Salbutamol for transient tachypnea of the newborn

Skip sharing on social media links
Share this:

Authors

Luca Moresco1, Matteo Bruschettin2, Amnon Cohen1, Alberto Gaiero1, Maria Grazia Calevo3

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Pediatric and Neonatology Unit, Ospedale San Paolo Savona, Savona, Italy [top]
2Department of Paediatrics, Lund University, Skane University Hospital, Lund, Sweden [top]
3Epidemiology, Biostatistics and Committees Unit, Istituto Giannina Gaslini, Genoa, Italy [top]

Citation example: Moresco L, Bruschettini M, Cohen A, Gaiero A, Calevo MG. Salbutamol for transient tachypnea of the newborn. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD011878. DOI: 10.1002/14651858.CD011878.pub2.

Contact person

Matteo Bruschettini

Department of Paediatrics
Lund University, Skane University Hospital
Lund
Sweden

E-mail: matteo.bruschettini@med.lu.se
E-mail 2: matbrus@gmail.com

Dates

Assessed as Up-to-date: 17 March 2016
Date of Search: 17 March 2016
Next Stage Expected: 17 March 2018
Protocol First Published: Issue 9, 2015
Review First Published: Issue 5, 2016
Last Citation Issue: Issue 5, 2016

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.

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 in the treatment of transient tachypnea of the newborn in infants born at 34 weeks' gestational age or more.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 3), MEDLINE (1996 to March 2016), EMBASE (1980 to March 2016) and CINAHL (1982 to March 2016). 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 2015 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

For each of the included trials, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, duration of oxygen therapy, need for continuous positive airway pressure and need for mechanical ventilation, duration of mechanical ventilation, etc.) and assessed the risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). The primary outcomes considered in this review were duration of oxygen therapy, need for continuous positive airway pressure and need for mechanical ventilation.

Main results

Three trials, which included 140 infants, met the inclusion criteria. All three trials compared a nebulized dose of salbutamol with placebo; in one of the three trials newborns were assigned to two different doses of the intervention. We found differences in the duration of oxygen therapy (mean difference (MD) -43.10 hours, 95% confidence interval (CI) -81.60 to -4.60). There were no differences in 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; 1 study, 46 infants) or the need for mechanical ventilation (RR 1.50, 95% CI 0.06 to 34.79; RD 0.03, 95% CI -0.08 to 0.14; 1 study, 46 infants). Tests for heterogeneity were not applicable for any of the analyses as only one study was included. Among secondary outcomes, we found no differences in terms of duration of hospital stay and tachypnea. The quality of the evidence was very low due to the imprecision of the estimates. One trial is ongoing.

Authors' conclusions

At present there is insufficient evidence to determine the efficacy and safety of salbutamol in the management of transient tachypnea of the newborn. The quality of evidence was low due to paucity of included trials, small sample sizes and overall poor methodologic quality.

[top]

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 is 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 within the lungs called the alveoli. 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 March 2016, we identified and included three clinical trials with 140 newborns comparing salbutamol with placebo. Two 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 one additional trial that is still underway.

Results: Salbutamol reduced the duration of treatment with oxygen in newborns with transient tachypnea (reported in one study); whereas it did not affect the need for respiratory support or any other relevant outcomes.

Conclusions: The results of this systematic review were consistent with either a benefit or a detrimental effect of salbutamol and did not provide a definitive answer to the review question.

[top]

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 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 furosemide has already been published (Kassab 2013). 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. However, none of these medical interventions has been confirmed as effective.

[top]

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 in the treatment of transient tachypnea of the newborn in infants born at 34 weeks' gestational age or more.

[top]

Methods

Criteria for considering studies for this review

Types of studies

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

Infants with transient tachypnea of the newborn without any respiratory support prior study entry who were born at 34 weeks' gestational age or more 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 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

See: Cochrane Neonatal Review Group search strategy External Web Site Policy.

Electronic searches

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

  1. the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3);
  2. MEDLINE (January 1996 to 17 March 2016);
  3. EMBASE (January 1980 to 17 March 2016);
  4. CINAHL (1982 to 17 March 2016);
  5. Australian New Zealand Clinical Trials Registry (PSANZ; 2005 to September 2015);
  6. abstracts of the Pediatric Academic Societies (PAS; 2000 to September 2015).

Appendix 1 shows the full search strategies for each database. 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 the International Standard Randomized Controlled Trial Number (ISRCTN) registry (www.controlled-trials.com/ External Web Site Policy).

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group 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, AG) used Cochrane's statistical software, RevMan 2014, to enter all the data.

Assessment of risk of bias in included studies

Two review authors (LM, MGC) independently assessed risk of bias in all the included studies using Cochrane's tool for assessing risk of bias (Higgins 2011).

We assessed the following items.

  1. Random sequence generation: selection bias due to inadequate generation of a randomized sequence.
  2. Allocation concealment: selection bias due to inadequate concealment of allocations prior to assignment.
  3. Blinding of participants and personnel: performance bias due to knowledge of the allocated interventions by participants and personnel during the study.
  4. Blinding of outcome assessment: detection bias due to knowledge of the allocated interventions by outcome assessors.
  5. Incomplete outcome data: attrition bias due to amount, nature or handling of incomplete outcome data.
  6. Selective reporting: reporting bias due to selective outcome reporting.
  7. Other bias: bias due to problems not covered elsewhere.

We used a 'Risk of bias' graph to illustrate risk across studies. We resolved any disagreements by consensus and, if necessary, by consulting a third review author (MB).

See Appendix 2 for the complete 'Risk of bias' tool.

Measures of treatment effect

We followed the standard methods of the Cochrane Neonatal Review Group 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 value < 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 2011).

Dealing with missing data

We planned to determine the drop-out rate for each trial (and each trial outcome). We planned to consider a drop-out 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 drop-out 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 concealment, blinding of outcome assessment, loss to follow-up, treatment type, co-interventions). We assessed statistical heterogeneity by examining the I2 statistic (Higgins 2011), 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 investigate publication by using funnel plots if the systematic review included at least 10 clinical trials (Egger 1997; Higgins 2011).

Data synthesis

We summarized all eligible studies using RevMan 2014. We used the standard methods of the Cochrane Neonatal Review Group to synthesize data using RRs, RDs, NNTB/NNTH, MDs and 95% CIs. We planned to use the fixed-effect model to perform meta-analyses.

Quality of evidence

We assessed the quality of evidence for the main comparison at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2011a). This methodologic approach considers RCTs as high quality evidence that may be 'down-rated' by limitations in any of five areas: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias (Guyatt 2011a).

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

  1. High: we were very confident that the true effect laid close to that of the estimate of the effect.
  2. Moderate: we were moderately confident in the effect estimate. The true effect was likely to be close to the estimate of the effect, but there was a possibility that it was substantially different.
  3. Low: our confidence in the effect estimate was limited. The true effect may have been substantially different from the estimate of the effect.
  4. Very low: we had very little confidence in the effect estimate. The true effect was likely to be substantially different from the estimate of effect (Schünemann 2013).

We independently assessed the quality of the evidence found for 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.

In cases where the study authors did not take measures to ensure concealment of allocation, randomized assignment, completed follow-up or blinded outcome assessment, we planned to downgrade the quality of evidence because of design limitations (Guyatt 2011b).

We evaluated consistency by similarity of point estimates, extent of overlap of the 95% CIs and statistical criteria including test for heterogeneity (I2 statistic). We planned to downgrade the quality of evidence when inconsistency across studies results was large and unexplained (i.e. some studies suggested important benefit and others no effect or harm without a clinical explanation) (Guyatt 2011c).

We assessed precision according to the 95% CI around the pooled estimation (Guyatt 2011d). When trials were conducted in populations other than the target population, we planned to downgrade the quality of evidence because of indirectness (Guyatt 2011e).

We entered data (i.e. pooled estimates of the effects and corresponding 95% CIs) and explicit judgments for each of the above aspects assessed into the GRADEpro (GRADEproGDT) (www.guidelinedevelopment.org/ External Web Site Policy), and created 'Summary of findings' tables. We explained all judgments involving in the assessment of the study characteristics described above in the 'Summary of findings' table.

Subgroup analysis and investigation of heterogeneity

  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.

[top]

Results

Description of studies

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

Results of the search

The literature search run in March 2013 identified 131 references (Figure 1). After screening, we included three RCTs (Armangil 2011; Kim 2014; Monzoy-Ventre 2015). We identified one ongoing trial (IRCT2014062518232N1), which is reported in the Characteristics of ongoing studies table.

Included studies

Three trials recruiting 140 infants met the inclusion criteria (Armangil 2011; Kim 2014; Monzoy-Ventre 2015). Details of the trials are described in the Characteristics of included studies table.

Armangil 2011 and Kim 2014 compared one nebulized dose of salbutamol to normal saline; whereas Monzoy-Ventre 2015 compared two different dosages to normal saline (administered every four hours, three times).

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 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. They 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.

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 neonatal intensive care unit 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).

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); 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); 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.

Excluded studies

None of the other identified studies were potentially eligible.

Risk of bias in included studies

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

Allocation (selection bias)

None of the included trials provided sufficient information on how the randomization sequence was generated and concealed and we judged them at unclear risk of selection bias.

Blinding (performance bias and detection bias)

In Armangil 2011, parents and investigators remained blinded to the administered medications throughout the study period.

Kim 2014 and Monzoy-Ventre 2015 did not provide sufficient information about blinding of the intervention.

Incomplete outcome data (attrition bias)

The three included studies reported outcomes for all randomized infants (no drop-outs).

Selective reporting (reporting bias)

None of the included trials were registered in a trial registry and we could not ascertain if there were deviations from the original protocol in the final publication.

Other potential sources of bias

The trial appeared free of other biases.

Effects of interventions

We identified three trials that included 140 newborns and compared salbutamol to placebo (saline) (Armangil 2011; Kim 2014; Monzoy-Ventre 2015). However, Armangil 2011 expressed data as medians and could not be pooled in the analyses. Kim 2014 and Monzoy-Ventre 2015 did not report the prespecified outcomes of this review, and, therefore, tests for heterogeneity were not applicable for any of the analyses.

Salbutamol versus placebo or no treatment

Primary outcomes
Duration of oxygen therapy (Outcome 1.1)

Kim 2014 reported duration of oxygen therapy and detected a statistically significant reduction in the salbutamol group compared to the placebo group (MD -43.10 hours, 95% CI -81.60 to -4.60; 1 study, 40 infants; P value < 0.01). The test for heterogeneity was not applicable. See: Analysis 1.1; Figure 4.

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

Monzoy-Ventre 2015 reported need for continuous positive airway pressure and found no significant difference between salbutamol and placebo (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. See: Analysis 1.2; Figure 5.

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

Monzoy-Ventre 2015 reported on need for mechanical ventilation and found no significant difference between salbutamol and placebo (RR 1.50, 95% CI 0.06 to 34.79; RD 1.50, 95% CI 0.06 to 34.79; 1 study, 46 infants). We obtained data for this outcome directly from the trial authors. The test for heterogeneity was not applicable. See: Analysis 1.3; Figure 6.

Secondary outcomes
Duration of respiratory support (intermittent positive pressure ventilation or continuous positive airway pressure)

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 value = 0.112). The test for heterogeneity was not applicable.

Duration of hospital stay (Outcome 1.4)

Kim 2014 reported on duration of hospital stay and found no significant difference between salbutamol and placebo (MD -0.30 days, 95% CI -2.62 to 2.02; 1 study, 40 infants). 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 value = 0.002). The test for heterogeneity was not applicable. See: Analysis 1.4.

Duration of tachypnea, defined as respiratory rate greater than 60 breaths per minute (Outcome 1.5)

Kim 2014 reported a statistically significant reduction in duration of tachypnea in the salbutamol group compared to the placebo group (MD -22.20 hours, 95% CI -55.51 to -11.11; 1 study, 40 infants). The test for heterogeneity was not applicable. See: Analysis 1.5.

Initiation of oral feeding (Outcome 1.6)

Kim 2014 reported on initiation of oral feeding and found no significant difference between salbutamol and placebo (MD -16.40 days, 95% CI -43.40 to 10.60; 1 study, 40 infants). The test for heterogeneity was not applicable. See: Analysis 1.6.

Duration of mechanical ventilation

None of the studies reported duration of mechanical ventilation.

Persistent pulmonary hypertension

None of the studies reported persistent pulmonary hypertension.

Pneumothorax

None of the studies reported pneumothorax.

Subgroup analysis

We were unable to conduct any of the planned subgroup analyses as the analyses included only two trials.

[top]

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. Only three trials, for 140 infants, met the inclusion criteria of this review (Armangil 2011; Kim 2014; Monzoy-Ventre 2015). The mean gestational age in the included studies was 37 weeks. Kim 2014 reported a statistically significant reduction in duration of tachypnea and oxygen therapy. Though not included in the outcomes of the present review, both Armangil 2011 and Monzoy-Ventre 2015 reported clinical improvement and reduction in respiratory rate following salbutamol administration. The quality of the evidence was limited due to the imprecision of the estimates.

Overall completeness and applicability of evidence

The available evidence was insufficient to understand if 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 a priori subgroup analysis (gestational age, birth weight, mode of delivery, route of administration and dosage) to detect differential effects as we could not pool the included trials in any meta-analyses.

Quality of the evidence

The overall quality of evidence was very low. The main limitation of the quality of evidence was linked to the imprecision of the estimate, due to paucity of the included trials, small sample sizes, imbalances in reported groups suggesting and the fact that the primary outcomes were not included in the published reports (see Summary of findings table 1). The trials reported random sequence generation and concealment of allocation insufficiently. Only one trial achieved blinding of interventions (Armangil 2011).

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 one trial 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, data extraction and 'risk of bias' rating (LM, MGC). 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.

Agreements and disagreements with other studies or reviews

We are not aware of other reviews that address the same clinical question. We described the characteristics of the clinical trials that have been published.

[top]

Authors' conclusions

Implications for practice

There was insufficient evidence to establish the efficacy and safety of salbutamol in the management of transient tachypnea of the newborn. One of the included trials showed a shorter duration of oxygen therapy following salbutamol administration; the studies reported no other differences in any clinically relevant outcomes. Given the limited and low quality of the evidence available, it was impossible to 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.

[top]

Acknowledgements

We thank Roger Soll for his valuable advice; Yolanda Brosseau and Colleen Ovelman for their kind and efficient support; and Marìa Alejandra Monzoy-Ventre for providing additional data.

We thank Dr. Henry Halliday for his advice as the external referee.

[top]

Contributions of authors

LM and MB reviewed the literature and wrote the review.

MGC excerpted and analyzed the data.

MGC and AG assisted in the review of literature and in writing of the review.

AC commented on and reviewed the review.

[top]

Declarations of interest

All review authors declare to have no competing financial conflict of interest.

[top]

Differences between protocol and review

We deleted the comparison between salbutamol and ventilation strategies (in Objectives and Types of interventions).

We added the methodology and plan for 'Summary of findings' tables and GRADE recommendations, which were not included in the original protocol (see Summary of findings table 1).

[top]

Characteristics of studies

Characteristics of included studies

Armangil 2011

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)

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 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: no predisposing factor such as diffuse pulmonary opacities on radiography, severe hypoxia, sepsis, the syndrome of multiple organ failure, disseminated intravascular coagulation, and 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 g in the salbutamol group and 36.7 ± 1.6 weeks and 2990 ± 574 g 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 5-6 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

Clinical score of transient tachypnea, respiratory rate, heart rate, FiO2, PaO2, PaCO2, pH, serum K+, and serum glucose values

Notes

Limited power to address clinically relevant outcomes

Risk of bias table
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) Low risk

Parents and investigators remained blinded to the administered medications throughout the study period

Blinding of outcome assessment (detection bias) Low risk

Investigators remained blinded to the administered medications throughout the study period

Incomplete outcome data (attrition bias) 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

Kim 2014

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)

Infants with TTN were determined based on the following clinical symptoms and chest radiography results:

  1. greater than/or equal to 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 g in the salbutamol group and 37.5 ± 1.0 weeks and 3203.3 ± 432.4 g 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 min

Outcomes

Primary outcomes: duration of tachypnea, oxygen treatment and hospitalization

Secondary outcomes: extent and duration of tachypnea, duration of oxygen treatment, use of continuous positive airway pressure or a ventilator, duration of empiric antibiotic therapy, time of initiating enteral nutrition, duration of hospitalization, tachycardia and arrhythmias

Notes

Limited power to address clinically relevant outcomes

Risk of bias table
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) 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) Unclear risk

No information provided

Incomplete outcome data (attrition bias) 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

Monzoy-Ventre 2015

Methods

Clinical trial

Single-center: NICU of the Hospital Aurelio Valdivieso, Oaxaca, Mexico, between February 2012 and February 2013

Participants

46 newborns (15 children in the control group)

Newborns were eligible for enrollment if they were diagnosed with TTN and were < 6 hours old; greater than/or equal to 34 weeks' gestational age; respiratory distress < 6 hours after birth and persisted 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: meconium aspiration; other causes of tachypnea (e.g. neonatal respiratory distress syndrome, pneumonia); early-onset neonatal sepsis; 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

Respiratory rate, heart rate, FiO2, PaO2, PaCO2

Notes

Limited power to address clinically relevant outcomes

Risk of bias table
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) Unclear risk

No information provided

Blinding of outcome assessment (detection bias) Unclear risk

No information provided

Incomplete outcome data (attrition bias) 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

Footnotes

FiO2: fraction of inspired oxygen; min: minute; NICU: neonatal intensive care unit; PaCO2: partial pressure of carbon dioxide in arterial blood; PaO2: partial pressure of oxygen in arterial blood; SD: standard deviation; TTN: transient tachypnea of the newborn; WCC: white blood cell count.

Characteristics of excluded studies

None noted.

Characteristics of studies awaiting classification

None noted.

Characteristics of ongoing studies

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: tachypnea (at 30 minutes, and 1, 4 and 6 hours later)
Secondary: respiratory rate, heart rate, oxygen requirement, feeding initiation time, duration of hospitalization, retraction score and oxygen saturation percent (all measured at 30 minutes, and 1, 4 and 6 hours later); 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  

[top]

Summary of findings tables

1 Salbutamol compared to placebo/no treatment for transient tachypnea of the newborn

Salbutamol compared to placebo/no treatment for transient tachypnea of the newborn

Patient or population: infants with transient tachypnea of the newborn
Settings: neonatal intensive care unit
Intervention: salbutamol
Comparison: placebo/no treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo/no treatment

Salbutamol

Duration of oxygen therapy (hours)

-

Mean duration of oxygen therapy (hours) in the intervention groups was
43.1 lower
(81.6 to 4.6 lower)

-

40
(1 study)

⊕⊝⊝⊝
very low 1,2,3

-

Need for continuous positive airway pressure (yes/no)

Study population

RR 0.73
(0.38 to 1.39)

46
(1 study)

⊕⊝⊝⊝
very low 1,2,3

-

533 per 1000

389 per 1000
(203 to 741)

Need for mechanical ventilation (yes/no)

Study population

RR 1.5
(0.06 to 34.79)

46
(1 study)

⊕⊝⊝⊝
very low 1,2,3

-

0 per 1000

0 per 1000
(0 to 0)

Duration of hospital stay (days)

-

Mean duration of hospital stay (days) in the intervention groups was
0.3 lower
(-2.62 lower to 2.02 higher)

-

40
(1 study)

⊕⊝⊝⊝
very low 1,2,3

-

*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 quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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 quality: We are very uncertain about the estimate.

Footnotes

1 No explanation was provided.
2 The study included relatively few newborns and few events and thus had wide confidence intervals around the estimate of the effect.
3 One trial.

[top]

References to studies

Included studies

Armangil 2011

[CRSSTD: 2799497]

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. [CRSREF: 2799498]

Kim 2014

[CRSSTD: 2799499]

Kim MJ, Yoo JH, Jung JA, Byun SY. The effects of inhaled albuterol in transient tachypnea of the newborn. Allergy, Asthma & Immunology Research 2014;6(2):126-30. [CRSREF: 2799500]

Monzoy-Ventre 2015

[CRSSTD: 2799501]

Monzoy-Ventre MA, Rosas-Sumano AB, Hernández-Enríquez NP, Galicia-Flores L. Inhaled salbutamol in newborn infants with transient tachypnea [Salbutamol inhalado en los niños recién nacidos con taquipnea transitoria]. Revista Mexicana de Pediatria 2015;82(1):5-9. [CRSREF: 4242384]

Excluded studies

None noted.

Studies awaiting classification

None noted.

Ongoing studies

IRCT2014062518232N1

[CRSSTD: 2799503]

IRCT2014062518232N1. The effect of salbutamol in treatment of transient tachypnea of newborn. www.irct.ir/searchresult.php?id=18232&number=1 (accessed 17 March 2016). [CRSREF: 4242385]

[top]

Other references

Additional references

Avery 1966

Avery ME, Gatewood OB, Brumley G. Transient tachypnea of newborn. Possible delayed resorption of fluid at birth. American Journal of Diseases of Children 1966;111(4):380-5. [PubMed: 5906048]

Barker 2002

Barker PM, Olver RE. Invited review: clearance of lung liquid during the perinatal period. Journal of Applied Physiology 2002;93(4):1542-8. [PubMed: 12235057]

Clark 2005

Clark RH. The epidemiology of respiratory failure in neonates born at an estimated gestational age of 34 weeks or more. Journal of Perinatology 2005;25(4):251-7. [PubMed: 15605071]

Cochrane EPOC Group 2013

Effective Practice and Organisation of Care (EPOC). Data extraction and management. EPOC Resources for review authors. Oslo: Norwegian Knowledge Centre for the Health Services; 2013. epoc.cochrane.org/epoc-specific-resources-review-authors (accessed 15 May 2016).

Davies 2004

Davies JC. Ion transport in lung disease. Pediatric Pulmonology 2004;26:147-8. [PubMed: 15029633]

Di Marco 2012

Di Marco F, Guazzi M, Sferrazza Papa GF, Vicenzi M, Santus P, Busatto P, et al. Salmeterol improves fluid clearance from alveolar-capillary membrane in COPD patients: a pilot study. Pulmonary Pharmacology & Therapeutics 2012;25(1):119-23. [PubMed: 22245487]

Egger 1997

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):629-34. [PubMed: 9310563]

Faxelius 1983

Faxelius G, Hägnevik K, Lagercrantz H, Lundell B, Irestedt L. Catecholamine surge and lung function after delivery. Archives of Disease in Childhood 1983;58(4):262-6. [PubMed: 6847229]

Frank 2000

Frank JA, Wang Y, Osorio O, Matthay MA. Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats. Journal of Applied Physiology 2000;89(4):1255-65. [PubMed: 11007557]

Guglani 2008

Guglani L, Lakshminrusimha S, Ryan RM. Transient tachypnea of the newborn. Pediatrics in Review 2008;29(11):e59-65. [PubMed: 18977854]

Guyatt 2011a

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction - GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4):383-94. [PubMed: 21195583]

Guyatt 2011b

Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence - study limitations (risk of bias). Journal of Clinical Epidemiology 2011;64(4):407-15. [PubMed: 21247734]

Guyatt 2011c

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 7. Rating the quality of evidence - inconsistency. Journal of Clinical Epidemiology 2011;64(12):1294-302. [PubMed: 21803546]

Guyatt 2011d

Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, et al. GRADE guidelines 6. Rating the quality of evidence - imprecision. Journal of Clinical Epidemiology 2011;64(12):1283-93. [PubMed: 21839614]

Guyatt 2011e

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 8. Rating the quality of evidence - indirectness. Journal of Clinical Epidemiology 2011;64(12):1303-10. [PubMed: 21802903]

Hansen 2008

Hansen AK, Wisborg K, Uldbjerg N, Henriksen TB. Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study. BMJ 2008;336(7635):85-7. [PubMed: 18077440]

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557-60. [PubMed: 12958120]

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

Karabayir 2010

Karabayir N. Intravenous furosemide therapy in transient tachypnea of the newborn. Pediatrics International 2010;52(5):851. [PubMed: 20880312]

Kassab 2013

Kassab M, Khriesat WM, Bawadi H, Anabrees J. Furosemide for transient tachypnoea of the newborn. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD003064. DOI: 10.1002/14651858.CD003064.pub2.

Kumar 1996

Kumar A, Bhat BV. Epidemiology of respiratory distress of newborns. Indian Journal of Pediatrics 1996;63(1):93-8. [PubMed: 10829971]

Licker 2008

Licker M, Tschopp JM, Robert J, Frey JG, Diaper J, Ellenberger C. Aerosolized salbutamol accelerates the resolution of pulmonary edema after lung resection. Chest 2008;133(4):845-52. [PubMed: 17989152]

Liem 2007

Liem JJ, Huq SI, Ekuma O, Becker AB, Kozyrskyj AL. Transient tachypnea of the newborn may be an early clinical manifestation of wheezing symptoms. Journal of Pediatrics 2007;151(1):29-33. [PubMed: 17586187]

Ma 2010

Ma XL, Xu XF, Chen C, Yan CY, Liu YM, Liu L, et al. Epidemiology of respiratory distress and the illness severity in late preterm or term infants: a prospective multi-center study. Chinese Medical Journal 2010;123(20):2776-80. [PubMed: 21034581]

Miller 1980

Miller LK, Calenoff L, Boehm JJ, Riedy MJ. Respiratory distress in the newborn. JAMA 1980;243(11):1176-9. [PubMed: 7359671]

Minakata 1998

Minakata Y, Suzuki S, Grygorczyk C, Dagenais A, Berthiaume Y. Impact of β-adrenergic agonist on Na+ channel and Na+-K+-ATPase expression in alveolar type II cells. American Journal of Physiology 1998;275(2 Pt 1):L414-22. [PubMed: 9700104]

Morrison 1995

Morrison JJ, Rennie JM, Milton PJ. Neonatal respiratory morbidity and mode of delivery at term: influence of timing of elective caesarean section. British Journal of Obstetrics and Gynaecology 1995;102(2):101-6. [PubMed: 7756199]

Perkins 2006

Perkins GD, McAuley DF, Thickett DR, Gao F. The Beta-Agonist Lung injury TrIal (BALTI): a randomized placebo-controlled clinical trial. American Journal of Respiratory and Critical Care Medicine 2006;173(3):281-7. [PubMed: 16254268]

RevMan 2014

Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Sakuma 1994

Sakuma T, Okaniwa G, Nakada T, Nishimura T, Fujimura S, Matthay MA. Alveolar fluid clearance in the resected human lung. American Journal of Respiratory and Critical Care Medicine 1994;150(2):305-10. [PubMed: 8049807]

Sakuma 1996

Sakuma T, Suzuki S, Usuda K, Handa M, Okaniwa G, Nakada T, et al. Preservation of alveolar epithelial fluid transport mechanisms in rewarmed human lung after severe hypothermia. Journal of Applied Physiology 1996;80(5):1681-6. [PubMed: 8727555]

Sartori 2002

Sartori C, Alleman Y, Duplain H, Lepori M, Egli M. Salmeterol for prevention of high-altitude pulmonary edema. New England Journal of Medicine 2002;346(21):1631-6.

Schünemann 2013

Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from www.guidelinedevelopment.org/handbook.

Stroustrup 2012

Stroustrup A, Trasande L, Holzman IR. Randomized controlled trial of restrictive fluid management in transient tachypnea of the newborn. Journal of Pediatrics 2012;160(1):38-43.e1. [PubMed: 21839467]

Tudehope 1979

Tudehope DI, Smyth MH. Is "transient tachypnoea of the newborn" always a benign disease? Report of 6 babies requiring mechanical ventilation. Australian Paediatric Journal 1979;15(3):160-5. [PubMed: 518409]

Weintraub 2013

Weintraub AS, Cadet CT, Perez R, De Lorenzo E, Holzman IR, Stroustrup A. Antibiotic use in newborns with transient tachypnea of the newborn. Neonatology 2013;103(3):235-40. [PubMed: 23428585]

Classification pending references

None noted.

[top]

Data and analyses

1 Salbutamol versus placebo/no treatment

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Duration of oxygen therapy (hours) 1 40 Mean Difference (IV, Fixed, 95% CI) -43.10 [-81.60, -4.60]
1.2 Need for continuous positive airway pressure (yes/no) 1 46 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.38, 1.39]
1.3 Need for mechanical ventilation (yes/no) 1 46 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [0.06, 34.79]
1.4 Duration of hospital stay (days) 1 40 Mean Difference (IV, Fixed, 95% CI) -0.30 [-2.62, 2.02]
1.5 Duration of tachypnea (hours) 1 40 Mean Difference (IV, Fixed, 95% CI) -22.20 [-55.51, 11.11]
1.6 Initiation of oral feeding (hours) 1 40 Mean Difference (IV, Fixed, 95% CI) -16.40 [-43.40, 10.60]
 

[top]

Figures

Figure 1

Refer to Figure 1 caption below.

Study flow diagram (Figure 1).

Figure 2

Refer to Figure 2 caption below.

Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies (Figure 2).

Figure 3

Refer to Figure 3 caption below.

Risk of bias summary: review authors' judgments about each risk of bias item for each included study (Figure 3).

Figure 4 (Analysis 1.1)

Refer to Figure 4 caption below.

Forest plot of comparison: 1 Salbutamol versus placebo, outcome: 1.1 Duration of oxygen therapy (hours) (Figure 4).

Figure 5 (Analysis 1.2)

Refer to Figure 5 caption below.

Forest plot of comparison: 1 Salbutamol versus placebo, outcome: 1.2 Need for continuous positive airway pressure (yes/no) (Figure 5).

Figure 6 (Analysis 1.3)

Refer to Figure 6 caption below.

Forest plot of comparison: 1 Salbutamol versus placebo, outcome: 1.3 Need for mechanical ventilation (yes/no) (Figure 6).

[top]

Sources of support

Internal sources

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

    LM, AC and AG are 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

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

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

[top]

Appendices

1 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' 2000-2015 Archive (www.abstracts2view.com/pasall/ External Web Site Policy): "transient tachypnea" OR "transitory tachypnea" OR TTN OR TTNB
  • ClinicalTrials.gov (clinicaltrials.gov/), International Standard Randomized Controlled Trial Number (ISRCTN) registry (www.controlled-trials.com/ External Web Site Policy) and Australian New Zealand Clinical Trials Registry (www.anzctr.org.au/ External Web Site Policy): ("transient tachypnea" OR "transitory tachypnea" OR TTN OR TTNB) AND infant

2 'Risk of bias' tool

Random sequence generation and allocation concealment (selection bias)

Random sequence generation

For each included study, we categorized the risk of bias regarding random sequence generation as follows.

  1. Low risk: the investigators described a random component in the sequence generation process such as referring to a random number table, using a computer random number generator, coin tossing, shuffling cards or envelopes, throwing dice, drawing of lots, minimization.
  2. High risk: the investigators described a nonrandom component in the sequence generation process (sequence generated by odd or even date of birth, sequence generated by some rule based on date or day of admission, sequence generated by some rule based on hospital or clinic record number, allocation by judgment of the clinician, allocation by preference of the participant, allocation based on the results of a laboratory test or a series of tests, allocation by availability of the intervention).
  3. Unclear risk: no or unclear information provided.
Allocation concealment

For each included study, we categorized the risk of bias regarding allocation concealment as follows.

  1. Low risk: participant and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based and pharmacy-controlled randomization), sequentially numbered drug containers or identical appearance, sequentially numbered sealed opaque envelopes.
  2. High risk: participant and investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on open random allocation schedule (e.g. a list of random numbers), unsealed or nonopaque envelopes, alternation or rotation, date of birth, case record number.
  3. Unclear risk: no or unclear information provided.
Blinding of study participants and personnel (performance bias)

For each included study, we categorized the methods used to blind study participants and personnel from knowledge of which intervention a participant received as follows.

  1. Criteria of a judgment of 'low risk' of bias: no blinding or incomplete blinding, but the review authors judged that the outcome was not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
  2. Criteria of a judgment of 'high risk' of bias: no blinding or incomplete blinding, and the outcome was likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome was likely to be influenced by lack of blinding.
  3. Unclear risk: no or unclear information provided.
Blinding of outcome assessors (detection bias)

For each included study, we categorized the methods used to blind outcome assessors from knowledge of which intervention a participant received as follows.

  1. Criteria of a judgment of 'low risk' of bias: no blinding or incomplete blinding, but the review authors judged that the outcome was not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
  2. Criteria of a judgment of 'high risk' of bias: no blinding of outcome assessment, but the review authors judged that the outcome measurement was not likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement was likely to be influenced by lack of blinding.
  3. Unclear risk: no or unclear information provided.
Incomplete outcome data (attrition bias)

For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis as follows.

  1. Criteria of a judgment of 'low risk' of bias:
    1. no missing outcome data;
    2. reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias);
    3. missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups;
    4. for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate;
    5. for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size;
    6. missing data were imputed using appropriate methods.
  2. Criteria of a judgment of 'high risk' of bias:
    1. reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups;
    2. for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate;
    3. for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size;
    4. 'as-treated' analysis done with substantial departure of the intervention received from that assigned at randomization;
    5. potentially inappropriate application of simple imputation.
  3. Unclear risk: no or unclear information provided.
Selective reporting (reporting bias)

For each included study, we described how we investigated the risk of selective outcome reporting bias and what we found. We attempted to access all the protocols of the included studies through clinical trials registries (e.g. ClinicalTrials.gov (clinicaltrials.gov/), the International Standard Randomized Controlled Trial Number (ISRCTN) registry (www.controlled-trials.com/ External Web Site Policy)) and direct contact with the authors.

We assessed the methods as follows.

  1. Low risk: the study protocol was available and all of the study's prespecified (primary and secondary) outcomes that were of interest in the review were reported in the prespecified way; the study protocol was not available but it was clear that the published reports included all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon).
  2. High risk: not all of the study's prespecified primary outcomes were reported; one or more primary outcomes was reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not prespecified; one or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review were reported incompletely so that they could not be entered in a meta-analysis; the study report did not include results for a key outcome that would be expected to have been reported for such a study.
  3. Unclear risk: no or unclear information provided (the study protocol was not available).
Other potential sources of bias (other bias)

For each included study, we described any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design used).

We assessed whether each study was free of other problems that could put it at risk of bias as follows.

  1. Low risk: the study appeared to be free of other sources of bias.
  2. High risk: the study had at least one important risk of bias (e.g. the study had a potential source of bias related to the specific study design used or was claimed to have been fraudulent or had some other problem).
  3. Unclear risk: there may have been a risk of bias, but there was either: insufficient information to assess whether an important risk of bias existed or insufficient rationale or evidence that an identified problem may have introduced bias.

 


This review is published as a Cochrane review in The Cochrane Library, Issue 5, 2016 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.