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. 2021 Feb 5;2021(2):CD011878. doi: 10.1002/14651858.CD011878.pub3

Salbutamol for transient tachypnea of the newborn

Luca Moresco 1, Matteo Bruschettini 2,5,✉, Marina Macchi 3, Maria Grazia Calevo 4
Editor: Cochrane Neonatal Group
PMCID: PMC8094231  PMID: 33543473

Abstract

Background

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 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, 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.

Keywords: Humans; Infant, Newborn; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-2 Receptor Agonists/therapeutic use; Albuterol; Albuterol/therapeutic use; Continuous Positive Airway Pressure; Continuous Positive Airway Pressure/statistics & numerical data; Intermittent Positive-Pressure Ventilation; Intermittent Positive-Pressure Ventilation/statistics & numerical data; Length of Stay; Length of Stay/statistics & numerical data; Nebulizers and Vaporizers; Oxygen Inhalation Therapy; Oxygen Inhalation Therapy/statistics & numerical data; Randomized Controlled Trials as Topic; Time Factors; Transient Tachypnea of the Newborn; Transient Tachypnea of the Newborn/drug therapy

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

Summary of findings 1. Salbutamol versus placebo/no treatment for transient tachypnea of the newborn.

Salbutamol versus placebo/no treatment for transient tachypnea of the newborn
Patient or population: patients with transient tachypnea of the newborn
Settings: neonatal units in Iran (4 trials), Korea (1 trial), Mexico (1 trial) and Turkey (1 trial); See Table 2.
Intervention: salbutamol versus placebo/no treatment
Outcomes Illustrative comparative risks* (95% CI) Relative effect
(95% CI) No of Participants
(studies) Certainty of the evidence
(GRADE) Comments
Assumed risk Corresponding risk
Control Salbutamol versus placebo/no treatment
Duration of oxygen therapy (hours) range 26 to 77 The mean duration of oxygen therapy (hours) in the intervention groups was
19.24 lower
(23.76 to 14.72 lower)   338
(4 studies) ⊕⊝⊝⊝
very low1,2,3  
Need for continuous positive airway pressure (yes/no) Study population RR 0.73 
(0.38 to 1.39) 46
(1 study) ⊕⊝⊝⊝
very low1,4  
533 per 1000 389 per 1000
(203 to 741)
Medium risk population
533 per 1000 389 per 1000
(203 to 741)
Need for mechanical ventilation (yes/no) Study population RR 0.6 
(0.13 to 2.86) 254
(3 studies) ⊕⊝⊝⊝
very low1,4  
25 per 1000 15 per 1000
(3 to 71)
Medium risk population
27 per 1000 16 per 1000
(4 to 77)
Duration of respiratory support (intermittent positive pressure ventilation or continuous positive airway pressure; hours). range 22‐30 The mean duration of respiratory support (intermittent positive
pressure ventilation or continuous positive airway pressure; hours). in the intervention groups was
9.24 lower
(14.24 to 4.23 lower)		   228
(2 studies) ⊕⊝⊝⊝
very low1,4  
Duration of hospital stay (days) range 5‐9 The mean duration of hospital stay (days) in the intervention groups was
1.48 lower
(1.8 to 1.16 lower)   338
(4 studies) ⊕⊕⊝⊝
low1,3  
Duration of mechanical ventilation (hours)   Not reported   Not reported    
Pneumothorax (yes/no)   One study reported no differences however without providing the number of events RR not measurable 80
(1 study)		 ⊕⊝⊝⊝
very low1,5  
*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
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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; I² > 50%)
3 Downgraded by one level for imprecision due to low sample size 
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

1. Overview of the seven included trials.

Study ID
(no. infants) 		Country Population at
study entry 		Mean GA (SD)
Salbutamol
group 		Mean GA (SD)
Control
group 		Salbutamol
dosea 		Notes
Armangil 2011
(54) 		 Turkey  < 6 hours old 37.0 weeks
(1.6)		  36.7 weeks
(1.6)		 0.15 mg/kg One dose, over 20 minutes;
with continuous flow of oxygen at 5 to 6 L/min
 
Babaei 2019
(80) 		Iran GA > 35 weeks 36.7 weeks
(1.1)		 36.3 weeks
(1.4)		 0.15 mg/kg One dose
Kim 2014
(40) 		 Korea  GA > 35 weeks 37.6 weeks
(1.9)		 37.5 weeks
(1.0)		 0.15 mg/kg One dose, over 10 minutes;
with continuous flow of oxygen at 5 L/min
 
Malakian 2018
(148) 		 Iran  < 6 hours old 37.6 weeks
(1.5)		 37.4 weeks
(1.9)		 0.15 mg/kg One dose; additional doses every 6 hours for maximum 72, if needed;
with continuous flow of oxygen at 5 to 6 L/min over 20 mins
Mohammadzadeh 2017
(70)  		 Iran  < 6 hours old 256.7 days
(12)		 258.2 days
(14)		 0.15 mg/kg One dose, over 10 minutes
 
Monzoy‐Ventre 2015
(46)b 		 Mexico  < 6 hours old 36.2 weeks (2.2)b; 
36.6 weeks
(1.7)b 		36.6 weeks
(2.5)		 0.10 or 0.15 mg/kg Three doses; every 4 hours, 3 times
 
Mussavi 2017
(60) 		 Iran  GA > 35 weeks 37.0 weeks
(1.7)		 36.9 weeks
(1.7)		 0.15 mg/kg Every 6 hours for 24 hours; over 10 minutes
 
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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

Background

Description of the condition

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 salbutamol increases the activity and expression of epithelial sodium channels and sodium‐potassium adenosine triphosphatase at the plasmatic membrane (Minakata 1998).

How the intervention might work

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 safe for infants born at 34 weeks’ gestational age with this diagnosis.

Methods

Criteria for considering studies for this review

Types of studies

We included prospective randomized controlled trials (RCTs), and quasi‐randomized trials. We planned to include cluster‐RCTs if the definition of participants and clusters was sufficiently clear. We excluded cross‐over trials.

Types of participants

We included infants with transient tachypnea of the newborn, without any respiratory support prior to study entry who were born at 34 weeks' or more gestational age and less than three days of age.

Diagnostic criteria of transient tachypnea of the newborn included tachypnea and imaging studies characterized by nonspecific signs, such as increased lung volumes with flat diaphragms, mild cardiomegaly and prominent vascular markings in a sunburst pattern originating at the hilum.

We excluded infants with pneumonia, surfactant deficiency, aspiration syndromes, congenital diaphragmatic hernia, pneumothorax, and congenital heart disease.

Types of interventions

Salbutamol compared to placebo, no treatment or any other drugs (e.g. epinephrine, diuretics, steroids) administered  to treat transient tachypnea of the newborn, in the first three days of life.

We included any dose, mode of administration (oral aerosolized or intravenous) and duration of therapy.

Types of outcome measures

Primary outcomes

  1. Duration of oxygen therapy (hours).

  2. Need for continuous positive airway pressure (yes/no).

  3. Need for mechanical ventilation (yes/no).

Secondary outcomes

  1. Duration of mechanical ventilation (intermittent positive pressure ventilation; hours).

  2. Duration of respiratory support (intermittent positive pressure ventilation or continuous positive airway pressure; hours).

  3. Duration of hospital stay (days).

  4. Duration of tachypnea (hours), defined as respiratory rate greater than 60 breaths per minute.

  5. Initiation of oral feeding (days).

  6. Persistent pulmonary hypertension (yes/no), either diagnosed clinically or by at least one of the following echocardiographic findings (or both): high right ventricular systolic pressure, right to left or bidirectional shunt at patent foramen ovale or patent ductus arteriosus, severe tricuspid regurgitation.

  7. Pneumothorax (yes/no), diagnosis on chest X‐ray.

Search methods for identification of studies

Electronic searches

We used the criteria and standard methods of Cochrane and Cochrane Neonatal. We undertook a comprehensive search in the following electronic sources:

  1. the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 4) in the Cochrane Library;

  2. PubMed (January 1996 to 22 April 2020);

  3. Embase (January 1980 to 22 April 2020);

  4. CINAHL (1982 to 22 April 2020);

For the 2020 update, we developed a new search strategy (Appendix 1). The previous search methods (2016) are available in Appendix 2.

We did not apply any language restrictions. We also screened the reference lists of any cited articles.

Searching other resources

We searched clinical trials registries for ongoing or recently completed trials (e.g. ClinicalTrials.gov (clinicaltrials.gov/), and, for the 2016 search (Moresco 2016), the International Standard Randomized Controlled Trial Number (ISRCTN) registry (www.controlled-trials.com/).

Data collection and analysis

We used the standard methods of Cochrane Neonatal, as described below.

Selection of studies

Two review authors (LM, MB) independently searched and identified eligible trials that met the inclusion criteria. We screened the titles and abstracts to identify potentially relevant citations, and retrieved the full texts of all potentially relevant articles. We independently assessed the eligibility of the studies by filling out eligibility forms designed in accordance with the specified inclusion criteria. We reviewed studies for relevance based on study design, types of participants, interventions and outcome measures. We resolved any disagreements by discussion and, if necessary, by consulting a third review author (MGC). We planned to provide details of studies excluded from the review in the 'Characteristics of excluded studies' table along with the reasons for exclusion. We contacted the trial authors if the details of the primary trials were unclear.

Data extraction and management

Two review authors (LM, MB) independently extracted data using a data extraction form developed ad hoc and integrated with a modified version of the Cochrane Effective Practice and Organisation of Care Group data collection checklist (Cochrane EPOC Group 2013).

We extracted the following characteristics from each included study.

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

  2. Details of the study: study design; type, duration and completeness of follow‐up (i.e. greater than 80%); country and location of study informed consent and ethics approval.

  3. Details of participants: sex, birth weight, gestational age, and number of participants.

  4. Details of intervention: modality of administration, 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 Systematic Reviews of Interventions (Higgins 2019).

Dealing with missing data

We planned to determine the dropout rate for each trial (and each trial outcome). We planned to consider a dropout rate that was equal to or greater than the event rate of the control group significant. We planned to perform a sensitivity analysis to evaluate the overall results with and without the inclusion of studies with significant dropout rates. If a trial reported outcomes only for participants completing the trial or only for participants who 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 inappropriate.

Subgroup analysis and investigation of heterogeneity

We planned to carry out the following subgroup analyses:

  1. Gestational age: term (37 weeks or greater) versus late preterm infants (34 weeks to less than 37 weeks).

  2. Birth weight: less than 2500 g versus 2500 g or greater.

  3. Mode of delivery: vaginal versus cesarean section.

  4. Route of administration: inhaled versus systemic administration.

  5. Dosage: single versus multiple doses.

Sensitivity analysis

We planned to conduct sensitivity analyses to explore the effect of the methodologic quality of the trials, checking to ascertain if studies with a high risk of bias overestimated the effect of treatment.

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach as outlined in the GRADE Handbook (Schünemann 2013) to assess the certainty of evidence for the following outcomes identified as critical or important for clinical decision‐making: need for continuous positive airway pressure, need for mechanical ventilation, duration of mechanical ventilation, duration of respiratory support, duration of oxygen therapy, duration of hospital stay, and pneumothorax.

Two review authors (MGC, MM) independently assessed the certainty of the evidence for each of the outcomes above. We considered evidence from RCTs as high certainty but downgraded the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias. We used the GRADEpro GDT Guideline Development Tool to create ‘Table 1 to report the certainty of the evidence.

The GRADE approach results in an assessment of the certainty of a body of evidence as one of four grades.

  1. High certainty: further research is very unlikely to change our confidence in the estimate of effect.

  2. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

  3. 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.

  4. Very low certainty: we are very uncertain about the estimate.

Results

Description of studies

We have provided results of the search for this review update in the study flow diagram (Figure 1).

1.

1

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See Characteristics of included studies and Characteristics of ongoing studies tables.

Results of the search

We searched the databases in April 2020 and identified 1102 references for the updated review (Figure 1). After screening, we added four new RCTs (Babaei 2019; Malakian 2018; Mohammadzadeh 2017; 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 2.

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 salbutamol 4 mL (Ventolin Nebules 2.5 mg) in 0.9% saline solution. The standard dose of salbutamol was 0.15 mg/kg. The study authors evaluated the following parameters after four hours of administration: clinical score of transient tachypnea of the newborn, respiratory rate, heart rate, fraction of inspired oxygen (FiO2), partial pressure of oxygen in arterial blood (PaO2), partial pressure of carbon dioxide in arterial blood (PaCO2), pH, serum potassium ions (K+), and serum glucose values.

Babaei 2019 enrolled 80 neonates with a gestational age of at least 35 weeks, and physical examination and radiologic findings suggesting transient tachypnea of the newborn diagnosis in the NICU of Imam Reza Hospital in Kermanshah, Iran, during 2017. The newborns with a history of meconium aspiration, respiratory distress syndrome, 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 infection (positive blood culture), meconium aspiration, respiratory distress syndrome (based on the radiographs), intrauterine growth retardation, history of fetal distress, pneumonitis, congenital heart disease, disseminated intravascular coagulation (DIC), multi‐organ failure, hypoxemia, hypoglycemia, and polycythemia. The considered outcomes were the duration of hospitalization, time of oral feeding initiation, duration of oxygen therapy, need for nasal CPAP therapy, and mechanical ventilation.

Mohammadzadeh 2017 studied 70 neonates enrolled in this double‐blinded randomized clinical trial conducted from June through December 2014 in three urban tertiary care centers of Babol, North of Iran. The neonates born at 34 weeks of gestational age and older who were diagnosed with transient tachypnea of the newborn in the first six hours of life were eligible for inclusion in this study. Exclusion criteria consisted of gestational age less than 34 weeks, congenital gross anomalies, neonates born with meconium aspiration, birth trauma or asphyxia, chorioamnionitis, positive history of mother(s) receiving corticosteroid during seven days before birth, neonatal sepsis (positive blood culture, positive CRP, radiologic findings consistent with pneumonia), persistent pulmonary hypertension of neonate, respiratory distress syndrome (RDS), neonates with a confirmed metabolic disorder (e.g. hypoglycemia, hypokalemia, etc.), and neonatal cardiovascular disease (diagnosed with echocardiography). The intervention group received 0.15 mL/kg (equal to 0.15 mg/kg) inhaled salbutamol plus 4 mL normal saline 0.9% by nebulizer within 10 minutes. The placebo group received 0.15 mL/kg normal saline 0.9% plus 4 mL normal saline 0.9% by nebulizer within 10 minutes. The primary objective was to assess the effect of salbutamol on major clinical outcomes including duration of oxygen therapy and improvement of respiratory symptoms. The secondary outcomes were: the time of initiation of first enteral feeding and duration of hospitalization.

Monzoy‐Ventre 2015 studied 46 newborn infants of 34 to 42 weeks of gestational age with transient tachypnea of the newborn. Inclusion criteria were: respiratory distress less than six hours after birth which persisted for 12 hours (i.e. respiratory rate greater than 60 breaths per minute, grunting, nasal flaring or retraction); and typical chest radiography findings (i.e. fluid in minor fissures, hyperinflation and prominent vascular/perihilar markings). Exclusion criteria were: meconium aspiration; other causes of tachypnea (e.g. neonatal respiratory distress syndrome and pneumonia); and early‐onset neonatal sepsis. Newborns were randomized to receive one nebulized dose of 0.9% normal saline solution or salbutamol 0.15 mg/kg in 0.9% saline solution or salbutamol 0.10 mg/kg in 0.9% saline solution. The analysis combined the two treatment groups (31 newborns) versus the controls (15 newborns). The primary outcome was improvement of tachypnea (respiratory rate, Silverman test, oxygen saturation, PaO2, PaCO2). The secondary outcome was safety of nebulized salbutamol (heart rate and blood glucose concentration). This study was translated from Spanish by the authors of the present review.

Mussavi 2017 included 60 neonates with transient tachypnea of the newborn and respiratory distress score > 4 and < 10 enrolled in the NICU of Taleghani hospital in Tabriz, Iran from August to December 2015. Exclusion criteria were: meconium aspiration, other causes of tachypnea (i.e. respiratory distress syndrome, persistent pulmonary hypertension, pneumonia, sepsis, neonates under the age of 35 weeks, polycythemia, or hypoglycemia), congenital heart diseases, and tachycardia (heart rate more than 180/min) or arrhythmia, and infants with respiratory distress score less than 5 and more than 10. The treatment group received 0.15 mg/kg albuterol in 2 mL of normal saline, and the 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. The main objective of this study was to evaluate the effectiveness of nebulized albuterol in reducing respiratory distress as well as the neediness for respiratory continuous positive airway pressure (CPAP) support in infants suffering from transient tachypnea of the newborn. The secondary objective was to assess the safety and possible side effects of nebulized albuterol in the treatment of transient tachypnea of the newborn.

Excluded studies

None of the other identified studies was potentially eligible.

Risk of bias in included studies

Figure 2 and Figure 3 summarize the risk of bias of the trials included in this updated review.

2.

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Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.

3.

3

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Risk of bias summary: review authors' judgments about each risk of bias item for each included study.

Allocation

In Babaei 2019 and Malakian 2018, the randomization sequence was generated through a random number table, while in Mussavi 2017 it was computer‐generated. Four studies did not provide information on how the random sequence was generated (Armangil 2011; Kim 2014; Mohammadzadeh 2017; Monzoy‐Ventre 2015). In addition, in two studies there was also imbalance in participants across groups (more infants in the salbutamol arm) (Armangil 2011; Kim 2014).

None of the included trials provided sufficient information on allocation concealment (opaque, numbered envelopes); we judged them at unclear risk.

Blinding

In Armangil 2011, parents and investigators remained blinded to the administered medications throughout the study period. In Malakian 2018, all assistants, NICU nurses, patients, physicians, and statistics experts remained blinded to the administered medications throughout the study period. Kim 2014 and Mohammadzadeh 2017 reported that double‐blinding was provided however who was blinded and who was not blinded was not clearly reported. In Mussavi 2017, both salbutamol and placebo were prepared and presented similarly in shape and color coded by a single person who was not involved in infants’ care.

Two studies did not provide sufficient information about blinding of the intervention (Babaei 2019; Monzoy‐Ventre 2015).

Incomplete outcome data

Most trials reported outcomes for all randomized infants (no dropouts). However, Armangil 2011 was characterized by a significant imbalance between the number of newborns in the intervention and the control group; it was unclear whether this was due to randomization itself or participants lost to follow‐up.

Selective reporting

In one trial (Mohammadzadeh 2017), no deviations from the original protocol were found. In four trials (Armangil 2011; Babaei 2019; Kim 2014; Monzoy‐Ventre 2015), protocols were not available and, in two trials, there were discrepancies between the outcomes listed in the protocol and in the final publication (Malakian 2018; Mussavi 2017).

Other potential sources of bias

The included trials appeared free of other biases.

Effects of interventions

See: Table 1

We identified seven trials that included 498 newborns and compared salbutamol to placebo (saline) (Armangil 2011; Babaei 2019; Kim 2014; Malakian 2018; Mohammadzadeh 2017; Monzoy‐Ventre 2015; Mussavi 2017). However, Armangil 2011 expressed data as medians and could not be pooled in the analyses.

Salbutamol versus placebo or no treatment

Primary outcomes
Duration of oxygen therapy (outcome 1.1)

Four trials (N = 338) (Babaei 2019; Kim 2014; Malakian 2018; Mohammadzadeh 2017), reported duration of oxygen therapy (MD ‐19.24 hours, 95% CI ‐23.76 to ‐14.72; I2 = 72%; 4 studies, 338 infants; Analysis 1.1; Figure 4). The certainty of the evidence (GRADE) was very low due to study limitations (risk of bias), inconsistency in effect estimates (high heterogeneity) and imprecision of the estimates due to low sample size.

1.1. Analysis.

1.1

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Comparison 1: Salbutamol versus placebo/no treatment, Outcome 1: Duration of oxygen therapy

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Forest plot of comparison: 1 Salbutamol versus placebo, outcome: 1.1 Duration of oxygen therapy (hours).

Need for continuous positive airway pressure (yes/no) (outcome 1.2)

Monzoy‐Ventre 2015 reported need for continuous positive airway pressure (RR 0.73, 95% CI 0.38 to 1.39; RD ‐0.15, 95% CI ‐0.45 to 0.16; 1 study, 46 infants). We obtained data for this outcome directly from the trial authors. The test for heterogeneity was not 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.

1.2. Analysis.

1.2

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Comparison 1: Salbutamol versus placebo/no treatment, Outcome 2: Need for continuous positive airway pressure (yes/no)

5.

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Forest plot of comparison: 1 Salbutamol versus placebo, outcome: 1.2 Need for continuous positive airway pressure (yes/no).

Babaei 2019 reported that they had not observed any significant difference between the two groups but did not report the percentages.

Need for mechanical ventilation (yes/no) (outcome 1.3)

Three trials (N = 254) (Malakian 2018; Monzoy‐Ventre 2015; Mussavi 2017), reported this outcome (typical RR 0.60, 95% CI 0.13 to 2.86; typical RD ‐0.01, 95% CI ‐0.05 to 0.03; I2 = 0% for RR and RD; 3 studies; 254 participants; Analysis 1.3; Figure 6). 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.

1.3. Analysis.

1.3

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Comparison 1: Salbutamol versus placebo/no treatment, Outcome 3: Need for mechanical ventilation (yes/no)

6.

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Forest plot of comparison: 1 Salbutamol versus placebo, outcome: 1.3 Need for mechanical ventilation (yes/no).

Babaei 2019 reported that they had not observed any 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 ‐1.80 to ‐1.16; I² = 47%; 4 studies, 338 infants; Analysis 1.4)

1.4. Analysis.

1.4

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Comparison 1: Salbutamol versus placebo/no treatment, Outcome 4: Duration of hospital stay

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; I² = 0%; 2 studies, 120 infants; Analysis 1.5).

1.5. Analysis.

1.5

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Comparison 1: Salbutamol versus placebo/no treatment, Outcome 5: Duration of tachypnea

Initiation of oral feeding (outcome 1.6)

Kim 2014 and Malakian 2018 reported this outcome (MD ‐28.49 days, 95% CI ‐38.14 to ‐18.84; I² = 0%; 2 studies, 188 infants; Analysis 1.6).

1.6. Analysis.

1.6

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Comparison 1: Salbutamol versus placebo/no treatment, Outcome 6: Initiation of oral feeding

Duration of respiratory support (intermittent positive pressure ventilation or continuous positive airway pressure) (outcome 1.7)

Babaei 2019 and Malakian 2018 reported this outcome (MD ‐9.24 hours, 95% CI ‐14.24 to ‐4.23; I² = 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).

1.7. Analysis.

1.7

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Comparison 1: Salbutamol versus placebo/no treatment, Outcome 7: Duration of respiratory support (intermittent positive pressure ventilation or continuous positive airway pressure)

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 reduce duration of hospital stay. Five trials are ongoing.

Overall completeness and applicability of evidence

The available evidence was insufficient to determine whether salbutamol is an effective treatment of transient tachypnea of the newborn in infants born at 34 weeks' gestational age or more. There were insufficient data available to assess the primary outcomes of this review, and other important outcomes such as duration of tachypnea and hospital stay. We could not perform an a priori subgroup analysis (gestational age, birth weight, mode of delivery, route of administration and dosage) to detect differential effects because of the paucity of included trials.

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 Table 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.

Implications for research.

Future trials should be undertaken including different doses and schedules of salbutamol administration, as efficacy of high doses of intravenous and nebulized salbutamol have been reported to reduce pulmonary edema in adults (Licker 2008; Perkins 2006). Moreover, nebulized salbutamol might be compared with systemic administration, other pharmacologic interventions (e.g. epinephrine and diuretics) or non‐invasive ventilation strategies. In the five ongoing trials, salbutamol will be administered by nebulization at a dose ranging from 0.15 to 1 mg/kg bodyweight. Non‐randomized studies would be useful to identify safety data.

What's new

Date Event Description
22 April 2020 New citation required and conclusions have changed Salbutamol administration might reduce the duration of 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.
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History

Protocol first published: Issue 9, 2015
Review first published: Issue 5, 2016

Acknowledgements

We thank Maria Björklund (Library and ICT services, Lund University) for defining and running the search strategy of this review.

We thank Marìa Alejandra Monzoy‐Ventre for providing additional data.

We would like to thank Cochrane Neonatal: Roger Soll (Co‐co‐ordinating editor) for his valuable advice, Colleen Ovelman (Managing Editor), and Jane Cracknell (Assistant Managing Editor) for their kind and efficient support.

As a Cochrane Neonatal Associate Editor, Sarah Hodgkinson has peer reviewed and offered feedback for this review.

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

AND

(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)

Pediatric Academic Societies' 2000 to 2015 Archive

"transient tachypnea" OR "transitory tachypnea" OR TTN OR TTNB

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);

  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.

Data and analyses

Comparison 1. Salbutamol versus placebo/no treatment.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1.1 Duration of oxygen therapy 4 338 Mean Difference (IV, Fixed, 95% CI) ‐19.24 [‐23.76, ‐14.72]
1.2 Need for continuous positive airway pressure (yes/no) 1   Risk Ratio (M‐H, Fixed, 95% CI) Totals not selected
1.3 Need for mechanical ventilation (yes/no) 3 254 Risk Ratio (M‐H, Fixed, 95% CI) 0.60 [0.13, 2.86]
1.4 Duration of hospital stay 4 338 Mean Difference (IV, Fixed, 95% CI) ‐1.48 [‐1.80, ‐1.16]
1.5 Duration of tachypnea 2 120 Mean Difference (IV, Fixed, 95% CI) ‐16.83 [‐22.42, ‐11.23]
1.6 Initiation of oral feeding 2 188 Mean Difference (IV, Fixed, 95% CI) ‐28.49 [‐38.14, ‐18.84]
1.7 Duration of respiratory support (intermittent positive pressure ventilation or continuous positive airway pressure) 2 228 Mean Difference (IV, Fixed, 95% CI) ‐9.24 [‐14.24, ‐4.23]
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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Armangil 2011.

Study characteristics
Methods Double‐blind randomized controlled trial
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;

  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 generation (selection bias) High risk No information provided on sequence generation; imbalance in participants across groups (more in salbutamol arm)
Allocation concealment (selection bias) Unclear risk No information provided
Blinding of participants and personnel (performance bias)
All outcomes Low risk Parents and investigators remained blinded to the administered medications throughout the study period.
Blinding of outcome assessment (detection bias)
All outcomes Low risk Investigators remained blinded to the administered medications throughout the study period.
Incomplete outcome data (attrition bias)
All outcomes Unclear risk Extreme imbalance between the number of newborns in the intervention and the control group: unclear whether due to randomization itself or participants lost to follow‐up
Selective reporting (reporting bias) Unclear risk The trial was not registered and there was no protocol available. 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
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Babaei 2019.

Study characteristics
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;

  6. early onset sepsis;

  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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Random number table
Allocation concealment (selection bias) Unclear risk No details available
Blinding of participants and personnel (performance bias)
All outcomes Unclear risk No information provided
Blinding of outcome assessment (detection bias)
All outcomes Unclear risk No information provided
Incomplete outcome data (attrition bias)
All outcomes Low risk All participants accounted for
Selective reporting (reporting bias) Unclear risk The secondary outcomes were not reported in the protocol.
Other bias Low risk Appeared free of other bias
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Kim 2014.

Study characteristics
Methods Double‐blind clinical trial
Single‐center: NICU of Dong‐A Medical Center, Busan, Korea, between January 2010 and December 2010
Participants 40 newborns (28 in the salbutamol group, 12 in the control group)
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:

  1. meconium aspiration;

  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.
Notes Limited power to address clinically relevant outcomes
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk No information provided on sequence generation; imbalance in participants across groups (more in salbutamol arm)
Allocation concealment (selection bias) Unclear risk No information provided
Blinding of participants and personnel (performance bias)
All outcomes Low risk Infants were randomly allocated in a double‐blind manner to receive 1 dose of 2 mL nebulized 0.9% normal saline (placebo) or 0.1 mL salbutamol (ventolin respiratory solution, salbutamol sulfate 5 mg/mL; GlaxoSmithKline Inc. UK) in 2 mL of 0.9% normal saline.
Blinding of outcome assessment (detection bias)
All outcomes Unclear risk No information provided
Incomplete outcome data (attrition bias)
All outcomes Low risk Extreme imbalance between the number of newborns in the intervention and the control group: unclear whether due to randomization itself or participants lost to follow‐up
Selective reporting (reporting bias) Unclear risk The trial was not registered and no protocol was available. 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
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Malakian 2018.

Study characteristics
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
Participants 148 newborns (74 in the salbutamol group, 74 in the control group)
Inclusion criteria:

  1. newborns with TTN were enrolled.


The following symptoms were assessed in all patients with TTN based on the clinical and paraclinical 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.


Exclusion criteria:

  1. the need for mechanical ventilation;

  2. congenital malformation;

  3. perinatal asphyxia;

  4. hypocalcemia;

  5. confirmed systemic infection (positive blood culture);

  6. meconium aspiration;

  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. hypoxemia;

  15. hypoglycemia;

  16. polycythemia.
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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk The eligible cases were randomly assigned into one of the study groups using a table of random numbers.
Allocation concealment (selection bias) Unclear risk No details available
Blinding of participants and personnel (performance bias)
All outcomes Low risk Patients were cared for by the assistants and NICU nurses who were blind to the study objectives and nature of the groups. All patients, physicians, and statistics experts were blind to the drug and placebo preparations and administrations, as well as treatment procedures.
Blinding of outcome assessment (detection bias)
All outcomes Low risk Patients were cared for by the assistants and NICU nurses who were blind to the study objectives and nature of the groups. All patients, physicians, and statistics experts were blind to the drug and placebo preparations and administrations, as well as treatment procedures.
Incomplete outcome data (attrition bias)
All outcomes Low risk All participants accounted for
Selective reporting (reporting bias) High risk Trial protocol registered retrospectively (IRCT2017062129336N3); discrepancy between the outcomes reported in the protocol and in the final publication
Other bias Low risk Appeared free of other bias
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Mohammadzadeh 2017.

Study characteristics
Methods This double‐blinded randomized clinical trial was conducted in 2014 in three urban tertiary care centers of Babol, North of Iran.
Participants 70 newborns (35 in the salbutamol group, 35 in the placebo group)
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, pulmonary 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 manufactured 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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk The exact method of random generation not mentioned
Allocation concealment (selection bias) Unclear risk No details available
Blinding of participants and personnel (performance bias)
All outcomes Low risk Double‐blinded randomized clinical trial
Blinding of outcome assessment (detection bias)
All outcomes Unclear risk Blinding of outcome assessors was not explicit.
Incomplete outcome data (attrition bias)
All outcomes Low risk All participants accounted for
Selective reporting (reporting bias) Low risk The trial was registered (IRCT2014062518232N1) and protocol was available.
Other bias Low risk Appeared free of other bias
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Monzoy‐Ventre 2015.

Study characteristics
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:

  1. meconium aspiration;

  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: 2.5 mL nebulized saline solution
The 2 treatment groups (31 newborns) were combined for analysis vs. controls (15 newborns)
All received nebulization every 4 hours 3 times.
Outcomes

  1. Respiratory rate

  2. Heart rate

  3. FiO2,

  4. PaO2

  5. PaCO2
Notes Limited power to address clinically relevant outcomes
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk No information provided
Allocation concealment (selection bias) Unclear risk No information provided
Blinding of participants and personnel (performance bias)
All outcomes Unclear risk No information provided
Blinding of outcome assessment (detection bias)
All outcomes Unclear risk No information provided
Incomplete outcome data (attrition bias)
All outcomes Low risk All reported outcomes provided with complete results
Selective reporting (reporting bias) Unclear risk The trial was not registered and no protocol was available. 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
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Mussavi 2017.

Study characteristics
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.
Participants 60 newborns (30 in the salbutamol group, 30 in the placebo group)
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 vascular/perihilar markers).


Exclusion criteria:

  1. meconium aspiration;

  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
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk All enrolled neonates were randomly (computer‐generated) allocated into 2 groups of treatment and placebo.
Allocation concealment (selection bias) Unclear risk No information provided
Blinding of participants and personnel (performance bias)
All outcomes Low risk Infants were randomly allocated in the groups by staff who were not involved in the infant’s care.
Blinding of outcome assessment (detection bias)
All outcomes Unclear risk No information provided
Incomplete outcome data (attrition bias)
All outcomes Low risk All participants accounted for
Selective reporting (reporting bias) High risk The outcomes reported did not match those specified in the protocol.
Other bias Low risk Appeared free of other bias
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b/min: beats per minute
CPAP: continuous positive airway pressure support
CRP: c‐reactive protein
CXR: chest X‐ray
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  
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IRCT2016010225811N1.

Study name Investigation of the effects of nebulized ventolin in transient tachypnea of newborn
Methods Double‐blind, randomized clinical controlled trial
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.com
Notes  
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IRCT201711139014N201.

Study name Effect of inhaler salbutamol versus placebo on treatment of neonatal transient tachypnea: a double‐blind randomized clinical trial
Methods Double‐blind, randomized clinical controlled 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.ac.ir
Notes  
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IRCT20190503043457N1.

Study name Comparison of inhaled salbutamol with placebo (water for inj.) on recovery process of newborns' transient tachypnea
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.ac.ir
Notes  
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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  
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CPAP: continuous positive airway pressure support
TTN: transient tachypnea of the newborn.

Differences between protocol and review

  1. Differences between the review published in 2016 (Moresco 2016), and the version updated in 2020:

    1. we now refer to the certainty of the evidence;

    2. 'risk of bias' language updated;

    3. 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):

    1. 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 Table 1).

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.

Sources of support

Internal sources

  • Pediatric and Neonatology Unit, Ospedale San Paolo, Savona, Italy

    LM is employed by this organization

  • 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

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.

New search for studies and content updated (conclusions changed)

References

References to studies included in this review

Armangil 2011 {published data only}

  1. Armangil D, Yurdakök M, Korkmaz A, Yiğit S, Tekinalp G. Inhaled beta-2 agonist salbutamol for the treatment of transient tachypnea of the newborn. Journal of Pediatrics 2011;159(3):398-403.e1. [DOI: 10.1016/j.jpeds.2011.02.028] [PMID: ] [DOI] [PubMed] [Google Scholar]

Babaei 2019 {published data only}

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References to ongoing studies

IRCT2014062518232N1 {published data only}

  1. 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).

IRCT2016010225811N1 {published data only}

  1. IRCT2016010225811N1. Investigation of the effects of nebulized ventolin in transient tachypnea of newborn [Investigation of the effects of nebulized ventolin and saline 0.%9 in transient respiratory distress of newborn]. irct.ir/trial/21548 (first received 18 March 2016).

IRCT201711139014N201 {published data only}

  1. IRCT201711139014N201. Effect of inhaler salbutamol versus placebo on treatment of neonatal transient tachypnea: 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}

  1. 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}

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