊕⊝⊝
(days) 1.48 lower (4 studies) low 1,3
(1.8 to 1.16 lower)
Informed
evidence.
Trusted
Duration of mechanical ventilation (hours)
Not reported Not reported
Pneumothorax (yes/no) RR without

One study reported no differences however not measur- able the number
providing
80 of events
⊕⊝⊝⊝
(1 study) very low 1,5
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95%
confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may
change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of
effect and is likely to change the estimate. Very low certainty: we are very uncertain about the
1
Downgraded by one level due to study limitations (risk of bias)
2
Downgraded by one level for inconsistency in effect estimates (moderate or high heterogeneity; IT > 50%)
3
Downgraded by one level for imprecision due to low sample size
Cochrane Database of Systematic

4
Downgraded by two levels for imprecision due to low sample size and wide confidence intervals
5
Downgraded by two levels for imprecision due to low sample size and unknown number of events
4
Cochr Trusted
evidence.
BACKGROUND salbutamol increases the activity and expression of

epithelial sodium channels and sodium- potassium
Description of the condition adenosine triphosphatase at the plasmatic membrane
(Minakata 1998).
Transient tachypnea of the newborn was originally
described in 1966 as the clinical manifestation of
delayed clearance of fetal lung fluid (Avery 1966).
Transient tachypnea of the newborn is characterized
by tachypnea (respiratory rate greater than 60
breaths per minute), and signs of respiratory distress
(grunting, flaring, retractions). The clinical features
typically appear immediately after birth or within the
first two hours of life in term and late preterm
newborn. Transient tachypnea of the newborn is a
clinical diagnosis that is supported by radiologic
findings from chest X-ray, such as increased lung
volumes with flat diaphragms, mild cardiomegaly and
prominent vascular markings in a sunburst pattern
originating at the hilum. In term and late preterm
newborns, transient tachypnea is the most common
cause of respiratory distress (Clark 2005). Other causes
of respiratory distress include surfactant deficiency
(respiratory distress syndrome), pneumonia, meconium
aspiration syndrome, asphyxia, pneumothorax and
congenital heart disease (Ma 2010). The incidence of
transient tachypnea of the newborn can reach up to
30% in term infants delivered by elective cesarean
section (Kumar 1996; Morrison 1995). Affected infants
often undergo evaluation with chest radiography,
laboratory exams and close cardiorespiratory
monitoring. Although transient tachypnea of the newborn
is usually a self-limited condition, one large retrospective
study reported that it was associated with wheezing
syndromes in late childhood (Liem 2007). Rarely,
affected infants may present persistent pulmonary
hypertension or pulmonary air leak requiring mechanical
ventilation (Miller 1980; Tudehope 1979).
Description of the intervention

Lung fluid clearance is promoted immediately after
birth by increasing fetal catecholamine secretion,
which activates the β-adrenergic receptors located in
the alveolar type-II cells, thereby stimulating sodium
absorption by increased epithelial sodium channels
and sodium-potassium adenosine triphosphatase
activity (Barker 2002). Sodium is transported in the
interstitium via ouabain-sensitive basolateral sodium-
potassium adenosine triphosphatase, and the
inhibition of the sodium channel reduces lung liquid
clearance in animal models. As sodium is transported
in the interstitium, it carries chloride and water
passively along with it through the paracellular and
intracellular pathways (Guglani 2008). The poor ability of
the fetal lung to switch from fluid secretion to fluid
absorption and the immaturity in the expression of
epithelial sodium channels may play important roles in
the development of transient tachypnea of the
newborn (Davies 2004). Faxelius and colleagues found
a statistically significant correlation between
catecholamine serum concentrations and lung
compliance at two hours of life in infants delivered by
cesarean section compared to neonates delivered
vaginally (Faxelius 1983). Stimulation of β-adrenergic
receptors with β-2 adrenergic agonists such as

Cochr Trusted
evidence.
How the intervention might work safe for infants born at 34 weeks’ gestational age with
this diagnosis.
The rationale for the use of salbutamol (also known as
albuterol) for transient tachypnea of the newborn is
based on the following findings:
1. experimental studies in ex-vivo human lungs

showed that β- agonists can accelerate the rate of
alveolar fluid clearance (Sakuma 1994; Sakuma
1996);
2. animal studies demonstrated that β-adrenergic
therapy improved lung liquid clearance (Frank 2000);
3. clinical data in adults suggested that inhaled or
intravenous β-adrenergic agonists, working via β-
adrenergic receptors, accelerated the clearance of
excess fluid from alveolar space (β- adrenergic
agonists reduced the risk of high-altitude pulmonary
edema) (Sartori 2002).
Moreover, one double-blind controlled trial

demonstrated the efficacy of aerosolized salbutamol
in reducing pulmonary edema after lung resection
(Licker 2008). Furthermore, sustained treatment with
intravenous β-agonists reduced extravascular lung
water in adults with acute lung injury or acute
respiratory distress syndrome (Perkins 2006). Finally, β-
adrenergic agonists appeared to prevent lung fluid
overload in adults affected by chronic obstructive
pulmonary disease (Di Marco 2012). Therefore,
salbutamol might work in both aerosolized and
intravenous administration (bolus or continuous).
Why it is important to do this review

Cesarean section, macrosomia, maternal diabetes,
family history of asthma and twin pregnancy are
associated with an increased incidence of transient
tachypnea of the newborn (Hansen 2008). Since these
prenatal risk factors are widespread, the majority of
transient tachypnea of the newborn occurs in level 1
neonatal units, where resources for immediate
respiratory support and oxygen supplementation may
be scarce, and where nasal continuous positive airway
pressure procedures are rarely utilized. Therefore, the
availability of a drug able to improve the natural
course of transient tachypnea of the newborn and
subsequently to reduce the need for intensive care
with or without transport to level 3 neonatal intensive
care units would be advantageous.
Many supportive therapies have been proposed, such

as fluid restriction (Stroustrup 2012), antibiotic therapy
(Weintraub 2013), and furosemide (Karabayir 2010).
One systematic review on diuretics has already been
published (Kassab 2015). There are ongoing Cochrane
Reviews exploring the role of fluid restriction for
transient tachypnea of the newborn and the effects of
continuous positive airway pressure in term neonates
with respiratory distress (Foster 2015; Gupta 2015).
However, none of these medical interventions has
been confirmed as effective.
OBJECTIVES
To assess whether salbutamol compared to placebo, no
treatment or any other drugs administered to treat
transient tachypnea of the newborn, is effective and
Cochr Trusted
evidence.
METHODS
Search methods for identification of studies
Criteria for considering studies for this review Electronic searches
Types of studies We used the criteria and standard methods of
Cochrane and Cochrane Neonatal. We undertook a
We included prospective randomized controlled trials
comprehensive search in the following electronic
(RCTs), and quasi-randomized trials. We planned to
sources:
include cluster-RCTs if the definition of participants and
clusters was sufficiently clear. We excluded cross-over 1. the Cochrane Central Register of Controlled Trials
trials. (CENTRAL; 2020, Issue 4) in the Cochrane Library;
Types of participants 2. PubMed (January 1996 to 22 April 2020);
3. Embase (January 1980 to 22 April 2020);
We included infants with transient tachypnea of the
4. CINAHL (1982 to 22 April 2020);
newborn, without any respiratory support prior to study
entry who were born at 34 weeks' or more gestational For the 2020 update, we developed a new search
age and less than three days of age. strategy (Appendix 1). The previous search methods
(2016) are available in Appendix 2.
Diagnostic criteria of transient tachypnea of the newborn
included tachypnea and imaging studies characterized We did not apply any language restrictions. We also
by nonspecific signs, such as increased lung volumes screened the reference lists of any cited articles.
with flat diaphragms, mild cardiomegaly and
prominent vascular markings in a sunburst pattern Searching other resources
originating at the hilum.
We searched clinical trials registries for ongoing or
We excluded infants with pneumonia, surfactant recently completed trials (e.g. ClinicalTrials.gov
deficiency, aspiration syndromes, congenital (clinicaltrials.gov/), and, for the 2016 search (Moresco
diaphragmatic hernia, pneumothorax, and congenital 2016), the International Standard Randomized
heart disease. Controlled Trial Number (ISRCTN) registry
(www.controlled-trials.com/).
Types of interventions
Data collection and analysis
Salbutamol compared to placebo, no treatment or any
other drugs (e.g. epinephrine, diuretics, steroids) We used the standard methods of Cochrane Neonatal, as
administered to treat transient tachypnea of the described below.
newborn, in the first three days of life.
Selection of studies
We included any dose, mode of administration (oral
aerosolized or intravenous) and duration of therapy. Two review authors (LM, MB) independently searched
and identified eligible trials that met the inclusion
Types of outcome measures criteria. We screened the titles and abstracts to identify
potentially relevant citations, and retrieved the full
Primary outcomes texts of all potentially relevant articles. We
1. Duration of oxygen therapy (hours). independently assessed the eligibility of the studies by
filling out eligibility forms designed in accordance with
2. Need for continuous positive airway pressure (yes/no).
the specified inclusion criteria. We reviewed studies for
3. Need for mechanical ventilation (yes/no). relevance based on study design, types of participants,
interventions and outcome measures. We resolved
Secondary outcomes any disagreements by discussion and, if necessary, by
1. Duration of mechanical ventilation (intermittent consulting a third review author (MGC). We planned to
positive pressure ventilation; hours). provide details of studies excluded from the review in
2. Duration of respiratory support (intermittent positive the 'Characteristics of excluded studies' table along with
pressure ventilation or continuous positive airway the reasons for exclusion. We contacted the trial authors
pressure; hours). if the details of the primary trials were unclear.
3. Duration of hospital stay (days). Data extraction and management
4. Duration of tachypnea (hours), defined as
respiratory rate greater than 60 breaths per minute. Two review authors (LM, MB) independently extracted
data using a data extraction form developed ad hoc
5. Initiation of oral feeding (days).
and integrated with a modified version of the
6. Persistent pulmonary hypertension (yes/no), either Cochrane Effective Practice and Organisation of Care
diagnosed clinically or by at least one of the following Group data collection checklist (Cochrane EPOC Group
echocardiographic findings (or both): high right 2013).
ventricular systolic pressure, right to left or
bidirectional shunt at patent foramen ovale or patent We extracted the following characteristics from each
ductus arteriosus, severe tricuspid regurgitation. included study.
7. Pneumothorax (yes/no), diagnosis on chest X-ray.

Cochr Trusted
evidence.
1. Administrative details: author(s); published or
unpublished; year of publication; year in which study
was conducted; details of other relevant papers cited.

Cochr Trusted
evidence.
2. Details of the study: study design; type, duration Systematic Reviews of Interventions (Higgins 2019).
and completeness of follow-up (i.e. greater than 80%);
country and location of study informed consent and Dealing with missing data
ethics approval. We planned to determine the dropout rate for each
3. Details of participants: sex, birth weight, gestational trial (and each trial outcome). We planned to consider
age, and number of participants. a dropout rate that was equal to or greater than the
4. Details of intervention: modality of administration, event rate of the control group
dose, frequency and duration of administration of
salbutamol.
5. Details of outcomes as described in Types of outcome
measures.
We resolved any disagreements by discussion. We

planned to describe the details of ongoing studies where
available, including the primary author, research
question(s), methods, outcome measures and an
estimate of the reporting date. We contacted the
authors of the original reports to request further details
when information regarding any of the above was
unclear.
Two review authors (MGC, MM) used Cochrane's

statistical software, RevMan 2020, to enter all the data.
Assessment of risk of bias in included studies

Two review authors (LM, MGC) independently assessed
the risk of bias (low, high, or unclear) of all included trials
using the Cochrane ‘Risk of bias’ tool (Higgins 2011) for
the following domains:
1. Sequence generation (selection bias);

2. Allocation concealment (selection bias);
3. Blinding of participants and personnel (performance
bias);
4. Blinding of outcome assessment (detection bias);
5. Incomplete outcome data (attrition bias);
6. Selective reporting (reporting bias);
7. Any other bias.
We resolved any disagreements by discussion or by a

third assessor (MB) . See Appendix 3 for a more detailed
description of risk of bias for each domain.
See Appendix 3 for the complete 'Risk of bias' tool.
Measures of treatment effect

We followed the standard methods of Cochrane Neonatal
for data synthesis. We extracted categorical data for
each intervention group and calculated risk ratios (RR)
and absolute risk differences (RD). We obtained means
and standard deviations for continuous data, and
performed analyses using mean differences (MD). For
each measure of effect, we also calculated the
corresponding 95% confidence interval (CI). We planned
to present the numbers needed to treat for an additional
beneficial (NNTB), and harmful (NNTH) outcome when
RDs were statistically significant (P < 0.05).
Unit of analysis issues

The unit of randomization was the intended unit of
analysis (individual neonate). If we found any cluster-
RCTs, we planned to adjust them for the designed effect
using the method stated in the Cochrane Handbook for
Cochr Trusted
evidence.
significant. We planned to perform a sensitivity analysis inappropriate.
to evaluate the overall results with and without the
inclusion of studies with significant dropout rates. If a Subgroup analysis and investigation of
trial reported outcomes only for participants heterogeneity
completing the trial or only for participants who We planned to carry out the following subgroup analyses:
followed the protocol, we planned to contact
author(s) and ask them to provide additional
information to facilitate an intention-to- treat analysis.
We planned no assumptions regarding the outcome of
infants lost to follow-up. We planned to calculate and
report the percentage lost to follow-up if there was a
discrepancy in the number randomized and the numbers
analyzed in each treatment group. Moreover, we
planned to request additional data from the author(s) of
each trial if data on outcomes were missing or unclear.
Assessment of heterogeneity
We planned to assess clinical heterogeneity by
comparing the distribution of important participant
factors between trials and trial factors (randomization
method, allocation concealment, blinding of outcome
assessment, loss to follow-up, treatment type, co-
interventions). We assessed statistical heterogeneity by
examining the I2 statistic (Higgins 2019), a quantity
that describes the proportion of variation in point
estimates that is due to variability across studies rather
than sampling error.
We interpreted the I2 statistic as described by Higgins

2003:
1. less than 25%: no heterogeneity;

2. 25% to 49%: low heterogeneity;
3. 50% to 74%: moderate heterogeneity;
4. 75% or greater: high heterogeneity.
We considered statistical heterogeneity to be

substantial when the I2 statistic was greater than 50%.
In addition, we used the Chi2 test of homogeneity to
determine the strength of evidence that heterogeneity
was genuine.
Assessment of reporting biases

We planned to follow the recommendations in section
10.4 of the Cochrane Handbook for Systematic Reviews
of Interventions to examine a funnel plot to explore
possible small-study biases (Sterne 2017). In
interpreting funnel plots, we planned to examine the
different possible reasons for funnel plot asymmetry and
relate this to the results of the review. If we are able to
pool more than 10 trials, we will undertake formal
statistical tests to investigate funnel plot asymmetry.
Data synthesis
We summarized all eligible studies using RevMan 2020.
We used the standard methods of Cochrane Neonatal
to synthesize data using RRs, RDs, NNTB/NNTH, MDs
and 95% CIs. We used the fixed-effect model to
perform meta-analyses. We undertook meta- analyses
only where this was meaningful: that is, if the
treatments, participants, and the underlying clinical
questions were similar enough for pooling to make
sense. We planned to analyze and interpret individual
trials separately when we judged meta-analysis to be

Cochr Trusted
evidence.
1. Gestational age: term (37 weeks or greater) versus

considered evidence from RCTs as high certainty but
late preterm infants (34 weeks to less than 37 weeks).
downgraded the evidence one level for serious (or two
2. Birth weight: less than 2500 g versus 2500 g or greater. levels for very serious) limitations based upon the
3. Mode of delivery: vaginal versus cesarean section. following: design (risk of bias), consistency across
4. Route of administration: inhaled versus studies, directness of the evidence, precision of
systemic administration. estimates, and presence of publication bias. We used the
5. Dosage: single versus multiple doses. GRADEpro GDT Guideline Development Tool to create
‘Summary of findings 1 to report the certainty of the
Sensitivity analysis evidence.
We planned to conduct sensitivity analyses to explore The GRADE approach results in an assessment of the
the effect of the methodologic quality of the trials, certainty of a body of evidence as one of four grades.
checking to ascertain if studies with a high risk of bias
overestimated the effect of treatment. 1. High certainty: further research is very unlikely to
change our confidence in the estimate of effect.
Summary of findings and assessment of the 2. Moderate certainty: further research is likely to
certainty of the evidence have an important impact on our confidence in the
We used the GRADE approach as outlined in the GRADE estimate of effect and may change the estimate.
Handbook (Schünemann 2013) to assess the 3. Low certainty: further research is very likely to have
certainty of evidence for the following outcomes an important impact on our confidence in the estimate
identified as critical or important for clinical decision- of effect and is likely to change the estimate.
making: need for continuous positive airway pressure, 4. Very low certainty: we are very uncertain about the
need for mechanical ventilation, duration of mechanical estimate.
ventilation, duration of respiratory support, duration of
oxygen therapy, duration of hospital stay, and RESULTS
pneumothorax.
Description of studies
Two review authors (MGC, MM) independently
assessed the certainty of the evidence for each of the We have provided results of the search for this review
outcomes above. We update in the study flow diagram (Figure 1).

Cochr Trusted
evidence.
Figure 1.

Cochr Trusted
evidence.
See Characteristics of included studies and salbutamol 4 mL (Ventolin Nebules 2.5 mg) in 0.9% saline
Characteristics of ongoing studies tables. solution. The standard dose of salbutamol was 0.15
mg/kg. The study authors evaluated the following
Results of the search parameters after four hours of administration: clinical
We searched the databases in April 2020 and score of transient tachypnea of the newborn, respiratory
identified 1102 references for the updated review rate, heart rate, fraction of inspired oxygen (FiO2), partial
(Figure 1). After screening, we added four new RCTs pressure of oxygen in arterial blood (PaO2), partial
(Babaei 2019; Malakian 2018; Mohammadzadeh 2017; pressure of carbon dioxide in arterial
Mussavi 2017), to the three RCTs (Armangil 2011; Kim
2014; Monzoy-Ventre 2015), already included in the 2016
published Cochrane Review (Moresco 2016).
We identified five ongoing trials

(IRCT2014062518232N1; IRCT2016010225811N1;
IRCT201711139014N201;
IRCT20190503043457N1; NCT03208894) in the April 2020
literature search, which are reported in the
Characteristics of ongoing studies table.
Included studies
We included seven trials recruiting 498 infants (270 in
salbutamol groups, 228 in control groups) in the
updated review (Armangil 2011; Babaei 2019; Kim
2014; Malakian 2018; Mohammadzadeh
2017; Monzoy-Ventre 2015; Mussavi 2017). Details of the
trials are described in the Characteristics of included
studies table and in Table 1.
Four studies were conducted in Iran (Babaei 2019;

Malakian 2018; Mohammadzadeh 2017; Mussavi 2017),
and the other three studies in Turkey (Armangil 2011),
Korea (Kim 2014), and Mexico (Monzoy- Ventre 2015).
One study was conducted at multiple centers
(Mohammadzadeh 2017).
Four studies used one single dose of salbutamol

(Armangil 2011; Babaei 2019; Kim 2014;
Mohammadzadeh 2017); in Malakian 2018, additional
doses were administered if needed; in Monzoy- Ventre
2015 and Mussavi 2017, three to four doses were
provided. Monzoy-Ventre 2015 compared two different
salbutamol dosages to normal saline, i.e. 0.15 mg/kg
(same dose as in the other six trials) or 0.10 mg/kg.
Armangil 2011 included 54 infants with transient

tachypnea of the newborn born between 34 and 39
weeks of gestational age recruited in a neonatal
intensive care unit (NICU) in one hospital in Turkey,
between January 2007 and January 2009. Inclusion
criteria were: onset of tachypnea within six hours after
birth (respiratory rate more than 60 breaths per
minute); persistence of tachypnea for at least 12
hours; chest radiograph indicating at least one of the
following: prominent central vascular marking, widened
interlobar fissures of pleural fluid, symmetrical perihilar
congestion and hyperaeration; exclusion of other known
causes of tachypnea (respiratory: meconium aspiration,
respiratory distress syndrome, pneumonia and
congenital heart disease; nonrespiratory: hypocalcemia,
hypoglycemia and polycythemia). After informed consent
was obtained, infants were randomized in a blinded
manner to receive one nebulized dose of either 0.9%
normal saline solution 4 mL (placebo) or a solution of

Cochr Trusted
evidence.
blood (PaCO2), pH, serum potassium ions (K+), and infection (positive blood culture), meconium
serum glucose values. aspiration, respiratory distress syndrome (based on
the radiographs), intrauterine growth retardation,
Babaei 2019 enrolled 80 neonates with a history of fetal distress, pneumonitis, congenital heart
gestational age of at least 35 weeks, and physical disease, disseminated intravascular coagulation (DIC),
examination and radiologic findings suggesting multi-organ failure, hypoxemia, hypoglycemia, and
transient tachypnea of the newborn diagnosis in the polycythemia. The considered outcomes were the
NICU of Imam Reza Hospital in Kermanshah, Iran, duration of hospitalization, time of oral feeding initiation,
during 2017. The newborns with a history of duration of oxygen therapy, need for nasal CPAP therapy,
meconium aspiration, respiratory distress syndrome, and mechanical ventilation.
congenital pneumonia, polycythemia, hypoglycemia,
early-onset sepsis, cardiac disorders, tachycardia
(heart rate > 180 b/min), cardiac arrhythmia, and
congenital anomaly were excluded. Infants were
randomly assigned to receive one dose of nebulized
salbutamol (dose of
0.15 mL/kg in 2 mL of normal saline) and only 2 mL
0.9% normal saline without salbutamol. Respiratory
rate, heart rate, oxygen saturation, a fraction of
inspired oxygen (Fio2), respiratory distress score
(according to Anderson Silverman Retraction Score
scale) were evaluated before the treatment, 30 and 60
minutes, and four hours after nebulization (Silverman
1956). Moreover, arterial blood gas was measured four
hours after the intervention. The duration of tachypnea,
oxygen therapy, mechanical ventilation, continuous
positive airway pressure support (CPAP), hospital stay,
and the time of initiating enteral nutrition were
observed. All neonates were monitored for tachycardia
and arrhythmia.
Kim 2014 investigated 40 newborn infants born at

35 weeks of gestational age or greater with transient
tachypnea of the newborn (defined as respiratory
distress less than six hours and radiological findings
such as fluid in minor fissures, hyperinflation and
prominent vascular perihilar markings), recruited in a
NICU in one hospital in Korea, between January 2010
and December 2010. Exclusion criteria were:
meconium aspiration; other causes of tachypnea:
respiratory distress syndrome, persistent pulmonary
hypertension of the newborn, sepsis, polycythemia
and hypoglycemia; heart murmur and tachycardia.
Newborns were randomized to receive one nebulized
dose of either 0.9% normal saline solution or salbutamol
0.15 mg/kg in 0.9% saline solution. The primary
outcomes were: extent and duration of tachypnea,
duration of oxygen treatment and use of continuous
positive airway pressure or mechanical ventilation. The
secondary outcomes were: duration of empiric antibiotic
therapy, the time of initiating enteral nutrition, duration
of hospitalization and safety of salbutamol
(monitoring heart rate and arrhythmias).
Malakian 2018, a triple-blind clinical trial,
investigated 148 inpatients diagnosed with transient
tachypnea of the newborn in the NICU of Imam
Khomeini Hospital, affiliated with Ahvaz Jundishapur
University of Medical Sciences, Ahvaz, Iran.
Investigators randomly assigned infants divided into two
groups. The treatment group received inhaled
salbutamol (dose of 0.15 mL/kg) and the placebo
group received inhaled normal saline. The exclusion
criteria were the need for mechanical ventilation
during the study, congenital malformation, perinatal
asphyxia, hypocalcemia, confirmed systemic
Cochr Trusted
evidence.
Mohammadzadeh 2017 studied 70 neonates enrolled

solution or salbutamol 0.15 mg/kg in 0.9% saline
in this double-blinded randomized clinical trial
solution or salbutamol 0.10 mg/kg in 0.9% saline
conducted from June through December 2014 in three
solution. The analysis combined the two treatment
urban tertiary care centers of Babol, North of Iran. The
groups (31 newborns) versus the controls (15
neonates born at 34 weeks of gestational age and older
newborns). The primary outcome was improvement of
who were diagnosed with transient tachypnea of the
tachypnea (respiratory rate, Silverman test, oxygen
newborn in the first six hours of life were eligible for
saturation, PaO2, PaCO2). The secondary outcome was
inclusion in this study. Exclusion criteria consisted of
gestational age less than 34 weeks, congenital gross safety of nebulized salbutamol (heart rate and blood
anomalies, neonates born with meconium aspiration, glucose concentration). This study was translated from
birth trauma or asphyxia, chorioamnionitis, positive Spanish by the authors of the present review.
history of mother(s) receiving corticosteroid during Mussavi 2017 included 60 neonates with transient
seven days before birth, neonatal sepsis (positive tachypnea of the newborn and respiratory distress score
blood culture, positive CRP, radiologic findings > 4 and < 10 enrolled in the NICU of Taleghani hospital
consistent with pneumonia), persistent pulmonary in Tabriz, Iran from August to December 2015.
hypertension of neonate, respiratory distress Exclusion criteria were: meconium aspiration, other
syndrome (RDS), neonates with a confirmed metabolic causes of tachypnea (i.e. respiratory distress
disorder (e.g. hypoglycemia, hypokalemia, etc.), and syndrome, persistent pulmonary hypertension,
neonatal cardiovascular disease (diagnosed with pneumonia, sepsis, neonates under the age of 35
echocardiography). The intervention group received weeks, polycythemia, or hypoglycemia), congenital
0.15 mL/kg (equal to 0.15 mg/kg) inhaled salbutamol heart diseases, and tachycardia (heart rate more than
plus 4 mL normal saline 0.9% by nebulizer within 10 180/min) or arrhythmia, and infants with respiratory
minutes. The placebo group received 0.15 mL/kg normal distress score less than 5 and more than 10. The
saline 0.9% plus 4 mL normal saline 0.9% by nebulizer treatment group received 0.15 mg/kg albuterol in 2 mL of
within 10 minutes. The primary objective was to normal saline, and the placebo group received 2 mL of
assess the effect of salbutamol on major clinical normal saline every 6 hours for 24 hours. Each dose of
outcomes including duration of oxygen therapy and drug or placebo was nebulized within 10 minutes by jet
improvement of respiratory symptoms. The secondary nebulizer. The main objective of this study was to
outcomes were: the time of initiation of first enteral evaluate the effectiveness of nebulized albuterol in
feeding and duration of hospitalization. reducing respiratory distress as well as the neediness
Monzoy-Ventre 2015 studied 46 newborn infants of 34 for respiratory continuous positive airway pressure
to 42 weeks of gestational age with transient tachypnea (CPAP) support in infants suffering from transient
of the newborn. Inclusion criteria were: respiratory tachypnea of the newborn. The secondary objective
distress less than six hours after birth which persisted was to assess the safety and possible side effects of
for 12 hours (i.e. respiratory rate greater than 60 nebulized albuterol in the treatment of transient
breaths per minute, grunting, nasal flaring or tachypnea of the newborn.
retraction); and typical chest radiography findings (i.e. Excluded studies
fluid in minor fissures, hyperinflation and prominent
vascular/perihilar markings). Exclusion criteria were: None of the other identified studies was potentially
meconium aspiration; other causes of tachypnea (e.g. eligible.
neonatal respiratory distress syndrome and pneumonia);
and early-onset neonatal sepsis. Newborns were Risk of bias in included studies
randomized to receive one nebulized dose of 0.9% Figure 2 and Figure 3 summarize the risk of bias of the
normal saline trials included in this updated review.
Figure 2. Risk of bias graph: review authors' judgments about each risk of bias item
presented as percentages across all included studies.
Random sequence generation (selection

bias) Allocation concealment (selection
bias)
Blinding of participants and personnel (performance bias): All outcomes
Blinding of outcome assessment (detection bias): All outcomes
Incomplete outcome data (attrition bias): All outcomes
Selective reporting (reporting bias)
Other bias
0% 25% 50% 75% 100%
Low risk of biasUnclear risk of biasHigh risk of bias

Cochr Trusted
evidence.
Figure 3. Risk of bias summary: review authors' judgments about each risk of bias item for
each included study.
outcomes Incomplete outcome data (attrition bias): All outcomes

outcomes Blinding of outcome assessment (detection bias): All
Blinding of participants and personnel (performance bias): All
Random sequence generation (selection
bias) Allocation concealment (selection
Selective reporting (reporting bias)

bias)
Armangil 2011 - ? + + ? ?+
Babaei 2019 + ? ? ? + ?+
Kim 2014 - ? + ? + ?+
Malakian 2018 + ? + + + -+
Mohammadzadeh 2017 ? ? + ? + + +
Monzoy-Ventre 2015 ? ? ? ? + ? +
Mussavi 2017 + ? + ? + - +

Cochr Trusted
evidence.
Allocation
Selective reporting
In Babaei 2019 and Malakian 2018, the randomization
In one trial (Mohammadzadeh 2017), no deviations
sequence was generated through a random number
from the original protocol were found. In four trials
table, while in Mussavi 2017 it was computer-
(Armangil 2011; Babaei 2019; Kim 2014; Monzoy-Ventre
generated. Four studies did not provide information on
2015), protocols were not available and, in two trials,
how the random sequence was generated (Armangil
there were discrepancies between the outcomes listed in
2011; Kim 2014; Mohammadzadeh 2017; Monzoy-Ventre
the protocol and in the final publication (Malakian 2018;
2015). In addition, in two studies there was also
Mussavi 2017).
imbalance in participants across groups (more infants in
the salbutamol arm) (Armangil 2011; Kim 2014). Other potential sources of bias
None of the included trials provided sufficient The included trials appeared free of other biases.
information on allocation concealment (opaque,
numbered envelopes); we judged them at unclear risk. Effects of interventions
Blinding See: Summary of findings 1 Salbutamol versus
placebo/no treatment for transient tachypnea of the
In Armangil 2011, parents and investigators remained newborn
blinded to the administered medications throughout
the study period. In Malakian 2018, all assistants, NICU We identified seven trials that included 498 newborns
nurses, patients, physicians, and statistics experts and compared salbutamol to placebo (saline) (Armangil
remained blinded to the administered medications 2011; Babaei 2019; Kim 2014; Malakian 2018;
throughout the study period. Kim 2014 and Mohammadzadeh 2017; Monzoy-
Mohammadzadeh 2017 reported that double-blinding Ventre 2015; Mussavi 2017). However, Armangil 2011
was provided however who was blinded and who was not expressed data as medians and could not be pooled in
blinded was not clearly reported. In Mussavi 2017, both the analyses.
salbutamol and placebo were prepared and presented
similarly in shape and color coded by a single person who Salbutamol versus placebo or no treatment
was not involved in infants’ care. Primary outcomes
Two studies did not provide sufficient information about Duration of oxygen therapy (outcome 1.1)
blinding of the intervention (Babaei 2019; Monzoy-Ventre
Four trials (N = 338) (Babaei 2019; Kim 2014;
2015).
Malakian 2018; Mohammadzadeh 2017), reported
Incomplete outcome data duration of oxygen therapy (MD
-19.24 hours, 95% CI -23.76 to -14.72; I2 = 72%; 4 studies,
Most trials reported outcomes for all randomized 338 infants; Analysis 1.1; Figure 4). The certainty of the
infants (no dropouts). However, Armangil 2011 was evidence (GRADE) was very low due to study limitations
characterized by a significant imbalance between the (risk of bias), inconsistency in effect estimates (high
number of newborns in the intervention and the control heterogeneity) and imprecision of the estimates due to
group; it was unclear whether this was due to low sample size.
randomization itself or participants lost to follow-up.
Figure 4. Forest plot of comparison: 1 Salbutamol versus placebo, outcome: 1.1 Duration of
oxygen therapy (hours).
Salbutamol Control Mean Difference Mean Difference Risk of Bias
Study or Subgroup Mean [hours] SD [hours] Total Mean [hours] SD [hours] Total Weight IV, Fixed, 95% CI [hours] IV, Fixed, 95% CI [hours] A B C D E F G
Kim 2014 34.2 32.2 28 77.3 64.7 12 1.4% -43.10 [-81.60 , -4.60] - ? + ? + ? +
Malakian 2018 30.36 19.52 74 58.92 33.87 74 25.7% -28.56 [-37.47 , -19.65] + ? + + + - +
Babaei 2019 + ? ? ? + ? +
41.8 7.77 40 60.05 18.15 40 54.5% -18.25 [-24.37 , -12.13]
? ? + ? + + +
Mohammadzadeh 2017 18.7 12.5 35 26 29.3 35 18.3% -7.30 [-17.85 , 3.25]
Total (95% CI) 177 161 100.0% -19.24 [-23.76 , -

Heterogeneity: ChiZ = 10.70, df = 3 (P = 0.01); IZ = 72% 14.72]
Test for overall effect: Z = 8.34 (P < 0.00001) -50 -25 0 25 50
Test for subgroup differences: Not applicable Favors salbutamol Favors control
Risk of bias legend

(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
(G) Other bias
Need for continuous positive airway pressure (yes/no) Monzoy-Ventre 2015 reported need for continuous
(outcome 1.2) positive airway pressure (RR 0.73, 95% CI 0.38 to 1.39; RD -
0.15, 95% CI -0.45 to 0.16;
Cochr Trusted
evidence.
1 study, 46 infants). We obtained data for this outcome
the trial authors. The test for heterogeneity was not
directly from applicable; Analysis 1.2; Figure 5). The certainty of the
evidence (GRADE) was very low due to study limitations
(risk of bias) and serious concern for imprecision of the
estimates due to low sample size and wide confidence
intervals.

Cochr Trusted
evidence.
Figure 5. Forest plot of comparison: 1 Salbutamol versus placebo, outcome: 1.2 Need for
continuous positive airway pressure (yes/no).
Salbutamol
Control Risk Ratio Risk Ratio Risk of Bias
Study or Subgroup Events Total Events Total M-H, Fixed, 95% CI M-H, Fixed, 95% CI A B C D E F G
Monzoy-Ventre 2015 12 31 8 150.73 [0.38 , 1.39] ? ? ? ? + ? +
Risk of bias legend 0.05 0.2 1 5 20

Favors salbutamol Favors control
(G) Other bias
Babaei 2019 reported that they had not observed any

significant difference between the two groups but did typical RD -0.01, 95% CI -0.05 to 0.03; I2 = 0% for RR
not report the percentages. and RD; 3 studies; 254 participants; Analysis 1.3; Figure
6). The certainty of the evidence (GRADE) was very low
Need for mechanical ventilation (yes/no) (outcome 1.3) due to study limitations (risk of bias) and serious concern
for imprecision of the estimates due to low sample size
Three trials (N = 254) (Malakian 2018; Monzoy-Ventre 2015; and wide confidence intervals.
Mussavi 2017), reported this outcome (typical RR 0.60, 95%
CI 0.13 to 2.86;
Figure 6. Forest plot of comparison: 1 Salbutamol versus placebo, outcome: 1.3 Need for
mechanical ventilation (yes/no).
Salbutamol
Control Risk Ratio Risk Ratio Risk of Bias
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI A B C D E F G
Malakian 2018 0 74 2 74 60.0% 0.20 [0.01 , 4.10] + ? + + + - +

Mussavi 2017 1 30 1 30 24.0% 1.00 [0.07 , 15.26] + ? + ? + - +
Monzoy-Ventre 2015 ? ? ? ? + ? +
1 31 0 15 16.0% 1.50 [0.06 , 34.79]
Total (95% CI) 135 119 100.0% 0.60 [0.13 , 2.86]

Total events: 2 3
Heterogeneity: ChiZ = 0.97, df = 2 (P = 0.62); IZ = 0%
0.02 0.1 1 10 50
Test for overall effect: Z = 0.64 (P = 0.52) Favors salbutamol Favors control
Test for subgroup differences: Not applicable
Risk of bias legend

(G) Other bias
Babaei 2019 reported that they had not observed any -1.80 to -1.16; IT = 47%; 4 studies, 338 infants; Analysis 1.4)
significant difference between the two groups but did
not report the percentages.
Secondary outcomes
Duration of hospital stay (outcome 1.4)
Four trials (N = 338) (Babaei 2019; Kim 2014;
Malakian 2018;
Mohammadzadeh 2017), reported this outcome (MD -1.48,
95% CI
Cochr Trusted
evidence.
Armangil 2011 reported that median duration of hospital
stay was 4 days (interquartile range 2 to 5) in the
salbutamol group versus 6 days (interquartile range 4 to
7) in the placebo group (P = 0.002).
Duration of tachypnea, defined as respiratory rate

greater than 60 breaths per minute (outcome 1.5)
Kim 2014 and Babaei 2019 reported this outcome (MD -
16.83 hours, 95% CI -22.42 to -11.23; IT = 0%; 2 studies, 120
infants; Analysis 1.5).

Cochr Trusted
evidence.
Initiation of oral feeding (outcome 1.6) reduce duration of hospital stay. Five trials are
ongoing.
Kim 2014 and Malakian 2018 reported this outcome
(MD -28.49 days, 95% CI -38.14 to -18.84; IT = 0%; 2
Overall completeness and applicability of
studies, 188 infants; Analysis
1.6). evidence
The available evidence was insufficient to determine
Duration of respiratory support (intermittent whether salbutamol is an effective treatment of
positive pressure ventilation or continuous positive
transient tachypnea of the newborn in infants born at
airway pressure) (outcome 1.7)
34 weeks' gestational age or
Babaei 2019 and Malakian 2018 reported this outcome
(MD -9.24 hours, 95% CI -14.24 to -4.23; IT = 0%; 2 studies,
228 infants).
Armangil 2011 reported that median time of
respiratory support was 30 hours (interquartile range 12
to 72) in the salbutamol group versus 48 hours
(interquartile range 24 to 96) in the placebo group (P =
0.112; Analysis 1.7).
Mussavi 2017 reported the time of respiratory support in

days and observed a reduction in duration of
respiratory support in the salbutamol group compared
to the control group (1.6 days ± 0.77 versus 3.3 days ±
0.98; P = 0.0001).
Duration of mechanical ventilation

Babaei 2019 reported the duration of mechanical
ventilation in days: 0.30 days (1.89) and 1.92 days (6.06)
in the salbutamol and in control group, respectively (P =
0.11).
Persistent pulmonary hypertension

None of the included studies reported persistent
pulmonary hypertension.
Pneumothorax
Babaei 2019 reported that they had not observed any
statistically significant difference between the two
groups but did not report the percentages.
Subgroup and sensitivity analysis

We were unable to conduct any of the planned
subgroup and sensitivity analyses (insufficient number
of studies included within meta-analysis).
DISCUSSION
Summary of main results

We evaluated the efficacy of salbutamol
administration in the treatment of transient tachypnea
of the newborn in infants born at 34 weeks' gestational
age or more. Seven trials, including 498 infants, met the
inclusion criteria of this updated review (Armangil 2011;
Babaei 2019; Kim 2014; Malakian 2018;
Mohammadzadeh
2017; Monzoy-Ventre 2015; Mussavi 2017). The mean
gestational age in the included studies was 37 weeks.
Very low-certainty evidence suggests that salbutamol
may reduce duration of oxygen therapy (which was
shorter in the salbutamol group by 19 hours) and
duration of respiratory support; there was no
difference in the need for continuous positive airway
pressure and need for mechanical ventilation. Low-
certainty evidence suggests that salbutamol may
Cochr Trusted
evidence.
more. There were insufficient data available to assess Implications for research
the primary outcomes of this review, and other
important outcomes such as duration of tachypnea Future trials should be undertaken including different
and hospital stay. We could not perform an a priori doses and schedules of salbutamol administration, as
subgroup analysis (gestational age, birth weight, mode efficacy of high doses of intravenous and nebulized
of delivery, route of administration and dosage) to salbutamol have been reported to reduce pulmonary
detect differential effects because of the paucity of edema in adults (Licker 2008; Perkins 2006).
included trials. Moreover, nebulized salbutamol might be compared
with
Quality of the evidence
The overall certainty of evidence was low to very low
because of imprecision of the estimate (due to paucity
of the included trials and small sample sizes),
limitations in study design and the fact that the
primary outcomes were not included in the published
reports (see Summary of findings 1). The trials reported
random sequence generation and concealment of
allocation insufficiently. In addition, the primary
outcome, duration of oxygen therapy, was affected by
high heterogeneity.
Potential biases in the review process

It is unlikely that the literature search applied to this
review may have missed relevant trials, thus we are
confident that this systematic review summarizes all
the presently available evidence from randomized trials
on salbutamol for transient tachypnea of the
newborn, with five trials identified as ongoing. We did
not exclude any potentially relevant trials. The methods
of the review were designed to minimize the
introduction of additional bias. Two review authors
independently completed data screening (LM, MM),
data extraction and 'risk of bias' rating (MGC, MM).
Some outcome data from Armangil 2011 were
expressed as medians and they could not be pooled in
the analyses. We obtained additional information on the
outcomes included in Monzoy-Ventre 2015 from the
main author. We did not explore possible publication
bias through generation of funnel plots because fewer
than 10 trials met the inclusion criteria of this review.
Agreements and disagreements with other

studies or reviews
We are not aware of other reviews that address the
same clinical question. We have described the
characteristics of the relevant clinical trials that have
been published in the Background section.
AUTHORS' CONCLUSIONS
Implications for practice

There was limited evidence to establish the benefits
and harms of salbutamol in the management of
transient tachypnea of the newborn. We are
uncertain whether salbutamol administration reduces
the duration of oxygen therapy, duration of tachypnea,
need for continuous positive airway pressure and for
mechanical ventilation. Salbutamol may slightly
reduce hospital stay. Five trials are ongoing. Given
the limited and low certainty of the evidence
available, we could not determine whether
salbutamol was safe or effective for the treatment of
transient tachypnea of the newborn.

Cochr Trusted
evidence.
systemic administration, other pharmacologic

We thank Marìa Alejandra Monzoy-Ventre for providing
interventions (e.g. epinephrine and diuretics) or non-
additional data.
invasive ventilation strategies. In the five ongoing
trials, salbutamol will be administered by We would like to thank Cochrane Neonatal: Roger Soll
nebulization at a dose ranging from 0.15 to 1 (Co-co-ordinating editor) for his valuable advice,
mg/kg bodyweight. Non-randomized studies would be Colleen Ovelman (Managing Editor), and Jane
useful to identify safety data. Cracknell (Assistant Managing Editor) for their kind and
efficient support.
ACKNOWLEDGEMENTS
As a Cochrane Neonatal Associate Editor, Sarah
We thank Maria Björklund (Library and ICT services, Hodgkinson has peer reviewed and offered feedback for
Lund University) for defining and running the search this review.
strategy of this review.

Cochr Trusted
evidence.
REFERENCES
References to studies included in this respiratory distress of newborn].

review irct.ir/trial/21548 (first received 18 March 2016).
Armangil 2011 {published data only} IRCT201711139014N201 {published data only}
Armangil D, Yurdakök M, Korkmaz A, Yiğit S, IRCT201711139014N201. Effect of inhaler salbutamol
Tekinalp G. Inhaled beta-2 agonist salbutamol for versus placebo on treatment of neonatal transient
the treatment of transient tachypnea of the tachypnea:
newborn. Journal of Pediatrics
2011;159(3):398-403.e1. [DOI: IRCT2016010225811N1 {published data only}
10.1016/j.jpeds.2011.02.028]
IRCT2016010225811N1. Investigation of the effects of
[PMID: 21481414]
nebulized ventolin in transient tachypnea of newborn
Babaei 2019 {published data only} [Investigation of the effects of nebulized ventolin and
saline 0.%9 in transient
Babaei H, Dabiri S, Pirkashani LM, Mohsenpour H.
Effects of salbutamol on the treatment of transient
tachypnea of the newborn. Iranian Journal of Neonatology
2019;10(1):42-9. [DOI: 10.22038/IJN.2018.31294.1430]
Kim 2014 {published data only}

Kim MJ, Yoo JH, Jung JA, Byun SY. The effects of inhaled
albuterol in transient tachypnea of the newborn.
Allergy, Asthma & Immunology Research 2014;6(2):126-
30. [DOI: 10.4168/ aair.2014.6.2.126] [PMID: 24587948]
Malakian 2018 {published data only}

* Malakian A, Dehdashtian M, Aramesh MR, Aletayeb
MH, Heidari S. The effect of inhaled salbutamol on
the outcomes of transient tachypnea of the
newborn. Journal of the Chinese Medical Association
2018;81(11):990-7. [DOI: 10.1016/ j.jcma.2018.01.015]
[PMID: 30131296]
Mohammadzadeh 2017 {published data only}

Mohammadzadeh I, Akbarian-Rad Z, Heidari F,
Zahedpasha Y, Haghshenas-Mojaveri M. The effect of
inhaled salbutamol in transient of tachypnea of the
newborn: a randomized clinical trial. Iranian Journal of
Pediatrics 2017;27(5):e9633. [DOI: 10.5812/ijp.9633]
Monzoy-Ventre 2015 {published data only}

Monzoy-Ventre MA, Rosas-Sumano AB, Hernández-
Enríquez NP, Galicia-Flores L. Inhaled salbutamol in
newborn infants with transient tachypnea [Salbutamol
inhalado en los niños recién nacidos con taquipnea
transitoria]. Revista Mexicana de Pediatria 2015;82(1):5-
9.
Mussavi 2017 {published data only}

* Mussavi M, Asadollahi K, Kayvan M, Sadeghvand
S. Effects of nebulized albuterol in transient
tachypnea of the newborn a clinical trial. Iranian
Journal of Pediatrics 2017;27(3):e8211. [DOI:
10.5812/ijp.8211]
References to ongoing studies

IRCT2014062518232N1 {published data only}
IRCT2014062518232N1. The effect of salbutamol in
treatment of transient tachypnea of newborn.
irct.ir/searchresult.php? id=18232&number=1 (first
received 7 August 2014).

Cochr Trusted
evidence.
a double blind randomized clinical trial [Effect of
inhaler salbutamol versus placebo on treatment of
neonatal transient tachypnea]. irct.ir/trial/9639 (first
received 15 November 2017).
IRCT20190503043457N1 {published data only}

IRCT20190503043457N1. Comparison of inhaled
salbutamol with placebo (water for inj.) on recovery
process of newborns' transient tachypnea
[Comparison of inhaled salbutamol with placebo
(water for inj.) as an add-therapies on the duration
of stay of newborns and the recovery process of
tachypnea and 02 dependence in transient
tachypnea of newborns in NICU in Qom hospitals: a
clinical trial study]. en.irct.ir/trial/39273 (first
received 28 May 2019).
NCT03208894 {published data only}

NCT03208894. Role of salbutamol and furosemide
in TTN [Role of salbutamol and furosemide in
transient tachypnea of newborn].
clinicaltrials.gov/ct2/show/NCT03208894 (first
received 6 July 2017).
Additional references
Avery 1966
Avery ME, Gatewood OB, Brumley G. Transient
tachypnea of newborn. Possible delayed resorption of
fluid at birth. American Journal of Diseases of Children
1966;111(4):380-5. [DOI: 10.1001/
archpedi.1966.02090070078010] [PMID: 5906048]
Barker 2002
Barker PM, Olver RE. Invited review: clearance of
lung liquid during the perinatal period. Journal of
Applied Physiology 2002;93(4):1542-8. [DOI:
10.1152/japplphysiol.00092.2002]
[PMID: 12235057]
Clark 2005
Clark RH. The epidemiology of respiratory failure in
neonates born at an estimated gestational age of 34
weeks or more.
Journal of Perinatology 2005;25(4):251-7. [DOI: 10.1038/
sj.jp.7211242] [PMID: 15605071]
Cochrane EPOC Group 2013

Effective Practice and Organisation of Care (EPOC).
Data extraction and management. EPOC Resources
for review authors. Oslo: Norwegian Knowledge
Centre for the Health Services; 2013.
epoc.cochrane.org/epoc-specific-resources-
review-authors (accessed 15 May 2016).
Davies 2004
Davies JC. Ion transport in lung disease. Pediatric
Pulmonology
2004;26:147-8. [DOI: 10.1002/ppul.70087] [PMID:
15029633]

Cochr Trusted
evidence.
Di Marco 2012 Higgins JP, Altman DG, Sterne JA, Cochrane Statistical
Di Marco F, Guazzi M, Sferrazza Papa GF, Vicenzi M, Methods Group and the Cochrane Bias Methods Group.
Santus P, Busatto P, et al. Salmeterol improves fluid Chapter 8: Assessing risk of bias in included studies. In:
clearance from alveolar-capillary membrane in Higgins JP, Green S, editor(s). Cochrane Handbook for
COPD patients: a pilot study. Pulmonary Systematic Reviews of Interventions Version 5.1.0
Pharmacology & Therapeutics 2012;25(1):119-23. (updated March 2011). The Cochrane
[DOI: 10.1016/j.pupt.2011.12.010] [PMID: 22245487]
Faxelius 1983
Faxelius G, Hägnevik K, Lagercrantz H, Lundell B,
Irestedt L. Catecholamine surge and lung function
after delivery. Archives of Disease in Childhood
1983;58(4):262-6. [DOI: 10.1136/ adc.58.4.262] [PMID:
6847229]
Foster 2015
Foster JP, Buckmaster A, Sinclair L, Lees S, Guaran
R. Nasal continuous positive airway pressure
(nCPAP) for term neonates with respiratory
distress. Cochrane Database of Systematic Reviews
2015, Issue 11. Art. No: CD011962. [DOI:
10.1002/14651858.CD011962]
Frank 2000
Frank JA, Wang Y, Osorio O, Matthay MA. Beta-
adrenergic agonist therapy accelerates the
resolution of hydrostatic pulmonary edema in
sheep and rats. Journal of
Applied Physiology 2000;89(4):1255-65. [DOI:
10.1152/ jappl.2000.89.4.1255] [PMID:
11007557]
GRADEpro GDT [Computer program]

McMaster University (developed by Evidence Prime)
GRADEpro GDT. Hamilton (ON): McMaster University
(developed by Evidence Prime), accessed 12 January
2021. Available at gradepro.org.
Guglani 2008
Guglani L, Lakshminrusimha S, Ryan RM. Transient
tachypnea of the newborn. Pediatrics in Review
2008;29(11):e59-65. [DOI: 10.1542/pir.29-11-e59]
[PMID: 18977854]
Gupta 2015
Gupta N, Chawla D. Fluid restriction in the management
of transient tachypnea of the newborn. Cochrane
Database of Systematic Reviews 2015, Issue 1. Art. No:
CD011466. [DOI: 10.1002/14651858.CD011466]
Hansen 2008
Hansen AK, Wisborg K, Uldbjerg N, Henriksen TB. Risk
of respiratory morbidity in term infants delivered by
elective caesarean section: cohort study. BMJ
2008;336(7635):85-7. [DOI:
10.1136/bmj.39405.539282.BE] [PMID: 18077440]
Higgins 2003
Higgins JP, Thompson SG, Deeks JJ, Altman DG.
Measuring inconsistency in meta-analyses. BMJ
2003;327(7414):557-60. [DOI:
10.1136/bmj.327.7414.557] [PMID: 12958120]
Higgins 2011
Cochr Trusted
evidence.
Collaboration, 2011. Available from 9700104]
training.cochrane.org/ handbook/archive/v5.1.
Morrison 1995
Higgins 2019 Morrison JJ, Rennie JM, Milton PJ. Neonatal respiratory
Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, morbidity and mode of delivery at term: influence of
Page MJ, et al (editor(s)). Cochrane Handbook for
Systematic Reviews of Interventions version 6.0
(updated July 2019). Cochrane, 2019. Available from
www.training.cochrane.org/handbook.
Karabayir 2010
Karabayir N. Intravenous furosemide therapy in
transient tachypnea of the newborn. Pediatrics
International 2010;52(5):851. [DOI: 10.1111/j.1442-
200X.2010.03226.x] [PMID:
20880312]
Kassab 2015
Kassab M, Khriesat WM, Anabrees J. Diuretics for
transient tachypnoea of the newborn. Cochrane
Database of Systematic Reviews 2013, Issue 11. Art.
No: CD003064. [DOI:
10.1002/14651858.CD003064.pub3]
Kumar 1996
Kumar A, Bhat BV. Epidemiology of respiratory distress
of newborns. Indian Journal of Pediatrics 1996;63(1):93-8.
[DOI: 10.1007/BF02823875] [PMID: 10829971]
Licker 2008
Licker M, Tschopp JM, Robert J, Frey JG, Diaper J,
Ellenberger C. Aerosolized salbutamol accelerates the
resolution of pulmonary edema after lung resection.
Chest 2008;133(4):845-52. [DOI: 10.1378/chest.07-
1710] [PMID: 17989152]
Liem 2007
Liem JJ, Huq SI, Ekuma O, Becker AB, Kozyrskyj AL.
Transient tachypnea of the newborn may be an
early clinical manifestation of wheezing symptoms.
Journal of Pediatrics 2007;151(1):29-33. [DOI:
10.1016/j.jpeds.2007.02.021] [PMID:
17586187]
Ma 2010
Ma XL, Xu XF, Chen C, Yan CY, Liu YM, Liu L, et al,
National Collaborative Study Group for Neonatal
Respiratory Distress in Late Preterm or Term Infants.
Epidemiology of respiratory distress and the illness
severity in late preterm or term infants: a
prospective multi-center study. Chinese Medical
Journal 2010;123(20):2776-80. [PMID: 21034581]
Miller 1980
Miller LK, Calenoff L, Boehm JJ, Riedy MJ. Respiratory
distress in the newborn. JAMA 1980;243(11):1176-9.
[PMID: 7359671]
Minakata 1998
Minakata Y, Suzuki S, Grygorczyk C, Dagenais A,
Berthiaume Y. Impact of β-adrenergic agonist on
Na+ channel and Na+-
K+-ATPase expression in alveolar type II cells.
American Journal of Physiology 1998;275(2 Pt 1):L414-
22. [DOI: 10.1152/ ajplung.1998.275.2.L414] [PMID:
Cochr Trusted
evidence.
timing of elective caesarean section. British Journal study ID]

of Obstetrics and Gynaecology 1995;102(2):101-6.
[DOI: 10.1111/ j.1471-0528.1995.tb09060.x] [PMID:
7756199]
Perkins 2006
Perkins GD, McAuley DF, Thickett DR, Gao F. The
Beta- Agonist Lung injury TrIal (BALTI): a
randomized placebo- controlled clinical trial.
American Journal of Respiratory and Critical Care
Medicine 2006;173(3):281-7. [DOI: 10.1164/
rccm.200508-1302OC] [PMID: 16254268]
Rawlings 1984
Rawlings JS, Smith FR. Transient tachypnea of the
newborn: an analysis of neonatal and obstetric risk
factors. American Journal of Diseases of Children
1984;138:869-71. [PMID: 6540983]
RevMan 2020 [Computer program]

Cochrane Collaboration Review Manager 5 (RevMan 5).
Version
5.4. Copenhagen: Cochrane Collaboration, 2020.
Sakuma 1994
Sakuma T, Okaniwa G, Nakada T, Nishimura T, Fujimura
S, Matthay MA. Alveolar fluid clearance in the resected
human lung. American Journal of Respiratory and Critical
Care Medicine 1994;150(2):305-10. [DOI:
10.1164/ajrccm.150.2.8049807] [PMID:
8049807]
Sakuma 1996
Sakuma T, Suzuki S, Usuda K, Handa M, Okaniwa G,
Nakada T, et al. Preservation of alveolar epithelial
fluid transport mechanisms in rewarmed human lung
after severe hypothermia. Journal of Applied Physiology
1996;80(5):1681-6. [DOI: 10.1152/jappl.1996.80.5.1681]
[PMID: 8727555]
Sartori 2002
Sartori C, Alleman Y, Duplain H, Lepori M, Egli M, Lipp
E, et al. Salmeterol for prevention of high-altitude
pulmonary edema. New England Journal of Medicine
2002;346(21):1631-6. [DOI: 10.1056/NEJMoa013183]
[PMID: 12023995]
Schünemann 2013
Schünemann H, Brożek J, Guyatt G, Oxman A, editor(s).
Handbook for grading the quality of evidence and the
strength of recommendations using the GRADE
approach (updated October 2013). GRADE Working
Group, 2013. Available from
gdt.guidelinedevelopment.org/app/handbook/handbook
.html.
Silverman 1956
Silverman WE, Anderson DH. Controlled clinical trial
of effects of water mist on obstructive respiratory
signs, death rate
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by

Cochr Trusted
evidence.
and necropsy findings among premature infants. Weintraub 2013
Pediatrics Weintraub AS, Cadet CT, Perez R, De Lorenzo E,
1956;17:1-10. [PMID: 13353856] Holzman IR, Stroustrup A. Antibiotic use in newborns
with transient tachypnea of the newborn. Neonatology
Sterne 2017 2013;103(3):235-40. [DOI: 10.1159/000346057] [PMID:
Sterne JAC, Egger M, Moher D, Boutron I (editors). 23428585]
Chapter 10: Addressing reporting biases. In:
Higgins JPT, Churchill R, Chandler J, Cumpston MS
(editors), Cochrane Handbookfor Systematic References to other published versions of this
Reviews of Interventions, Version 5.2.0 (updated review
June 2017), Cochrane. Available from
Moresco 2015
training.cochrane.org/ handbook 2017.
Moresco L, Bruschettini M, Cohen A, Gaiero A, Calevo
Stroustrup 2012 MG. Salbutamol for transient tachypnea of the
Stroustrup A, Trasande L, Holzman IR. Randomized newborn. Cochrane Database of Systematic Reviews
controlled trial of restrictive fluid management in 2015, Issue 9. Art. No: CD011878. [DOI:
transient tachypnea of the newborn. Journal of 10.1002/14651858.CD011878]
Pediatrics 2012;160(1):38-43.e1. [DOI:
Moresco 2016
10.1016/j.jpeds.2011.06.027] [PMID: 21839467]
Moresco L, Bruschettini M, Cohen A, Gaiero A, Calevo
Tudehope 1979 MG. Salbutamol for transient tachypnea of the
Tudehope DI, Smyth MH. Is "transient tachypnoea of newborn. Cochrane Database of Systematic Reviews
the newborn" always a benign disease? Report of 6 2016, Issue 5. Art. No: CD011878. [DOI:
babies requiring mechanical ventilation. Australian 10.1002/14651858.CD011878.pub2]
Paediatric Journal 1979;15(3):160-5. [DOI:
10.1111/j.1440-1754.1979.tb01215.x] * Indicates the major publication for the study
[PMID: 518409]
Armangil 2011
Study characteristics
Methods Double-blind randomized controlled trial

Cochr Trusted
evidence.
Armangil 2011
(Continued)
Single-center: NICU of Hacettepe University Children's Hospital, Ankara, Turkey, between
January 2007 and January 2009
Participants 54 newborns (32 in the salbutamol group, 22 in the control group)
Inclusion criteria
Newborns were eligible for enrollment if they were diagnosed with TTN and were < 6 hours
old. The diagnosis of TTN was according to the criteria of Rawlings and Smith (Rawlings
1984) on the basis of radiologic and laboratory findings of:
1. onset of tachypnea (respiratory rate exceeding 60 breaths/min) within 6 hours after birth
2. persistence of tachypnea for at least 12 hours
3. chest radiograph indicating at least 1 of the following: prominent central vascular
markings, widened interlobar fissures of pleural fluid, symmetrical perihilar congestion,
hyperaeration as evidenced by flattening and depression of the diaphragmatic domes
or increased anteroposterior diameter, or both
4. exclusion of other known respiratory disorders (meconium aspiration, respiratory
distress syndrome, pneumonitis, congenital heart diseases), and nonrespiratory
disorders (hypocalcemia, persistent hypoglycemia, polycythemia) likely to cause
tachypnea.
Excluding criteria for acute respiratory distress syndrome were as follows:
1. no predisposing factor such as diffuse pulmonary opacities on radiography;

2. severe hypoxia;
3. sepsis;
4. the syndrome of multiple organ failure;
5. disseminated intravascular coagulation;
6. iatrogenic lung injury (higher respiratory support techniques such as high tidal
volumes and pressure support).
Respiratory distress syndrome was excluded if there was no reticulogranular pattern on

the X-ray film and no surfactant therapy.
Meconium aspiration syndrome was excluded if there were no X-ray findings (irregular
pattern of increased density throughout the lung) and no meconium staining of the skin.
Infants who received diuretics and antibiotics were excluded from the study.
Gestational age and birth weight were similar in the 2 groups (mean ± SD), i.e. 37.0 ± 1.6
weeks and 2991 ± 536 grams in the salbutamol group and 36.7 ± 1.6 weeks and 2990 ±
574 grams in the control group.
Interventions Intervention group: solution of salbutamol 4 mL (ventolin nebules 2.5 mg) in 0.9%
saline solution Control group: 1 nebulized dose of 0.9% normal saline solution 4 mL
(placebo)
The standard dose of salbutamol was 0.15 mg/kg. Solutions were given with a jet type
nebulizer with continuous flow of oxygen at 5 to 6 L/min. 1 dose was administered over
20 minutes, and vital signs were monitored for 4 hours. Preparation and administration of
nebulized solutions were performed by a NICU nurse. Parents and investigators remained
blinded to the administered medications throughout the study period.
Outcomes 1. Clinical score of transient tachypnea;
2. Respiratory rate;
3. Heart rate;
4. FiO2;
5. PaO2;
6. PaCO2;
7. pH;

Cochr Trusted
evidence.
Armangil 2011
(Continued)
8. Serum K+;
9. Serum glucose values
Notes Limited power to address clinically relevant outcomes
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence High risk No information provided on sequence generation; imbalance in

generation (selection participants across groups (more in salbutamol arm)
bias)
Allocation Unclear risk No information provided

concealment
(selection bias)
Blinding of Low risk Parents and investigators remained blinded to the administered
participants and medications throughout the study period.
personnel (perfor-
mance bias)
All outcomes
Blinding of outcome Low risk Investigators remained blinded to the administered medications
assessment throughout the study period.
(detection bias) All
outcomes
Incomplete outcome Unclear risk Extreme imbalance between the number of newborns in the
data (attrition bias) intervention and the control group: unclear whether due to
All outcomes randomization itself or participants lost to follow-up
Selective reporting Unclear risk The trial was not registered and there was no protocol available.
(reporting bias) We could not ascertain if there were deviations from the original
protocol in the final publication.
Other bias Low risk Appeared free of other bias
Babaei 2019
Methods Clinical trial conducted on all hospitalized neonates diagnosed with TTN in the neonatal
intensive care unit (NICU) of Imam Reza Hospital in Kermanshah, Iran, during 2017
Participants 80 newborns (40 in the salbutamol group, 40 in the placebo group)
Inclusion criteria:
1. gestational age of at least 35 weeks; and

2. physical examination and radiologic findings suggesting TTN diagnosis.
Exclusion criteria:
1. meconium aspiration;
2. respiratory distress syndrome;
3. congenital pneumonia;
4. polycythemia;
5. hypoglycemia;

Cochr Trusted
evidence.
6. early onset sepsis;

Cochr Trusted
evidence.
Babaei 2019
(Continued)
7. cardiac disorders;
8. tachycardia (HR > 180 b/min);
9. cardiac
arrhythmia;
10. congenital
anomaly.
Interventions The treatment group received one dose of nebulized salbutamol (dose of 0.15 mL/kg in 2
mL of normal saline).
The placebo group received 2 mL 0.9% normal saline without

salbutamol.
Outcomes 1. Duration of tachypnea;

2. Oxygen therapy;
3. Mechanical ventilation;
4. Continuous positive airway pressure support (CPAP);
5. Hospital stay;
6. Time of initiating enteral feeding.
Notes The study was also registered in the Iranian Clinical Trials (IRCT2017081414333N80code).
Risk of bias
Random sequence Low risk Random number table

generation (selection
bias)
Allocation Unclear risk No details available

concealment
(selection bias)
Blinding of Unclear risk No information provided

participants and
personnel (perfor-
mance bias)
All outcomes
Blinding of outcome Unclear risk No information provided

assessment
outcomes
Incomplete outcome Low risk All participants accounted for

data (attrition bias)
All outcomes
Selective reporting Unclear risk The secondary outcomes were not reported in the protocol.
(reporting bias)
Kim 2014

Cochr Trusted
evidence.
Methods Double-blind clinical trial
Single-center: NICU of Dong-A Medical Center, Busan, Korea, between January 2010
and December 2010

Cochr Trusted
evidence.
Kim 2014 (Continued)
Inclusion criteria
Infants with TTN were determined based on the following clinical symptoms and chest
radiography results:
1. ≥ 35 weeks' gestational age;

2. respiratory distress < 6 hours after birth (i.e. respiratory rate > 60 breaths/min,
grunting, nasal flaring, or retraction);
3. typical chest radiography findings (i.e. fluid in minor fissures, hyperinflation, prominent
vascular/perihilar markings).
Newborns were excluded if they exhibited any of the following:
2. other causes of tachypnea (e.g. neonatal respiratory distress syndrome, persistent
pulmonary hypertension of the newborn, pneumonia, early-onset neonatal sepsis,
polycythemia or hypoglycemia);
3. heart murmur;
4. tachycardia (heart rate > 180 beats/min) or arrhythmia.
Meconium aspiration syndrome was excluded when there were no abnormal chest
radiography findings (irregular pattern of increased density throughout the lung) and no
meconium staining of the skin.
Respiratory distress syndrome was excluded when there were no reticulogranular

patterns on the chest radiograph and no surfactant therapy.
Persistent pulmonary hypertension of the newborn was excluded when the level of
preductal oxygen saturation was < 5% above postductal oxygen saturation.
Sepsis was excluded when there were no perinatal risk factors, WBC > 5000/mm3,
immature-to-total neutrophil ratio < 0.25, negative C-reactive protein and no focal
infiltration on chest X-ray.
Gestational age and birth weight were similar in the 2 groups, i.e. 37.6 ± 1.9 weeks and
3090.7 ± 591 grams in the salbutamol group and 37.5 ± 1.0 weeks and 3203.3 ± 432.4
grams in the control group.
Interventions Intervention group: 1 dose salbutamol 0.1 mL (ventolin respiratory solution,
salbutamol sulfate 5 mg/ mL; GlaxoSmithKline Inc., UK) in 2 mL of 0.9% normal saline
Control group: 1 dose of 2 mL nebulized 0.9% normal saline (placebo)
The standard dose of salbutamol was 0.15 mg/kg. Each dose was nebulized with a jet-
type nebulizer (PariBoy®, Pari-Werk, Starnberg, Germany) with continuous flow of
oxygen at 5 L/min and was administered over the course of 10 minutes.
Outcomes Primary outcomes:
1. duration of tachypnea;
2. oxygen treatment;
3. hospitalization.
Secondary outcomes:
1. extent and duration of tachypnea;

2. duration of oxygen treatment;
3. use of continuous positive airway pressure or a ventilator;
4. duration of empiric antibiotic therapy;
5. time of initiating enteral nutrition;
6. duration of hospitalization;
7. tachycardia and arrhythmias.

Cochr Trusted
evidence.
Kim 2014 (Continued)
Risk of bias
Random sequence High risk No information provided on sequence generation; imbalance in

generation (selection participants across groups (more in salbutamol arm)
bias)

concealment
(selection bias)
Blinding of Low risk Infants were randomly allocated in a double-blind manner to

participants and receive 1 dose of 2 mL nebulized 0.9% normal saline (placebo) or
personnel (perfor- 0.1 mL salbutamol (ventolin respiratory solution, salbutamol sulfate
mance bias) 5 mg/mL; GlaxoSmithKline Inc. UK) in 2 mL of 0.9% normal saline.
All outcomes

assessment
outcomes
Incomplete outcome Low risk Extreme imbalance between the number of newborns in the
data (attrition bias) intervention and the control group: unclear whether due to
All outcomes randomization itself or participants lost to follow-up
Selective reporting Unclear risk The trial was not registered and no protocol was available. We could
(reporting bias) not ascertain if there were deviations from the original protocol in
the final publication.
Malakian 2018
Methods Triple-blind, randomized, clinical trial (registration NO. IRCT2016081329336N1)

conducted during a year in the NICU of Imam Khomeini Hospital affiliated with Ahvaz
Jundishapur University of Medical Sciences, Ahvaz, Iran
Inclusion criteria:
1. newborns with TTN were enrolled.
The following symptoms were assessed in all patients with TTN based on the
clinical and para- clinical criteria of TTN: the incidence of tachypnea (RR > 60)
within the first 6 hours of birth and the CXR index, including at least 1 of the following
symptoms:
1. congestion of central lung vessels;

2. thickening of the interlobar fissures due to high altitude pulmonary edema;
3. symmetrical hilar congestion;
4. hyperaeration;
5. mean flattening of the diaphragm or an increased posteroanterior chest diameter or
both.
Cochr Trusted
evidence.
Exclusion criteria:
1. the need for mechanical ventilation;

Cochr Trusted
evidence.
Malakian 2018
(Continued)
2. congenital malformation;
3. perinatal asphyxia;
4. hypocalcemia;
5. confirmed systemic infection (positive blood culture);
7. respiratory distress syndrome (based on the radiographs);
8. intrauterine growth retardation;
9. history of fetal
distress;
10.pneumonitis;
11.congenital heart
disease;
12.disseminated intravascular coagulation
(DIC); 13.multi-organ failure;
14. hypoxe
mia;
15. hypogly
cemia;
16. polycyt
hemia.
Interventions Salbutamol or normal saline (placebo) was administered to the treatment or control
group, respectively. Patients inhaled the salbutamol/normal saline through the jet
ultrasonic nebulizer with the oxygen flow at 5 to 6 L/min within 20 minutes each time. In
the case of continuation of respiratory distress and the need for oxygen therapy, the
drug was administered every 6 hours for a maximum 72 hours after the initiation of
treatment. The salbutamol dose was 0.15 mg/kg of body weight.
Outcomes 1. The duration of hospitalization
2. Time of oral feeding initiation
3. Duration of oxygen therapy
4. Need for nasal CPAP therapy and mechanical ventilation
Notes
Risk of bias
Random sequence Low risk The eligible cases were randomly assigned into one of the study
generation (selection groups using a table of random numbers.
bias)
Allocation Unclear risk No details available

concealment
(selection bias)
Blinding of Low risk Patients were cared for by the assistants and NICU nurses who were
participants and blind to the study objectives and nature of the groups. All patients,
personnel (perfor- physicians, and statistics experts were blind to the drug and
mance bias) placebo preparations and adminis- trations, as well as treatment
All outcomes procedures.
Blinding of outcome Low risk Patients were cared for by the assistants and NICU nurses who were
assessment blind to the study objectives and nature of the groups. All patients,
(detection bias) All physicians, and statistics experts were blind to the drug and
outcomes placebo preparations and adminis- trations, as well as treatment
procedures.

Cochr Trusted
evidence.
All outcomes
Selective reporting High risk Trial protocol registered retrospectively (IRCT2017062129336N3);

(reporting bias) discrepancy between the outcomes reported in the protocol and in
the final publication

Cochr Trusted
evidence.
Malakian 2018 (Continued)
Mohammadzadeh 2017
Methods This double-blinded randomized clinical trial was conducted in 2014 in three urban
tertiary care centers of Babol, North of Iran.
Neonates born 34 weeks of gestational age and older who were diagnosed with TTN in
the first 6 hours of life. The diagnosis TTN was based on clinical evidence of tachypnea
(respiratory rate more than 60 bpm) with or without cyanosis, respiratory distress
(accessory muscle use, nasal flaring, grunting), and chest X-ray findings consistent with
TTN (at least one of the radiologic signs which include: lung hyperinflation, perihilar
congestion or streaking, fluid filled interlobar fissure, fluffy bilateral infiltration, pul-
monary edema).
Exclusion criteria:
1. gestational age less than 34 weeks;

2. congenital gross anomalies;
3. neonates born with meconium aspiration;
4. birth trauma or asphyxia;
5. chorioamnionitis;
6. positive history of mother receiving corticosteroid during 7 days before birth;
7. neonatal sepsis (positive blood culture, positive CRP, radiologic findings consistent with
pneumonia);
8. persistent pulmonary hypertension of neonate;
9. respiratory distress syndrome (RDS);
10. neonates with confirmed metabolic disorder (e.g. hypoglycemia,
hypokalemia, etc.); 11.neonatal cardiovascular disease (diagnosed with
echocardiography).
Interventions The intervention group received 0.15 mL/kg (equal to 0.15 mg/kg) inhaled salbutamol
(Astalin manu- factured by Cipla; India) plus 4 mL normal saline 0.9% by nebulizer
within 10 minutes. Placebo group received 0.15 mL/kg normal saline 0.9% plus 4 mL
normal saline 0.9% by nebulizer within 10 minutes.
Outcomes Primary objective:
1. to assess the effect of salbutamol on major clinical outcomes including duration of

oxygen therapy and improvement of respiratory symptoms
Secondary outcomes:
1. time of initiation of first enteral feeding;

2. duration of hospitalization.
Notes Iranian Registry of Clinical Trial ID: IRCT2014062518232N1
Risk of bias
Random sequence Unclear risk The exact method of random generation not mentioned
bias)

Cochr Trusted
evidence.
Mohammadzadeh 2017 (Continued)
Allocation concealment Unclear risk No details available

(selection bias)
Blinding of participants Low risk Double-blinded randomized clinical trial

and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Blinding of outcome assessors was not explicit.
sessment (detection
bias)
All outcomes

data
(attrition bias)
All outcomes
Selective reporting (re- Low risk The trial was registered (IRCT2014062518232N1) and protocol was
available.
porting bias)
Monzoy-Ventre 2015
Methods Clinical trial
Single-center: NICU of the Hospital Aurelio Valdivieso, Oaxaca, Mexico, between

February 2012 and February 2013
Participants 46 newborns (15 children in the control group)
Inclusion criteria:
1. diagnosed with TTN and were < 6 hours old;

2. ≥ 34 weeks' gestational age;
3. respiratory distress < 6 hours after birth and persisting for 12 hours (i.e. respiratory
rate > 60 breaths/ min, grunting, nasal flaring or retraction); typical chest radiography
findings (i.e. fluid in minor fissures, hyperinflation, prominent vascular/perihilar
markings).
Newborns were excluded if they exhibited any of the following:
2. other causes of tachypnea (e.g. neonatal respiratory distress syndrome, pneumonia);
3. early-onset neonatal sepsis;
4. tachypnea.
Gestational age and birth weight were similar in the 3 groups, i.e. 36.2 ± 2.2 weeks and
2425.6 ± 691.8 g in the salbutamol group 0.10 mg/kg/dose, 36.6 ± 1.7 weeks and 2454.6 ±
702.8 g in the salbutamol group 0.15 mg/kg/dose and 36.6 ± 2.5 weeks and 2519.3 ±
592.1 g in the control group.
Interventions Intervention group A: salbutamol 0.10
mg/kg/dose Intervention group B:
salbutamol 0.15 mg/kg/dose Control group:

Cochr Trusted
evidence.
2.5 mL nebulized saline solution
The 2 treatment groups (31 newborns) were combined for analysis vs. controls (15
newborns)

Cochr Trusted
evidence.
Monzoy-Ventre 2015
(Continued)
All received nebulization every 4 hours 3 times.
Outcomes 1. Respiratory rate

2. Heart rate
3. FiO2,
4. PaO2
5. PaCO2
Risk of bias
Random sequence Unclear risk No information provided

bias)

concealment
(selection bias)
Blinding of Unclear risk No information provided

participants and
personnel (perfor-
mance bias)
All outcomes

assessment
outcomes
Incomplete outcome Low risk All reported outcomes provided with complete results
All outcomes
Selective reporting Unclear risk The trial was not registered and no protocol was available. We could
(reporting bias) not ascertain if there were deviations from the original protocol in
the final publication.
Mussavi 2017
Methods Randomized, blinded, placebo-controlled clinical trial was conducted in neonatal

intensive care unit (NICU) of Taleghani hospital in Tabriz, Iran from August to
December 2015.
Infants with transient tachypnea of the newborn were characterized based on

the following clinical criteria:
1. at least 35 weeks' gestational age;

2. presence of respiratory distress less than 6 hours after birth (respiratory rate more
than 60/min, cyanosis, grunting, nasal flaring, or retraction);
3. typical chest radiography findings (fluid in minor fissures, hyperinflation, prominent
Cochr Trusted
evidence.
vascular/perihilar markers).

Cochr Trusted
evidence.
Mussavi 2017
(Continued)
Exclusion criteria:
2. other causes of tachypnea (i.e. respiratory distress syndrome, persistent pulmonary
hypertension, pneumonia, sepsis, neonates under the age of 35 weeks, polycythemia,
or hypoglycemia);
3. congenital heart diseases;
4. tachycardia (heart rate more than 180/min) or arrhythmia;
5. infants with respiratory distress scores less than 5 and more than 10.
Interventions Treatment group received 0.15 mg/kg albuterol (salbutamol sulfate 5 mg/mL, Glaxo
Smith Kline, UK) in 2 mL of normal saline, and placebo group received 2 mL of normal
saline every 6 hours for 24 hours. Each dose of drug or placebo was nebulized within 10
minutes by jet nebulizer (Omron Micro Air NE- U22E- Japan) through the input arm
CPAP set.
Outcomes Main objective:
1. to evaluate the effectiveness of nebulized albuterol in reducing respiratory distress

as well as the neediness to respiratory continuous positive airway pressure (CPAP)
support
Secondary objective:
1. to assess the safety and possible side effects of nebulized albuterol in the treatment of
TTN
Notes The project was registered via the Iranian registry of clinical trials and a registration ID
was allocated as IRCT201305188680N3, which, however, refers to another study.
Risk of bias
Random sequence Low risk All enrolled neonates were randomly (computer-generated)
generation (selection allocated into 2 groups of treatment and placebo.
bias)

concealment
(selection bias)
Blinding of Low risk Infants were randomly allocated in the groups by staff who were
participants and not involved in the infant’s care.
personnel (perfor-
mance bias)
All outcomes

assessment
outcomes

All outcomes
Selective reporting High risk The outcomes reported did not match those specified in the protocol.
(reporting bias)

Cochr Trusted
evidence.
b/min: beats per minute
CPAP: continuous positive airway pressure
support CRP: c-reactive protein
CXR: chest X-ray

Cochr Trusted
evidence.
DIC: disseminated intravascular

coagulation FiO2: fraction of inspired
oxygen
HR: heart rate; min: minute
NICU: neonatal intensive care unit
PaCO2: partial pressure of carbon dioxide in
arterial blood PaO2: partial pressure of oxygen in
arterial blood
RDS: respiratory distress
syndrome RR: risk ratio
SD: standard deviation
TTN: transient tachypnea of the
newborn vs: versus
WBC: white blood cell count
Characteristics of ongoing studies [ordered by study ID]
IRCT2014062518232N1
Study name The effect of salbutamol in treatment of transient tachypnea of newborn
Methods Double-blind, randomized clinical controlled trial
Participants 70 late preterm, term and post-term neonates with transient tachypnea of the
newborn during the first 6 hours after birth
Interventions Intervention group: 1 dose of salbutamol 0.15 mL/kg bodyweight) by nebulizer within 10
minutes
Control group: 1 dose of 0.15 mL/kg bodyweight of 0.9% normal saline by nebulizer
within 10 minutes
Outcomes Primary:
1. tachypnea (at 30 minutes, and 1, 4 and 6 hours later)
Secondary:
1. respiratory rate;
2. heart rate;
3. oxygen requirement;
4. feeding initiation time;
5. duration of hospitalization;
6. retraction score and oxygen saturation percent (all measured at 30 minutes, and 1,
4 and 6 hours later);
7. arterial blood gases (measured before and after intervention).
Starting date August 2014
Contact information Heydari Fatemeh

f.heydari@mubabol.ac.ir OR dr.fatmeh_heydari@yahoo.com
Notes
IRCT2016010225811N1
Study name Investigation of the effects of nebulized ventolin in transient tachypnea of newborn

Cochr Trusted
evidence.
IRCT2016010225811N1 (Continued)
Participants 90 1-day-old term/near-term neonates with transient tachypnea of newborn
Interventions Intervention group: salbutamol 1 mg/kg with 2 milliliter saline nebulization/6 hours
for 24 hours Control group: 2 mL saline nebulization/6 hours for 24 hours
Outcomes Primary:
1. admission duration (every 6 hours):

2. CPAC application (primary 24 hours);
3. mechanical ventilation (primary 24 hours).
Secondary:
1. arrhythmia
Starting date February 2016
Contact information Mousavi Mirhadi

drmussavihadi@yahoo.c
om
Notes
IRCT201711139014N201
Study name Effect of inhaler salbutamol versus placebo on treatment of neonatal transient
tachypnea: a double-blind randomized clinical trial
Participants 52 34 to 47 week neonates with transient tachypnea of newborn
Interventions Intervention group: 0.1 mL/kg salbutamol and 2 mL normal saline 0.9% plus 5 to 6
L/min oxygen for 20 minutes by nebulizer
Control group: 2 mL normal saline 0.9% plus 5 to 6 L/min oxygen for 20 minutes by
nebulizer
Outcomes Primary:
1. number of breaths (before and after 0.5, 1, 4 hours);

2. TTN clinical score (before and after 0.5, 1, 4 hours);
3. arterial oxygen saturation (before and after 4 hours).
Starting date November 2017
Contact information Behnaz Basiri
b.basiri@umsha.a
c.ir
Notes
IRCT20190503043457N1
Study name Comparison of inhaled salbutamol with placebo (water for inj.) on recovery process
of newborns' transient tachypnea

Cochr Trusted
evidence.
IRCT20190503043457N1 (Continued)
Methods Double-blind, randomized controlled clinical trial
Participants 60 1-day to 7-day old healthy term infants with mild to moderate respiratory
distress and diagnosed with transient tachypnea of the newborn
Interventions Intervention group: salbutamol 0.15 mg/kg body weight in 4 cc normal saline by
nebulizer for 10 minutes
Control group: 4 cc distilled water by nebulizer for 10 minutes
Outcomes Primary:
1. number of breaths (after 30 minutes, 1 and 4 hours);

2. percent saturation of oxygen (after 30 minutes, 1 and 4 hours);
3. heart rate (after 30 minutes, 1 and 4 hours).
Starting date March 2018
Contact information Alireza Saadati
a.rsaadati@muq.a
c.ir
Notes
NCT03208894
Study name Role of salbutamol and furosemide in transient tachypnea of newborn
Methods Single-blind, randomized clinical controlled trial
Participants 100 newborn babies with clinically diagnosed TTN
Interventions 1) salbutamol; 2) furosemide; 3) salbutamol and furosemide; 4) control: no intervention.
Outcomes Primary:
duration of oxygen requirement (up to 6 months)
Starting date November 2016
Contact information Arshad Khushdil
Notes
CPAP: continuous positive airway pressure

support TTN: transient tachypnea of the
newborn.
DATA AND ANALYSES

Cochr Trusted
evidence.
Comparison 1. Salbutamol versus placebo/no treatment
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1.1 Duration of oxygen therapy 4 338 Mean Difference (IV, -19.24 [-23.76,
Fixed,
95% CI) -14.72]
1.2 Need for continuous positive 1 Risk Ratio (M-H, Fixed, Totals not
airway pressure (yes/no) 95% CI) selected
1.3 Need for mechanical 3 254 Risk Ratio (M-H, Fixed, 0.60 [0.13, 2.86]
ventilation (yes/no) 95% CI)
1.4 Duration of hospital stay 4 338 Mean Difference (IV, -1.48 [-1.80, -1.16]
Fixed, 95% CI)
1.5 Duration of tachypnea 2 120 Mean Difference (IV, -16.83 [-22.42,

Fixed,
95% CI) -11.23]
1.6 Initiation of oral feeding 2 188 Mean Difference (IV, -28.49 [-38.14,
Fixed,
95% CI) -18.84]
1.7 Duration of respiratory 2 228 Mean Difference (IV, -9.24 [-14.24, -4.23]
support (intermittent positive Fixed, 95% CI)
pressure ventilation or
continuous positive airway
pressure)
Analysis 1.1. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 1: Duration

of oxygen therapy
Salbutamol
Control Mean Difference Mean Difference
Study or Subgroup Mean [hours] SD [hours] Total Mean [hours] SD [hours] Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI [hours]
[hours]
Kim 2014 34.2 32.2 28 77.3 64.7 12 1.4% -43.10 [-81.60 , -4.60]
Malakian 2018 30.36 19.52 74 58.92 33.87 74 25.7% -28.56 [-37.47 , -19.65]
Babaei 2019 41.8 7.77 40 60.05 18.15 40 54.5% -18.25 [-24.37 , -12.13]
Mohammadzadeh 2017 18.7 12.5 35 26 29.3 35 18.3% -7.30 [-17.85 , 3.25]
Total (95% CI)

177 161 100.0% -19.24 [-23.76 , -14.72]
Test for overall effect: Z = 8.34 (P < 0.00001)
Test for subgroup differences: Not applicable -50 -25 0 25 50
Analysis 1.2. Comparison 1: Salbutamol versus placebo/no

treatment, Outcome 2: Need for continuous positive airway
pressure (yes/no)
Salbutamol
Control Risk Ratio Risk Ratio
Study or Events Tota Events Tota M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Subgroup l l

Cochr Trusted
evidence.
Monzoy-Ventre 2015 12 31 8 15 0.73 [0.38 , 1.39]
0.05 0.2 1 5 20

Cochr Trusted
evidence.
Analysis 1.3. Comparison 1: Salbutamol versus

placebo/no treatment, Outcome 3: Need for
mechanical ventilation (yes/no)
Salbutamol
Control Risk Ratio Risk Ratio
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Malakian 2018 0 74 2 74 60.0% 0.20 [0.01 , 4.10]

Mussavi 2017 1 30 1 30 24.0% 1.00 [0.07 , 15.26]
Monzoy-Ventre 2015 1 31 0 15 16.0% 1.50 [0.06 , 34.79]
Total (95% CI)

135 11 100.0% 0.60 [0.13 , 2.86]
Total events: 9
2
3
0.02 0.1 1 10 50
Test for overall effect: Z = 0.64 (P = 0.52) Favors salbutamol Favors control
Analysis 1.4. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 4: Duration

of hospital stay
Salbutamol
Study or Subgroup Mean [days] SD [days] Tota Mean [days] SD [days] Tota Weigh IV, Fixed, 95% CI IV, Fixed, 95% CI [days]
l l t [days]
Malakian 2018 3.94 1.32 74 5.66 2.32 74 27.2% -1.72 [-2.33 , -1.11]
Babaei 2019 4.92 0.82 40 6.52 1.06 40 58.2% -1.60 [-2.02 , -1.18]
Mohammadzadeh 2017 4.8 1.2 35 5.4 2.4 35 12.7% -0.60 [-1.49 , 0.29]
Kim 2014 8.5 3.9 28 8.8 3.2 12 1.9% -0.30 [-2.62 , 2.02]
Total (95% CI) 177 161 100.0% -1.48 [-1.80 , -1.16]

Test for overall effect: Z = 9.16 (P < 0.00001) -20 -10 0 10 20
Test for subgroup differences: Not applicable Favors salbutamol Favors control
Analysis 1.5. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 5:

Duration of tachypnea
Salbutamol
Study or Subgroup Mean [hours] SD [hours] Tota Mean [hours] SD [hours] Tota Weigh IV, Fixed, 95% CI [hours] IV, Fixed, 95% CI [hours]
l l t
Kim 2014 31.3 23.7 28 53.5 56.8 12 2.8% -22.20 [-55.51 , 11.11]
Babaei 2019 34.45 8.74 40 51.12 16.09 40 97.2% -16.67 [-22.34 , -11.00]
Total (95% CI) 68

52 100.0% -16.83 [-22.42 , -11.23]
Test for subgroup differences: Not applicable -50 -25 25 50
0 Favors control
Favors salbutamol
Analysis 1.6. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 6: Initiation

of oral feeding
Study or Subgroup
Salbutamol Control Mean Difference Mean Difference
Mean SD Tota Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI
l
Malakian 2018 36.92 19.08 74 67.18 41.12 74 87.2% -30.26 [-40.59 , -19.93]
Kim 2014 12.1 19.9 28 28.5 45.9 12 12.8% -16.40 [-43.40 , 10.60] 5
Total (95% CI) 102 86 100.0% -28.49 [-38.14 , -18.84]
Cochr Trusted
evidence.
-50 -25 0 25 50

Cochr Trusted
evidence.
Analysis 1.7. Comparison 1: Salbutamol versus placebo/no treatment, Outcome 7:

Duration of respiratory support (intermittent positive pressure ventilation or
continuous positive airway pressure)
Salbutamol
Study or Subgroup Mean [hours] SD [hours] Tota Mean [hours] SD [hours] Tota Weigh IV, Fixed, 95% CI [hours] IV, Fixed, 95% CI [hours]
l l t
Malakian 2018 11.41 12.2 74 21.68 22.82 74 72.0% -10.27 [-16.17 , -4.37]
Babaei 2019 23.92 18.15 40 30.5 24.49 40 28.0% -6.58 [-16.03 , 2.87]
Total (95% CI)
114 114 100.0% -9.24 [-14.24 , -
4.23]
Test for overall effect: Z = 3.62 (P = 0.0003)
-50 -25 0 25 50
Test for subgroup differences: Not applicable Favours Salbutamol Favours Control
ADDITIONAL TABLES
Table 1. Overview of the seven included trials

Study ID
Country Mean GA Mean Salbut Notes
(no. GA a- mol
Populati (SD) (SD)
infants) on at dosea
Salbutam Contr
study
entry ol group ol
group
Arman Turkey <6 37.0 36.7 0.15 mg/kg One dose, over 20 minutes;
gil hours
2011 old weeks weeks with continuous flow of oxygen
at 5 to 6 L/min
(54) (1.6) (1.6)
Babaei 2019 Iran GA > 35 36.7 weeks 36.3 weeks 0.15 mg/kg One dose
weeks
(80) (1.1) (1.4)
Kim 2014 Korea GA > 35 37.6 weeks 37.5 weeks 0.15 mg/kg One dose, over 10 minutes;
(40 week
) s (1.9 (1.0 with continuous flow of oxygen at
) ) 5 L/min
Malakian Iran <6 37.6 37.4 0.15 mg/kg One dose; additional doses
2018 hours every 6
old weeks weeks hours for maximum 72, if needed;
(148)
(1.5) (1.9) with continuous flow of oxygen
at 5 to 6 L/min over 20 mins
Moham-
madzad Iran <6 0.15 mg/kg One dose, over 10 minutes
eh 2017 hours 256.7 258.2
old
(70) days days
(12) (14)

Cochr Trusted
evidence.
Monzoy- Mexico <6 36.2 36.6 0.10 or Three doses; every 4 hours, 3
Ven- tre hours 0.15 times
weeks
2015 old weeks mg/kg
(2.2)b;
(46)b 36.6
(2.5)
weeks
(1.7)b
Mussavi 2017 Iran GA > 37.0 weeks 36.9 weeks 0.15 mg/kg Every 6 hours for 24 hours; over
35 10
weeks minutes

Cochr Trusted
evidence.
Table 1. Overview of the seven included trials (Continued)

(60) (1.7) (1.7)
Notes:
a In all trials, interventions given via nebulization; normal saline was administered to all infants in the control group.
b In Monzoy-Ventre 2015, infants were randomized in three arms because salbutamol was given at two different doses.
GA = gestational age
IQR = interquartile
range SD = standard
deviation
APPENDICES
Appendix 1. 2020 Search strategies

PubMed
(transient tachypnea of newborn[MeSH Terms] OR transient tachypnea of newborn OR transient tachypnea OR TTN
OR TTNB OR newborn transient tachypneas OR transient tachypnoea of newborn OR transient tachypnoea) OR
transitory tachypnea OR transitory tachypnoea OR salbutamol OR albuterol OR Albuterol[Mesh])
AND
(newborn* or new born or new borns or newly born or baby* or babies or premature or prematurity or preterm or pre
term or low birth weight or low birthweight or VLBW or LBW or infant or infants or 'infant s' or infant's or infantile or
infancy or neonat*)
AND
(((((("randomized controlled trial"[Publication Type]) OR "controlled clinical trial"[Publication Type]) OR (randomized

OR randomised OR randomly OR groups OR trial OR placebo)) OR drug therapy[MeSH Terms]))) NOT ((animals [mh] NOT
humans [mh]))
Publication date filter: "2016/03/17"[PDat]: "2020/12/31"[PDat]
Embase (Elsevier)
'transient tachypnea of the newborn'/exp OR 'transient tachypnea of the newborn' OR (transient AND ('tachypnea'/exp
OR tachypnea) AND of AND the AND ('newborn'/exp OR newborn)) OR ttn OR ttnb OR 'newborn transient tachypnea'
OR (('newborn' OR 'newborn'/exp OR newborn) AND transient AND ('tachypnea' OR 'tachypnea'/exp OR tachypnea))
OR 'newborn transient tachypnoea' OR (('newborn' OR 'newborn'/exp OR newborn) AND transient AND
('tachypnoea' OR 'tachypnoea'/exp OR tachypnoea)) OR 'transient tachypnoea' OR (transient AND ('tachypnoea'
OR 'tachypnoea'/exp OR tachypnoea)) OR 'transient tachypnea' OR (transient AND ('tachypnea' OR 'tachypnea'/exp
OR tachypnea)) OR 'transitory tachypnea' OR (transitory AND ('tachypnea' OR 'tachypnea'/exp OR tachypnea))
OR 'transitory tachypnoea' OR (transitory AND ('tachypnoea' OR 'tachypnoea'/exp OR tachypnea OR salbutamol OR
'salbutamol'/exp))
AND
'newborn*':ab,ti OR 'new born':ab,ti OR 'new borns':ab,ti OR 'newly born baby*':ab,ti OR 'babies':ab,ti OR

'premature':ab,ti OR 'prematurity':ab,ti OR 'preterm':ab,ti OR 'pre term':ab,ti OR 'low birth weight':ab,ti OR 'low
birthweight':ab,ti OR 'vlbw':ab,ti OR 'lbw':ab,ti OR 'infant':ab,ti OR 'infants':ab,ti OR 'infantile':ab,ti OR
'infancy':ab,ti OR 'neonat*':ab,ti
AND
randomized OR randomised OR randomly OR groups OR trial OR placebo OR 'drug therapy' OR 'randomized controlled
trial topic'/exp OR 'randomized controlled trial'/exp OR 'controlled clinical trial'/exp OR ((single:ab,ti OR doubl*:ab,ti
OR tripl*:ab,ti OR treb*:ab,ti) AND (blind*:ab,ti OR mask*:ab,ti)) NOT (animals NOT humans)
Publication date filter [17-3-2016]/sd NOT [1-1-2021]/sd
CINAHL (Ebsco)
transient tachypnea of the newborn OR transient tachypnea OR TTN OR TTNB OR newborn transient tachypneas OR
transient tachypnoea of newborn OR transient tachypnoea OR transitory tachypnea OR transitory tachypnea
Cochr Trusted
evidence.
AND

Cochr Trusted
evidence.
(infant or infants or infant’s or infantile or infancy or newborn* or "new born" or "new borns" or "newly born" or
neonat* or baby* or babies or premature or prematures or prematurity or preterm or preterms or "pre term" or
premies or "low birth weight" or "low birthweight" or VLBW or LBW)
AND
(randomized controlled trial OR controlled clinical trial OR randomized OR randomised OR placebo OR clinical trials as
topic OR randomly OR trial OR PT clinical trial)
Publication date filter March 2016-December 2020
CENTRAL
MESH DESCRIPTOR Infant, Newborn EXPLODE OR MeSH descriptor: [Infant, Premature] explode all trees OR MeSH
descriptor: [Infant, Premature] explode all trees OR (infant OR infants OR infantile OR infancy or newborn* OR "new
born" OR "new borns" OR "newly born" OR neonat* OR baby* OR babies OR premature OR prematures OR prematurity
OR preterm OR preterms OR "pre term" OR premies OR "low birth weight" OR "low birthweight" OR VLBW OR LBW
OR ELBW OR NICU)
AND
MESH DESCRIPTOR Transient Tachypnea of The Newborn explode all trees OR transient tachypnea OR transient
tachypneas OR transient tachypnea OR transient tachypnoeas OR transitory tachypnea OR transitory tachypnoeas OR
TTN OR TTNB OR salbutamol OR albuterol
AND
(randomized controlled trial OR controlled clinical trial OR randomized OR randomised OR randomly OR trial OR
groups NOT (animals NOT humans))
Publication date filter 01032016-31122020
Clinicaltrials.gov
Search
Other
terms
Transient tachypnea
Appendix 2. Previous (2016) search strategies

CENTRAL
(transient tachypnea OR transitory tachypnea OR TTN OR TTNB) AND (infant or newborn or neonate or neonatal or
premature or very low birth weight or low birth weight or VLBW or LBW)
MEDLINE
(transient tachypnea OR transitory tachypnea OR TTN OR TTNB) AND ((infant, newborn[MeSH] OR newborn OR
neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized
controlled trial [pt] OR controlled clinical trial [pt] OR Clinical Trial[ptyp] OR randomized [tiab] OR placebo [tiab] OR
clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh]))
Embase
(transient tachypnea OR transitory tachypnea OR TTN OR TTNB) and (infant, newborn or newborn or neonate or
neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*)
and (human not animal) and (randomized controlled trial or controlled clinical trial or randomized or placebo or
clinical trials as topic or randomly or trial or clinical trial)).mp. [mp=title, abstract, subject headings, heading word,
drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]
CINAHL
(transient tachypnea OR transitory tachypnea OR TTN OR TTNB) AND (infant, newborn OR newborn OR neonate OR
neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized
controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR
trial OR PT clinical trial)

Cochr Trusted
evidence.
Pediatric Academic Societies' 2000 to 2015 Archive
"transient tachypnea" OR "transitory tachypnea" OR TTN OR TTNB

Cochr Trusted
evidence.
ClinicalTrials.gov; International Standard Randomized Controlled Trial Number (ISRCTN) registry;

Australian New Zealand Clinical Trials Registry
("transient tachypnea" OR "transitory tachypnea" OR TTN OR TTNB) AND infant
Appendix 3. 'Risk of bias' tool

1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately
generated?
For each included study, we categorized the method used to generate the allocation sequence as:
1. low risk (any truly random process e.g. random number table; computer random number generator);
2. high risk (any non-random process e.g. odd or even date of birth; hospital or clinic record number); or
3. unclear risk.
2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?
For each included study, we categorized the method used to conceal the allocation sequence as:
1. low risk (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);
2. high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); or
3. unclear risk.
3. Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the
allocated intervention adequately prevented during the study?
For each included study, we categorized the methods used to blind study participants and personnel from knowledge
of which intervention a participant received. Blinding was assessed separately for different outcomes or class of
outcomes. We categorized the methods as:
1. low risk, high risk or unclear risk for participants; and

2. low risk, high risk or unclear risk for personnel.
4. Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the
allocated intervention adequately prevented at the time of outcome assessment?
For each included study, we categorized the methods used to blind outcome assessment. Blinding was assessed
separately for different outcomes or class of outcomes. We categorized the methods as:
1. low risk for outcome assessors;

2. high risk for outcome assessors; or
3. unclear risk for outcome assessors.
5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol
deviations). Were incomplete outcome data adequately addressed?
For each included study and for each outcome, we described the completeness of data including attrition and
exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the
analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where
reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient
information was reported or supplied by the trial authors, we re-included missing data in the analyses. We
categorized the methods as:
1. low risk (< 20% missing data);

2. high risk (≥ 20% missing data); or
3. unclear risk.
6. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?
For each included study, we described how we investigated the possibility of selective outcome reporting bias and
what we found. For studies in which study protocols were published in advance, we compared prespecified outcomes
versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we
contacted study authors to gain access to the study protocol. We assessed the methods as:
1. low risk (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the
review have been reported);

Cochr Trusted
evidence.
2. high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary
outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; study
fails to include results of a key outcome that would have been expected to have been reported); or
3. unclear risk.
7. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk
of bias?
For each included study, we described any important concerns we had about other possible sources of bias (for
example, whether there was a potential source of bias related to the specific study design or whether the trial was
stopped early due to some data-dependent process). We assessed whether each study was free of other problems
that could put it at risk of bias as:
1. low risk;
2. high risk; or
3. unclear risk.
If needed, we explored the impact of the level of bias through undertaking sensitivity analyses.
WHAT'S NEW
DateEventDescription
22 April 2020 New citation required and Salbutamol administration might reduce the duration of
conclusions have changed oxygen therapy, the length of hospital stay and the
duration of tachypnea, whereas no difference in the
need for continuous positive airway pressure and for
mechanical ventilation was found (low to very low-
certainty evidence for all outcomes).
22 April 2020 New search has been performed We searched the literature in April 2020. We identified four
new
published trials and five ongoing trials.
HISTORY
Protocol first published: Issue 9, 2015
Review first published: Issue 5, 2016
CONTRIBUTIONS OF AUTHORS
LM and MB reviewed the literature and wrote the
review. MM contributed to the update of this
review.
MGC assisted in the review of literature and in writing of the review.
DECLARATIONS OF INTEREST
LM has no interest to declare.
MB has received research funding from ALF grant (non-profit - Lund University) and Crafoord Foundation (non-profit) for
research projects not related to Cochrane.
MM has no interest to declare.
MGC has no interest to
declare.
SOURCES OF SUPPORT

Cochr Trusted
evidence.
Internal sources
• Pediatric and Neonatology Unit, Ospedale San Paolo,
Savona, Italy LM is employed by this organization

Cochr Trusted
evidence.
• Institute for Clinical Sciences, Lund University, Lund,
Sweden MB is employed by this organization.

• Istituto Giannina Gaslini, Genoa,
Italy MGC is employed by this
organization.
External sources
• Vermont Oxford Network, USA
Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide
collaboration of health professionals dedicated to providing evidence-based care of the highest quality for
newborn infants and their families.
• Region Skåne, Skåne University Hospital, Lund University and Region Västra Götaland, Sweden
Cochrane Sweden is supported from Region Skåne, Skåne University Hospital Lund University and Region Västra
Götaland
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

1. Differences between the review published in 2016 (Moresco 2016), and the version updated in 2020:
a. we now refer to the certainty of the evidence;
b. 'risk of bias' language updated;
c. for the 2020 update, we developed a new search strategy. The previous search methods are available in Appendix
2;
2. Differences between the protocol (Moresco 2015), and the review published in 2016 (Moresco 2016):
a. we deleted the comparison between salbutamol and ventilation strategies (in Objectives and Types of
interventions); we added the methodology and plan for 'Summary of findings' tables and GRADE
recommendations, which were not included in the original protocol (see Summary of findings 1).
INDEX TERMS
Medical Subject Headings (MeSH)

Adrenergic beta-2 Receptor Agonists [*therapeutic use]; Albuterol [*therapeutic use]; Continuous Positive Airway
Pressure [statistics & numerical data]; Intermittent Positive-Pressure Ventilation [statistics & numerical data]; Length
of Stay [statistics & numerical data]; Nebulizers and Vaporizers; Oxygen Inhalation Therapy [statistics & numerical
data]; Randomized Controlled Trials as Topic; Time Factors; Transient Tachypnea of the Newborn [*drug therapy]
MeSH check words

Humans; Infant, Newborn


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Cochrane

Salbutamol for transient tachypnea of the newborn

Moresco L, Bruschettini M, Macchi M, Calevo MG

Moresco L, Bruschettini M, Macchi M, Calevo MG.

Salbutamol for transient tachypnea of the newborn (Review)

Copyright © 2021 The Cochrane Collaboration. Published by John

Salbutamol for transient tachypnea of the newborn (Review) i

Copyright © 2021 The Cochrane Collaboration. Published by John

Salbutamol for transient tachypnea of the newborn

Luca Moresco1, Matteo Bruschettini2,3, Marina Macchi4, Maria Grazia Calevo5

Contact: Matteo Bruschettini, matteo.bruschettini@med.lu.se, matbrus@gmail.com.

Editorial group: Cochrane Neonatal Group.

Data collection and analysis

Salbutamol for transient tachypnea of the newborn (Review) 1

Salbutamol for transient tachypnea of the newborn (Review) 2

PLAIN LANGUAGE SUMMARY

Salbutamol for transient tachypnea of the newborn (Review) 3

of the newborn Patient or population: patients with transient

tachypnea of the newborn

Outcomes Illustrative comparative risks* (95% CI) Relative No of Certainty of Comments

Need for continuous Study RR 0.73 46 ⊕⊝⊝⊝

Medium risk population

533 per 1000 389 per 1000

Cochrane Database of Systematic

Need for mechanical Study RR 0.6 254 ⊕⊝⊝⊝

Medium risk population

27 per 1000 16 per 1000

Pneumothorax (yes/no) RR without

GRADE Working Group grades of evidence

Cochrane Database of Systematic

BACKGROUND salbutamol increases the activity and expression of

Description of the intervention

Salbutamol for transient tachypnea of the newborn (Review) 5

1. experimental studies in ex-vivo human lungs

Moreover, one double-blind controlled trial

Why it is important to do this review

Many supportive therapies have been proposed, such

Salbutamol for transient tachypnea of the newborn (Review) 7

Salbutamol for transient tachypnea of the newborn (Review) 8

We resolved any disagreements by discussion. We

Two review authors (MGC, MM) used Cochrane's

Assessment of risk of bias in included studies

1. Sequence generation (selection bias);

We resolved any disagreements by discussion or by a

See Appendix 3 for the complete 'Risk of bias' tool.

Measures of treatment effect

Unit of analysis issues

We interpreted the I2 statistic as described by Higgins

1. less than 25%: no heterogeneity;

We considered statistical heterogeneity to be

Assessment of reporting biases

Salbutamol for transient tachypnea of the newborn (Review) 1

1. Gestational age: term (37 weeks or greater) versus

Salbutamol for transient tachypnea of the newborn (Review) 1

Salbutamol for transient tachypnea of the newborn (Review) 1

We identified five ongoing trials

Four studies were conducted in Iran (Babaei 2019;

Four studies used one single dose of salbutamol

Armangil 2011 included 54 infants with transient

Salbutamol for transient tachypnea of the newborn (Review) 1