Effects of salbutamol in transient tachypnoea of the newborn: a systematic review and meta-analysis

Graphical abstract

Does nebulised salbutamol improve transient tachypnoea of the newborn (TTN)? RCT: randomised controlled trial; MD: mean difference; O₂: oxygen; CPAP: continuous positive airway pressure.

Abstract

Background

Transient tachypnoea of the newborn (TTN) is a common cause of early respiratory distress, especially after caesarean delivery. Salbutamol, a β₂-agonist, may enhance alveolar fluid clearance and improve outcomes. The objective of the present study was to evaluate the benefits and harms of nebulised salbutamol compared with placebo or standard care in neonates with TTN, through a systematic review and meta-analysis of randomised controlled trials (RCTs).

Methods

We conducted a systematic search of five electronic databases and trial registries up to April 2025. Risk of bias was assessed with the Cochrane Risk of Bias 1 tool, and certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. Meta-analyses were performed when appropriate.

Results

21 RCTs (n=1223) were included. Repeated doses of salbutamol probably reduce hospital stay by 2.3 days (mean difference (MD) −2.3 days, 95% CI −3.2 to −1.4 days; moderate certainty) and a single dose may reduce oxygen therapy duration by 19.4 h (MD −19.4 h, 95% CI −26.0 to −12.9 h; low certainty) and duration of assisted ventilation by 12.7 h (MD −12.7 h, 95% CI −19.6 to −5.7 h; low certainty). Effects on need for mechanical ventilation (risk ratio 0.37, 95% CI 0.07–1.96; very low certainty) and continuous positive airway pressure (risk ratio 0.84, 95% CI 0.59–1.19; very low certainty) were very uncertain. In addition, single dose of salbutamol may reduce tachypnoea duration by 6.6 h (MD −6.6 h, 95% CI −12.6 to −0.7 h; low certainty) and clinical severity scores at 4 and 8 h (MD −3.0 and −3.4 points, respectively; low certainty).

Conclusion

Salbutamol shows modest benefits in TTN, particularly in reducing oxygen therapy duration and hospital stay with repeated doses. However, given the low certainty of the evidence for most outcomes, its use should be carefully weighed within each healthcare context. Further high-quality trials are needed.

Shareable abstract

A single salbutamol dose may reduce oxygen therapy duration (low certainty); repeated doses probably lower hospital stay in TTN (moderate certainty). Evidence for other outcomes (ventilation, CPAP, tachypnoea) is still uncertain. https://bit.ly/3JJmFjB

Introduction

Transient tachypnoea of the newborn (TTN) is the most common cause of early respiratory distress in term neonates [1]. It is characterised by tachypnoea, typically ranging between 60 and 80 breaths·min⁻¹, although it can sometimes exceed 80–100 breaths·min⁻¹. This increased respiratory rate usually appears within the first hours of life. It is often accompanied by signs of mild-to-moderate respiratory distress, including nasal flaring, grunting and intercostal retractions [2]. The condition arises from delayed clearance of fetal lung fluid, leading to transient pulmonary oedema and impaired gas exchange [3].

Physiologically, fetal lung fluid is absorbed around the time of delivery through hormonal and mechanical stimuli [4], particularly during labour and vaginal delivery [5]. In elective caesarean sections without labour, these mechanisms may be insufficient or absent, increasing the risk of TTN [1]. Other associated risk factors include male sex, late preterm birth, maternal diabetes, and macrosomia [1].

TTN affects ∼0.4% of term newborns and up to 6.4% of late preterm infants [6]. Its incidence is approximately seven times higher in those delivered by caesarean section compared to vaginal delivery [7]. Although typically self-limited and resolving within 48–72 h [8], it has significant clinical and healthcare implications. Affected neonates often require close monitoring, supplemental oxygen [9], intravenous fluids, and in some cases, admission to a neonatal intensive care unit (NICU) [10]. These interventions lead to increased use of hospital resources, higher costs and longer lengths of stay, which can be distressing for families and burdensome for healthcare systems [1].

Currently, the management of TTN is primarily supportive [11]. However, due to its transient nature and the underlying pathophysiology involving impaired alveolar fluid clearance, pharmacological strategies aimed at accelerating this process have gained interest. One such strategy involves the use of salbutamol [12], a short-acting β₂-adrenergic agonist. Salbutamol is widely used in paediatric and adult populations due to its bronchodilator effects [13]. Importantly, it also stimulates epithelial sodium channels in the alveoli, enhancing sodium and water reabsorption and promoting lung fluid clearance [14]. This pharmacological mechanism provides a rationale for its use in TTN, potentially shortening the course of illness and reducing the need for respiratory support [15].

Several randomised controlled trials (RCTs) have explored the use of nebulised salbutamol in neonates with TTN [16–19]. Some studies report reduced duration of tachypnoea [20, 21], shorter oxygen therapy requirements [18, 20, 22] and earlier discharge. However, results remain inconsistent, and questions persist regarding the safety and routine application of salbutamol in this population.

A systematic review by Moresco et al. [12], which included seven RCTs, suggested that salbutamol may reduce the duration of oxygen therapy and hospital stay in neonates with TTN. However, the certainty of the evidence was rated as low to very low due to methodological limitations, imprecision, and heterogeneity across studies. Moreover, the review did not assess the evidence against decision thresholds to inform clinical decision-making. Since then, additional RCTs evaluating this intervention have been published. Incorporating these newer studies into an updated analysis may strengthen the overall evidence base and provide greater clarity on the therapeutic role of salbutamol in the management of TTN.

Given the clinical relevance of TTN and the potential implications for patient outcomes and healthcare resource utilisation, this systematic review and meta-analysis aims to evaluate the benefits and harms of salbutamol in the treatment of TTN, using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to support evidence-based decision-making.

Methods

Study design and registration

We conducted a systematic review of RCTs, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [23] (supplementary material 1). The protocol was registered at the Prospective International Registry of Systematic Reviews (PROSPERO; www.crd.york.ac.uk/PROSPERO/, identifier number CRD42024606614).

Information sources and search strategy

We conducted a comprehensive, language-unrestricted search through August 2024 with an update on 11 April 2025. First, we developed a preliminary search strategy in PubMed/MEDLINE using Medical Subject Headings terms and synonyms related to “transient tachypnoea” and “salbutamol”. We then adapted this strategy for other databases, including the Cochrane Library (CENTRAL), Embase, Web of Science and Virtual Health Library (supplementary material 2). Additionally, we searched clinical trial registries in the USA (www.clinicaltrials.gov) and conducted a Google Scholar search, screening the first 100 results. To identify additional studies, we also screened the references of included studies and relevant systematic reviews on the topic [12].

Eligibility criteria

The systematic review and meta-analysis followed the population, intervention, comparator, and outcomes (PICO) framework to address the research question on the use of salbutamol in the management of TTN. The review focused on neonates born at ≥34 weeks of gestation with a clinical and radiographic diagnosis of TTN, excluding other potential causes of tachypnoea. We prioritised studies that enrolled participants within the first 12 h of life and before the initiation of ventilatory support, when feasible.

The intervention assessed was salbutamol administered by nebulisation, with no restrictions on dose or treatment duration. The comparison group received standard supportive care, with or without placebo. Critical outcomes of interest included all-cause mortality and the need for mechanical ventilation, while important outcomes included noninvasive ventilatory support requirements, the duration of oxygen therapy and hospital stay. The review also sought to evaluate the impact of salbutamol on clinical severity scores, oxygen saturation levels, respiratory rate and the duration of tachypnoea.

Only RCTs were included in this review, ensuring a robust evaluation of the intervention's effectiveness and safety in the treatment of TTN.

Study selection

Search results were imported into Rayyan (Qatar Computing Research Institute, Doha, Qatar) for automated deduplication and subsequent manual screening. Title and abstract screening were independently performed by two pairs of reviewers (M. Nombera-Aznaran and N. Nombera-Aznaran, and J. Nombera-Lossio and R. Aznaran-Torres) using a blinded, dual-review process to minimise bias. Any discrepancies were resolved through discussion, and if consensus could not be reached, an adjudicator (D. Fernandez-Guzman) was consulted. Full-text articles of potentially eligible studies were then reviewed following the same consensus-based approach to determine final inclusion.

Data extraction

Two pairs of investigators (M. Nombera-Aznaran and N. Nombera-Aznaran, and J. Nombera-Lossio and R. Aznaran-Torres) independently extracted pre-defined data from each full-text article using standardised data extraction spreadsheets. The extracted information included study characteristics, participant demographics, details of the salbutamol intervention and outcome measures. Entries were systematically cross-checked for accuracy, and discrepancies were resolved through consensus or adjudication by an adjudicator (D. Fernandez-Guzman) when necessary. The longest available follow-up period for primary or secondary outcomes was used in the analysis.

Risk-of-bias assessment

Two pairs of investigators (M. Nombera-Aznaran and N. Nombera-Aznaran, and J. Nombera-Lossio and R. Aznaran-Torres) independently assessed the risk of bias for each included primary study using the Cochrane Collaboration Risk of Bias 1 tool [24]. Any discrepancies were resolved through consensus or, if needed, by consulting a third investigator (D. Fernandez-Guzman). The assessment categorised studies as having low risk, high risk, or other concerns across multiple domains, including allocation sequence concealment (selection bias); blinding of participants, personnel and outcome assessors (performance and detection bias); incomplete outcome data (attrition bias); and selective outcome reporting (reporting bias). Additionally, we evaluated other potential sources of bias, such as imbalances in baseline characteristics, deviations from intended interventions, unexpected co-interventions during the trial, premature trial termination, unclear funding source roles, and the use of nonvalidated instruments for measuring key confounders or outcomes.

Data synthesis and statistical analysis

We performed all statistical analyses using Cochrane's Review Manager (RevMan). For dichotomous outcomes, we calculated pooled risk ratios with 95% confidence intervals. For continuous outcomes, we used the mean difference (MD) or, when different measurement scales were reported, the standardised mean difference, both with 95% confidence intervals.

A random-effects model (DerSimonian–Laird) was used for moderate to high heterogeneity (I²≥40%), while a fixed-effects model was applied for low heterogeneity (I²<40%). Statistical significance was set at p<0.05. Heterogeneity was classified as low (I²<40%), moderate (I²=40–80%) or high (I²>80%).

To explore heterogeneity, we conducted subgroup analyses based on follow-up (30 min, 1 h, 4 h, 8 h and 1 day since the intervention). Subgroup significance was evaluated using the interaction p-value (Chi-squared test in RevMan), with p<0.10 indicating a significant effect. We planned to assess publication bias using funnel plots in cases where the meta-analysis included >10 studies.

Certainty of evidence (GRADE)

We assessed the certainty of evidence for each main outcome as high, moderate, low or very low using the GRADE approach [25]. This method evaluates five key domains: risk of bias, inconsistency, indirectness, imprecision and publication bias.

For the assessment of evidence certainty, we applied a minimally contextualised approach, considering a single threshold for decision-making [26]. Certainty was not downgraded for risk of bias if ≥70% of the meta-analysis weight came from studies with a low risk of bias [27]. It was downgraded by one level if this percentage was 50–70%, and by two levels if it was <50%. To evaluate imprecision, we used the minimally important difference (MID) for each outcome [28], adopting established values when available. For outcomes without published MIDs, we defined potential MIDs by consensus among the authors (the MID was considered as five events per 100 persons for need for continuous positive airway pressure, three events per 100 persons for need for mechanical ventilation, 12 h for duration of oxygen therapy, 10 h for duration assisted ventilation, 1 day for length of hospital stay, 6 h for duration of tachypnoea, and 1 point for clinical score of TTN). Inconsistency was evaluated based on the variability of point absolute effects relative to the MID [29], with a one-level downgrade if 60–80% of the meta-analysis weight had their point effects on the same side of the MID as the overall effect, and a two-level downgrade if it was <60%. We carefully avoided double downgrading when domains were conceptually related. Specifically, we did not downgrade for both imprecision and inconsistency when the imprecision could reasonably be attributed to heterogeneity among study results. For indirectness, we considered the alignment of studies with the population, intervention, comparator, and outcomes, reducing certainty by one level if some studies did not fully meet these criteria and by two levels if >70% of the meta-analysis weight showed deficiencies in two or more PICO components. Publication bias was evaluated using a funnel plot and Egger test, with a one-level downgrade if there was suspicion of bias.

Results

Study selection

Our systematic search identified 113 records through electronic databases and an additional two from other sources. After removing duplicates, we screened titles and abstracts, yielding 15 full-text articles for eligibility assessment. Ultimately, 14 RCTs met our inclusion criteria. In addition, seven studies were retrieved through manual searches and reference screening (figure 1). A list of excluded studies, along with reasons for exclusion, is provided in supplementary material 3.

FIGURE 1.

Flow diagram of study selection.

Study characteristics

21 RCTs [15–22, 30–42] published between 2011 and 2025 were included, enrolling 1223 neonates diagnosed with TTN. Most studies were conducted in Middle Eastern countries: Iran (n=6), Pakistan (n=7) and Egypt (n=4), with additional studies from Turkey, Korea, Mexico and India. Sample sizes ranged from 30 to 284 participants. The majority of neonates were born late preterm or term and enrolled within the first 6 h of birth (table 1). All trials compared salbutamol with either placebo or standard care. In most studies, the intervention consisted of a single nebulised dose of salbutamol at 0.15 mg·kg⁻¹ administered within 6 h of birth. In studies using repeated doses, the most common regimen was 0.15 mg·kg⁻¹ every 6 h, for a total duration of 24–72 h, depending on clinical response. Nebulisation was delivered using jet or ultrasonic devices with continuous oxygen flow. Full dosing details are available in supplementary material 4 and table 1.

TABLE 1.

Study characteristics

First author, year [reference]	Country	Population	Sample size	Male %	Gestational age weeks	Birthweight g	Salbutamol dosage
Ahmed, 2022 [31]	Pakistan	<6 h old GA ≥37 weeks	IG: 30 CG: 30	IG: 46.7 CG: 46.7	IG: 38.4±1.4 CG: 38.3±1.2	IG: 2970.0±250.0 CG: 2990.0±270.0	0.15 mg·kg−1 one dose
Alvi, 2025 [32]	Pakistan	GA >35 weeks	IG: 30 CG: 30	IG: 56.7 GC: 53.3	IG: 37.7±1.0 CG: 37.9±1.2	IG: 3115±134 CG: 3131.7±129	0.15 mg·kg−1 one dose
Anwar, 2023 [18]	Pakistan	<6 h old	IG: 40 CG: 40	IG: 57.5 CG: 55	Not reported	IG: 2470±540 CG: 2460±590	0.15 mg·kg−1 one dose
Armangil, 2011 [33]	Turkey	<6 h old	IG: 32 CG: 22	IG: 66 CG: 77	IG: 37.0±1.6 CG: 36.7±1.6	IG: 2991±536 CG: 2990±574	0.15 mg·kg−1 one dose
Babaei, 2019 [20]	Iran	GA >35 weeks	IG: 40 CG: 40	IG: 60 CG: 72.5	IG: 36.7±1.1 CG: 36.3±1.4	IG: 3180.8±696.9 CG: 3068.8±577.0	0.15 mg·kg−1 one dose
Basiri, 2022 [34]	Iran	<6 h old GA 34–37 weeks	IG: 30 CG: 30	IG: 46.2 CG: 57.7	IG: 36.3±1.9 CG: 36.6±1.5	IG: 2873.7±580.4 CG: 2772.6±469.7	0.10 mg·kg−1 one dose
Choodbar, 2024 [21]	Iran	GA >35 weeks	IG: 30 CG: 30	Not reported	IG: 36.6±1.3 CG: 36.3±0.9	IG1: 3067.0±285 GC: 2816.0±484	1.25 mg one dose
Dhaka, 2024 [19]	India	GA ≥34 weeks	IG: 67 CG: 67	IG: 59.7 GC: 61.2	IG: 37.0±2.0 CG: 36.7±1.9	IG: 2769±579 CG: 2610±530	0.15 mg·kg−1 one dose
Hamed, 2022 [22]	Egypt	GA >36 weeks	IG: 50 CG: 50	IG: 52 CG: 56	Not reported	IG: 3040±640 CG: 3080±680	0.15 mg·kg−1 every 6 h for 72 h
Hussain, 2020 [16]	Pakistan	GA >35 weeks	IG: 142 CG: 142	IG: 51.4 GC: 50.7	IG: 38.8±1.4 CG: 38.7±1.4	IG: 2350.5±111.9 CG: 2347.9±88.1	0.15 mg·kg−1 four times daily for 24 h
Hussain, 2025 [30]	Pakistan	GA >35 weeks	IG: 30 CG: 30	IG: 60 GC: 55	IG: 38.5±1.2 CG: 38.4±1.1	IG: 3200±300 CG: 3100±200	0.15 mg·kg−1 one dose
Khushdil, 2022 [35]	Pakistan	GA >34 weeks	IG: 25 CG: 25	All: 48	All: 38.8 +6.2	All: 2558.0±620.0	0.2 mL one dose
Kim, 2014 [36]	Korea	GA >35 weeks	IG: 28 CG: 12	IG: 60.7 CG: 58.3	IG: 37.6±1.9 CG: 37.5±1	IG: 3090.7±591.0 CG: 3203.3±432.0	0.15 mg·kg−1 one dose
Malakian, 2018 [17]	Iran	<6 h old	IG: 74 CG: 74	IG: 72.9 CG: 63.5	IG: 37.6±1.5 CG: 37.4±1.9	IG: 2.8±0.4 CG: 2.8±0.5	0.15 mg·kg−1 one dose additional doses as required
Maroof, 2021 [37]	Pakistan	GA >37 weeks	IG: 50 CG: 50	IG: 52 GC: 52	IG: 39.9±1.4 CG: 40.0±1.5	IG: 2963.4±282.8 CG: 3034.9±273.6	0.15 mg·kg−1 two doses at a 4-h interval
Mohammadzadeh, 2017 [38]	Iran	<6 h old	IG: 35 CG: 35	IG: 65.7 CG: 62.9	IG: 36.9±2 CG: 36.7±1.7	IG: 2988.3±720.0 CG: 2988.3±720.0	0.15 mg·kg−1 one dose
Monzoy-Ventre, 2015 [39]	Mexico	6 h old	IG: 15 CG: 15	IG: 53.3 CG: 60	IG: 36.6±1.7 CG: 36.6±2.5	IG: 2454.6±702.8 CG: 2519.3±592.1	0.15 mg·kg−1 three doses, every 4 h, 3 times
Mussavi, 2017 [40]	Iran	GA >35 weeks	IG: 30 CG: 30	IG: 58 CG: 42	IG: 37.0±1.7 CG: 36.9±1.7	IG: 2676.3±611.1 CG: 2731.0±576.4	0.15 mg·kg−1 every 6 h for 24 h
Sabry, 2022 [41]	Egypt	GA >35 weeks	IG: 25 CG: 50	IG: 60 CG: 60	IG: 37.8±0.9 CG: 37.5±0.9	IG1: 3094.0±193 GC: 2965.0±440	0.15 mg·kg−1 one dose
Salama, 2020 [42]	Egypt	GA 35–39 weeks	IG: 50 CG: 50	IG: 48 GC: 52	IG: 38.5±0.9 CG: 38.4±0.8	IG: 3330±420 GC: 3340±390	0.15 mg·kg−1 one dose
Talaat, 2020 [15]	Egypt	>6 h old	IG: 54 CG: 46	IG: 59 GC: 59	IG: 36.7±1.7 CG: 36.9±1.6	IG: 2825.9±414.6 CG: 2883.2±437.9	0.15 mg·kg−1 one dose

GA: gestational age; IG: intervention group; CG: control group.

Risk-of-bias assessment

The risk of bias across included studies was variable. Unclear were most frequently related to random sequence generation (unclear in nine out of 21 RCTs) and allocation concealment (unclear in 17 out of 21 RCTs). In contrast, the risk of bias was generally low for incomplete outcome data and other potential sources of bias. Only one trial (Anwar et al. [18]) was judged to have a high risk of performance bias. Two studies (Choodbar et al. [21] and Dhaka et al. [19]), were assessed as having low risk of bias in most domains, meeting six out of seven criteria (figure 2).

FIGURE 2.

Summary of the risk-of-bias assessment. a) Risk-of-bias graph; b) risk-of-bias summary by study.

Primary outcomes

Mortality

None of the included trials reported on mortality. Therefore, the effect of salbutamol on mortality remains unknown.

Need for respiratory support

The evidence was very uncertain regarding the effect of salbutamol on the need for mechanical ventilation (risk ratio 0.37, 95% CI 0.07 to 1.96; risk difference (attributable risk) 2.4 fewer per 100; three RCTs; very low certainty) due to serious imprecision (figure 3a). Regarding the need for continuous positive airway pressure (CPAP), pooled data from six RCTs (n=535) suggest that salbutamol may have little to no effect (risk ratio 0.84, 95% CI 0.59 to 1.19; risk difference 8.5 fewer per 100; very low certainty); however, the evidence was uncertain (figure 3b).

FIGURE 3.

Meta-analysis of the effect of salbutamol versus placebo on a) need for mechanical ventilation; b) need for continuous positive airway pressure (CPAP); c) duration of respiratory support (intermittent positive pressure ventilation or CPAP); d) duration of oxygen therapy; e) duration of tachypnoea >60 breaths·min⁻¹. M-H: Mantel–Haenszel; IV: inverse variance; risk of bias: A: random sequence generation; B: allocation concealment; C: blinding of participants and personnel; D: blinding of outcome assessors; E: incomplete outcome data; F: selective reporting; G: other biases.

Salbutamol may reduce the duration of respiratory support, including CPAP and mechanical ventilation, by ∼13 h (MD −12.7 h, 95% CI −19.6 to −5.7 h; eight RCTs; low certainty) (figure 3c). Conversely, the intervention may lead to a meaningful reduction in duration of oxygen therapy (MD −19.4 h, 95% CI −26.0 to −12.9 h; 12 RCTs; low certainty) (figure 3d). There was no evidence of a difference in effect between single and repeated doses. Test for subgroup differences: p=0.29 for respiratory support; p=0.30 for oxygen therapy (supplementary material 5 and 6).

Duration of tachypnoea

Likewise, the intervention may reduce the duration of tachypnoea by ∼6.6 h (MD −6.6 h, 95% CI −12.6 to −0.7 h; four RCTs; low certainty) (figure 3e).

Length of hospital stay

A single dose of salbutamol may meaningfully reduce the length of hospital stay by ∼1.4 days compared with placebo (MD −1.2 days, 95% CI −1.9 to −0.5 days; 10 RCTs; low certainty) (figure 4). Repeated doses showed a greater and probably clinically meaningful reduction in length of hospital stay (MD −2.27 days, 95% CI −3.17 to −1.36; three RCTs; moderate certainty) (figure 4).

FIGURE 4.

Meta-analysis of the effect of salbutamol versus placebo (single versus repeated doses) on length of hospital stay. Risk of bias: A: random sequence generation; B: allocation concealment; C: blinding of participants and personnel; D: blinding of outcome assessors; E: incomplete outcome data; F: selective reporting; G: other biases.

Secondary outcomes

Clinical severity scores

Salbutamol may reduce the severity of TTN based on clinical scores measured across various time points. At 1 h post-intervention, pooled analysis from four RCTs showed a modest reduction of approximately 1 point in clinical severity score (MD −1.0, 95% CI −1.7 to −0.3; four RCTs; low certainty). Furthermore, salbutamol may lead to a meaningful reduction in the TTN clinical score at 4 h (MD −3.0, 95% CI −4.1 to −1.9; 10 RCTs; low certainty) and at 8 h (MD −3.4, 95% CI −3.8 to −3.0; one RCT, low certainty) (supplementary material 7).

Blood oxygen saturation

Salbutamol may not lead to a meaningful increase in oxygen saturation during the first hours after administration. At 30 min, the pooled estimate from two trials showed a modest increase (MD +1.2%, 95% CI +0.4 to +1.9; two RCTs; low certainty), but the magnitude was below the MID. Similar findings were observed at 1 h (MD +1.6%, 95% CI +0.4 to +2.8; two RCTs; moderate certainty) and at 4 h (MD +2.0%, 95% CI +1.5 to +2.4; seven RCTs; low certainty). At 24 h, one trial showed no clear effect (MD +0.4%, 95% CI −0.6 to +1.4; one RCT) (supplementary material 8).

Respiratory rate

Salbutamol is unlikely to lead to a meaningful reduction in respiratory rate within the first hour of administration. At 30 min, the pooled estimate from six trials showed a small reduction (MD −2.1 breaths·min⁻¹, 95% CI −3.6 to −0.6 breaths·min⁻¹; moderate certainty), and at 1 h the effect was slightly greater (MD −4.6 breaths·min⁻¹, 95% CI −7.9 to −1.3 breaths·min⁻¹; five RCTs; moderate certainty); however, both effects were probably below the MID (change in 10 breaths·min⁻¹). At 4 h, the reduction appeared larger (MD −9.3 breaths·min⁻¹, 95% CI −12.9 to −5.7 breaths·min⁻¹; 11 RCTs, low certainty). One trial at 24 h found no clear effect (MD −3.3 breaths·min⁻¹, 95% CI −10.4 to +3.9 breaths·min⁻¹; one RCT) (supplementary material 9).

Adverse effects

Only one trial [30] explicitly reported on adverse events, although no details were available in the summary data. Therefore, the safety profile of salbutamol in this population remains uncertain.

Publication bias

Funnel plots were visually inspected to assess the potential for publication bias in the outcomes of duration of oxygen therapy, length of hospital stay and respiratory rate (supplementary materials 10–12). The plots showed a relatively symmetrical distribution for hospital stay and respiratory rate outcomes, while some asymmetry was observed for the duration of oxygen therapy. Egger's linear regression test was conducted to evaluate this formally. For all three outcomes, the test did not indicate significant funnel plot asymmetry (p>0.05).

Certainty of the evidence

The certainty of the evidence was predominantly low or very low across outcomes (table 2 and supplementary material 13). Most outcomes were downgraded due to concerns about risk of bias (related to unclear randomisation methods and allocation concealment), inconsistency (moderate to high heterogeneity), and imprecision (particularly when the number of events or participants was low).

TABLE 2.

Summary of findings of salbutamol versus placebo or no treatment for transient tachypnoea of the newborn (TTN) (follow-up during hospitalisation)

	Number and type of studies (population)	Intervention: salbutamol n/N (%)	Control: placebo/standard care n/N (%)	Relative effect (95% CI)	Absolute difference (95% CI)	Certainty of the evidence (GRADE)	Comments
Mortality	No evidence was found for this outcome
Need for mechanical ventilation	3 RCTs (n=258)	1/129 (0.8%)	5/129 (3.9%)	Risk ratio 0.37 (0.07 to 1.96)	RD −2.4 (−3.6 to +3.7) per 100	⨁○○○ Very low#,¶	The evidence is very uncertain regarding the effect of salbutamol on the need for mechanical ventilation
Need for CPAP	6 RCTs (n=535)	106/255 (41.6%)	149/280 (53.2%)	Risk ratio 0.84 (0.59 to 1.19)	RD −8.5 (−21.8 to +10.1) per 100	⨁○○○ Very low#,¶	The evidence is very uncertain regarding the effect of salbutamol on the need for CPAP
Duration of assisted ventilation, including intermittent positive pressure ventilation or CPAP	8 RCTs (n=667)	Range of means 1.0 to 49.2 h	Range of means 8.2 to 79.2 h		MD −12.7 (−19.6 to −5.7)	⨁⨁○○ Low#,+	Salbutamol may lead to a meaningful reduction in duration of assisted ventilation
Duration of oxygen therapy	12 RCTs (n=1116)	Range of means 1.9 to 61.1 h	Range of means 6.9 to 85.3 h		MD −19.4 (−26.0 to −12.9) h	⨁⨁○○ Low#,§	Salbutamol may lead to a meaningful reduction in duration of oxygen therapy
Length of hospital stay (single dose of salbutamol)	10 RCTs (n=691)	Range of means 1.8 to 8.5 days	Range of means 2.7 to 8.8 days		MD −1.2 (−1.9 to −0.5) days	⨁⨁○○ Low#,+	Single dose of salbutamol may lead to a meaningful reduction in length of hospital stay
Length of hospital stay (repeated doses of salbutamol)	3 RCTs (n=532)	Range of means 2.0 to 3.9 days	Range of means 5.1 to 5.7 days		MD −2.3 (−3.2 to −1.4) days	⨁⨁⨁○ Moderate#	Repeated doses of salbutamol probably led to a meaningful reduction in length of hospital stay
Duration of tachypnoea, defined as a respiratory rate >60 breaths·min−1	4 RCTs (n=314)	Range of means 1.5 to 34.5 h	Range of means 6.4 to 53.5 h		MD −6.6 (−12.6 to −0.7) h	⨁⨁○○ Low#,+	Salbutamol may lead to a meaningful reduction in duration of tachypnoea
Clinical score of TTN, with a total range of 0–10 points. A higher score indicates more severe TTN (follow-up: 4 h)	10 RCTs (n=721)	Range of means 0.03 to 5.1 points	Range of means 0.9 to 7.6 points		MD −3.0 (−4.1 to −2.0) points	⨁⨁○○ Low#,§	Salbutamol may lead to a meaningful reduction in the clinical TTN score at 4 h
Clinical score of TTN, with a total range of 0–10 points. A higher score indicates more severe TTN (follow-up: 8 h)	1 RCT (n=100)	Mean 4.3 points	Mean 7.6 points		MD −3.4 (−3.8 to −3.0) points	⨁⨁○○ Low#,§	Salbutamol may lead to a meaningful reduction in the clinical TTN score at 8 h

The minimal important difference (MID) was considered as five events per 100 persons for need for continuous positive airway pressure (CPAP), three events per 100 persons for need for mechanical ventilation, 12 h for duration of oxygen therapy, 10 h for duration assisted ventilation, 1 day for length of hospital stay, 6 h for duration of tachypnoea, and 1 point for clinical score of TTN. GRADE: Grading of Recommendations Assessment, Development, and Evaluation; RCT: randomised controlled trial; RD: risk difference (attributable risk); MD: mean difference. ^#: certainty was downgraded by one level for risk of bias, as ∼70% of the meta-analysis weight came from studies assessed as low risk of bias; ^¶: certainty was downgraded by two levels for imprecision, as the 95% confidence interval of the absolute effect crossed two MIDs; ⁺: certainty was downgraded by one level for imprecision, as the 95% confidence interval of the absolute effect crossed one MID; ^§: certainty was downgraded by one level for inconsistency due to moderate heterogeneity and partial inconsistency in point estimates relative to the MID.

Discussion

Main findings

This systematic review synthesises randomised evidence on salbutamol for TTN, suggesting potential short-term benefits, although the overall certainty of evidence was low to very low for most outcomes. Salbutamol may lead to a meaningful reduction in the duration of oxygen therapy, and repeated doses probably led to a meaningful reduction in the length of hospital stay, while the evidence is very uncertain regarding a meaningful effect from a single dose. The evidence is also very uncertain regarding a meaningful effect on the need for mechanical ventilation, CPAP, duration of assisted ventilation and duration of tachypnoea. Furthermore, salbutamol may lead to a meaningful reduction in the clinical TTN score at 4 and 8 h, but the evidence is very uncertain at 30 min and 1 h. It may not lead to a meaningful increase in oxygen saturation at 30 min, 1 h or 4 h, and is unlikely to lead to a meaningful reduction in respiratory rate at 30 min or 1 h, with very uncertain evidence at 4 h.

We included 21 randomised controlled trials involving 1223 neonates, mostly from middle-income countries. Most studies enrolled term or late preterm infants, and salbutamol was typically compared to placebo. Heterogeneity in diagnostic criteria and intervention protocols limited consistency, and many studies had methodological limitations.

Comparison with other studies and implications for clinical practice

Our findings align with previous narrative reviews [2] and meta-analyses [12] that suggested potential short-term benefits of salbutamol for neonates with TTN. However, this review provides the most comprehensive and current synthesis of randomised evidence, incorporating the largest number of trials published through 2025. By applying the GRADE framework and interpreting results against MIDs, we offer enhanced clinical relevance.

Although current neonatal respiratory guidelines do not routinely recommend salbutamol for TTN, our results indicate that future updates might consider its use as adjunctive therapy for selected neonates, particularly those with more severe disease, pending confirmation of efficacy and safety in further trials. Other interventions such as corticosteroids, diuretics and supplemental oxygen lack consistent high-certainty evidence of benefit [43]. CPAP remains the cornerstone of management, but typically necessitates NICU admission, which imposes significant financial and logistical burdens.

A recent review [1] estimated TTN-related NICU care costs between EUR 20 and 63 million annually across five high-income countries, with daily NICU expenses reaching EUR 2500. TTN also contributes to NICU overcrowding, inter-hospital transfers, and delays in admitting critically ill neonates, while imposing psychosocial and logistical challenges on families. In this context, a low-cost intervention such as salbutamol, if effective in reducing respiratory support or hospital stay, could yield meaningful clinical, public health and economic benefits. Even modest reductions in hospitalisation could improve NICU bed availability and resource utilisation, especially in publicly funded systems.

Nonetheless, substantial clinical and methodological heterogeneity, including variations in TTN severity, dosing protocols and the absence of standardised diagnostic criteria, probably contributed to imprecision and variability in observed effects. Additionally, the near-complete lack of adverse event reporting limits conclusions on safety. Known β₂-agonist side-effects, such as tachycardia and hyperglycaemia [13], were not documented, but remain plausible and should be carefully monitored in future studies.

Physiological rationale and heterogeneity

Salbutamol's mechanism of action, enhancing alveolar fluid clearance through β₂-adrenergic stimulation, provides a biologically plausible basis for its use in TTN. By activating epithelial sodium channels and sodium/potassium-ATPase activity in the pulmonary epithelium, salbutamol promotes reabsorption of fetal lung fluid, directly targeting the primary pathophysiological mechanism of TTN [44]. Early administration, often within the first hours after birth, may be critical to maximise this effect by addressing the period of greatest pulmonary fluid overload [12].

Repeated dosing may sustain or amplify these physiological benefits. In our review, repeated doses probably led to a meaningful reduction in hospital length of stay, whereas the evidence for a single dose was very uncertain. This suggests a possible dose–response relationship that merits further evaluation to determine the most effective regimen.

Limitations and strengths

This study has several limitations. First, many of the included RCTs presented methodological concerns, particularly related to random sequence generation, allocation concealment, and lack of blinding of participants and outcome assessors, which may have introduced bias. Second, there was substantial clinical and statistical heterogeneity across studies, attributed to variations in TTN diagnostic criteria, dosing schedules, timing of salbutamol administration, and definitions and measurements of outcomes. Third, the limited reporting of adverse events hindered a thorough assessment of the safety profile of salbutamol in this population. Fourth, the generalisability of our findings may be constrained, as most studies were conducted in middle-income countries and excluded extremely preterm or critically ill neonates. Moreover, the supportive care protocols were not standardised across studies, and salbutamol regimens varied in both dose and frequency. These factors limit comparability and prevent robust assessment of a dose–response relationship. Importantly, none of the included trials randomised participants to different dosing strategies, which limits our ability to draw conclusions about optimal dosing. Future RCTs should consider stratified or factorial designs to evaluate the effect of dose and frequency more systematically. Additionally, the MIDs used to assess the certainty of the evidence under a minimally contextualised approach have not been externally validated and should be taken into account when interpreting the findings for public health decision-making.

Despite these limitations, our review also has several important strengths. It represents the most comprehensive analysis to date on the use of salbutamol in TTN, including the largest number of RCTs with broad geographic representation. Our methodology followed a prespecified protocol registered in PROSPERO and adhered to rigorous standards, including duplicate screening, validated risk of bias assessment tools, and independent data extraction. We applied the GRADE approach to assess the certainty of evidence, using MIDs for clinically relevant outcomes. Finally, this review focused on outcomes of direct clinical importance such as duration of oxygen therapy, length of hospital stay, and clinical severity scores which strengthens the applicability of the findings for clinical decision-making and health system planning.

Conclusion

Salbutamol may provide modest but clinically meaningful benefits for neonates with TTN, including a reduction in the duration of oxygen therapy and, with repeated dosing, a probable clinically important reduction in length of hospital stay (moderate certainty). These short-term effects are consistent with the transient nature of TTN, the pharmacological profile of salbutamol as a short acting β₂-agonist, and the timing of the outcomes assessed in the available trials. While evidence remains very uncertain for other outcomes such as the need for mechanical ventilation, CPAP use, and duration of tachypnoea, salbutamol could be considered as an adjunctive therapy, particularly in low-resource settings where even modest reductions in reducing hospital stay may lessen the burden on healthcare systems. Nevertheless, given the overall low to very low certainty of evidence and methodological limitations, routine use of salbutamol cannot yet be recommended. Further high-quality randomised trials are needed to confirm these findings, clarify safety, and assess cost-effectiveness before broader clinical adoption.

Supplementary material

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Supplementary material

00741-2025.SUPPLEMENT