NEBULIZED CORTICOSTEROIDS FOR ACUTE ASTHMATIC ATTACKS: A SYSTEMATIC REVIEW OF RANDOMIZED CONTROL TRIALS

Saleh Farhan M. Alanazi^1*, Abdulkarim Ahmed M Alshammari², Rayan Ahmed Alanazi², Turki Hani S Alhazmi³, Saud Ghadeer M Alanazi³, Kholoud Obeid H Al Bathaly⁴, Ahmed Rahil S Alanazi⁵ and Fahad Wadi S Alanazi^5
*Correspondence: Saleh Farhan M. Alanazi, Emergency and Critical Care Consultant, Prince Abdulaziz Bin Musaad Hospital, Arar, Saudi Arabia, Email:

Keywords

Nebulized corticosteroids; Acute asthma exacerbations; Emergency treatment; Systematic review.

Introduction

Respiratory symptoms, reversible airflow restriction, and hyper-responsiveness are all hallmarks of asthma, a chronic inflammatory disease of the airways [1, 2]. In both the developed and developing worlds, it is the most prevalent chronic lung disease. Evidence suggests that its prevalence has risen globally during the past 20 years [3–5].

Every asthmatic patient is susceptible to exacerbations, which are marked by a progressive worsening of coughing, wheezing, chest tightness, and shortness of breath, as well as a reduction in expiratory airflow. This condition has been referred to as acute asthma (AA) or asthma attack. Exacerbations can range in severity from minor to potentially fatal. Although deterioration typically occurs over hours, days, or weeks, some individuals have abrupt and unanticipated increases in airway blockage (over minutes). At least 12 different places worldwide have reported experiencing epidemic asthma, which is the simultaneous occurrence of an abnormally large number of asthma attacks in one region at one time [6].

ED and critical care professionals frequently deal with asthma attack as a medical emergency. Adolescents and young adults are the age groups most likely to seek treatment at the emergency department (ED), with asthma ranking as the eleventh most common ED diagnosis in the US [7]. Hospitalization and ED visits for asthma attack are twice as common among women as among males [8].

Management is based on how severe asthma flare-ups are. The objectives of treatment can be summed up as follows: reducing airway inflammation and preventing future relapses by early systemic corticosteroid administration; relieving airflow obstruction with repeated administration of rapid-acting inhaled bronchodilators (such as -agonists and anticholinergics); and maintaining adequate arterial oxygen saturation with supplemental oxygen [9].

While systemic corticosteroids have long been the standard treatment for acute asthma attacks due to their anti-inflammatory properties, they come with the potential for significant side effects, particularly with repeated or long-term use [15]. In recent years, nebulized corticosteroids have emerged as a promising alternative. Administered directly into the lungs, nebulized corticosteroids may provide a more targeted approach, reducing systemic absorption and potentially lowering the risk of side effects associated with systemic administration [17]. However, despite their increasing use in clinical settings, the efficacy and safety profile of nebulized corticosteroids in treating acute asthmatic attacks remain under debate. Given the growing interest in optimizing asthma management while minimizing adverse effects, a systematic review of randomized controlled trials (RCTs) assessing the outcomes of nebulized corticosteroids is crucial to determine their role in acute asthma treatment. This systematic review aims to evaluate the effectiveness and safety of nebulized corticosteroids in the management of acute asthmatic attacks

Methods

Search strategy

The systematic review adhered to the PRISMA and GATHER criteria. A thorough search was undertaken to locate relevant studies on the effectiveness and safety of nebulized corticosteroids in the management of acute asthmatic attacks. The reviewers looked at four electronic databases: PubMed, Cochrane, Web of Science, and SCOPUS. Studies published between 2019-2024 were included. We uploaded all of the titles and abstracts identified through electronic searches into Rayyan, removing any duplicates. All texts from papers that met the inclusion criteria based on title or abstract were collected and thoroughly inspected. Two reviewers independently evaluated the appropriateness of the extracted publications and resolved any contradictions through discussion.

Study population-selection

The PICO (Population, Intervention, Comparison, and Outcome) factors were implemented as inclusion criteria for our review: (i) Population: Patients with acute asthmatic attacks, (ii) Intervention: Nebulized corticosteroids, (iii) Comparator: Other anti-asthmatic medications, (iv) Outcome: Effectiveness and safety of nebulized corticosteroids. Only primary investigations studying the administration of biological treatment to pustular psoriasis were included.

Data extraction

Two unbiased reviewers retrieved data from studies that met the inclusion criteria in a consistent and established format. The following information was retrieved and recorded: (i) First author (ii) Year of publication, (iii) Study design, (iv) Country, (v) Sample size, (vi) Gender, (vii) Age (viii) Population type, (ix) Intervention/ dosage, (x) Main outcomes (effectiveness and safety).

Quality review

The Cochrane Risk of Bias Instrument [10] was used to conduct a critical appraisal of the identified RCTs. This tool evaluates the risk of bias in seven fields: arbitrary sequence generation, allocation secrecy, blinding of participants and employees, blinding of outcome evaluation, inadequate outcome data, selective reporting, and additional bias sources. The risk of bias in each of these domains was classified as low, unclear, or high.

Results

The specified search strategy yielded 513 publications (Figure 1). After removing duplicates (n = 287), 226 articles were evaluated based on title and abstract. Of these, 189 failed to satisfy eligibility criteria, leaving just 37 full-text articles for comprehensive review. A total of 5 satisfied the requirements for eligibility with evidence synthesis for analysis (Figure 1).

Sociodemographic and clinical outcomes

We included 5 studies with a total of 361 patients (176 in the case group and 185 in the control group) and less than half of them were females 163 (45.2%). All of the included studies RCTs [12-16]. One study was implemented in Iran [12], one in Tunisia [13], one in Turkey [14], one in Pakistan [15], and one in Iraq [16].

In adults, the use of nebulized corticosteroids, specifically budesonide, appears to offer potential benefits in managing acute asthma attacks. Nebulized budesonide may contribute to hastening recovery by improving respiratory flow and potentially shortening hospital stays when included as part of a comprehensive treatment regimen. This regimen often includes oxygen, systemic corticosteroids, and short-acting beta agonists (SABA). However, in emergency settings, nebulized corticosteroids, when used alongside other medications like hydrocortisone, may not consistently provide additional benefits compared to the effects of hydrocortisone alone [12, 13].

In children, nebulized budesonide has shown promising results, particularly in cases of moderate asthma attacks. Studies indicate that low-dose nebulized budesonide may be just as effective as systemic steroids in reducing the severity of symptoms and hospital stay length. Moreover, when combined with nebulized salbutamol, budesonide significantly improves clinical outcomes and reduces emergency room stays, providing a substantial benefit in managing acute exacerbations in pediatric patients [14-16] (Table 1, Figure 2).

NS=Not-Specified
Table 1. Outcome measures of the included studies.

Discussion

This systematic review demonstrated that in adults, nebulized budesonide may enhance recovery, improve respiratory flow, and shorten hospital stays when added to standard asthma treatment; however, any additional benefit beyond hydrocortisone administered alone remains uncertain. Similarly, Kearns et al. validated the effectiveness of ICS for patients with acute asthma who visit the emergency department. When treating moderate-to-severe asthma exacerbations in the emergency department, there is some evidence that large doses of ICS, when combined with systemic corticosteroids, lower the likelihood of hospitalization [17]. Krishnan et al. also found that Oral and ICS combinations may reduce the chance of relapse after hospital or emergency department discharge [18].

It is interesting to consider the possible mechanisms through which ICS may have acute effects on asthmatic patients experiencing a severe exacerbation. 30 minutes after inhaling fluticasone [19] and budesonide [20], ICS temporarily decrease airway mucosal blood flow in asthmatic patients by acutely suppressing airway hyperperfusion. This short-lived nongenomic action has a quick onset and is linked to the plasma membrane rather than glucocorticoid receptors [21]. The extra effectiveness of ICS when given in addition to SCS in the acute context may be explained by the fact that the genomic effects of corticosteroids take at least 6 to 12 hours to fully manifest [22].

This review also found that nebulized budesonide was effective in treating a moderate asthma attack in children, especially in combination with nebulized salbutamol, offering a clinically comparable response to systemic steroids with regard to mean symptom score and duration of hospital stay. These results highlight nebulized corticosteroids as a potentially useful alternative in the management of acute asthma, especially in pediatric patients. In the line with our results, Castro‐Rodriguez et al. reported that adding budesonide to systemic corticosteroid reduces length of stay and improves acute asthma score in children in an emergency department setting, but it has no effect on hospitalization rate when compared to systemic corticosteroid alone [23]. Direkwattanachai et al. also found that in order to treat acute asthma flare-ups of any severity, nebulized corticosteroids may be a useful treatment choice. Nebulized budesonide is the corticosteroid of choice [24].

This would mean that nebulized corticosteroids could replace systemic corticosteroids in clinical practice, especially in children, where the avoidance of systemic adverse effects is desirable. Such a mode of treatment might prove particularly useful in the emergency setting, where quick improvement and, consequently, shorter hospitalization may actually mean less cost and better patient throughput. In adults, nebulized corticosteroids may confer some benefits; however, the overall role of these agents, in addition to other modalities such as hydrocortisone, is not well defined and may not be consistently advantageous. In general, nebulized corticosteroids seem promising for both pediatric and adult populations, but the most solid support in favor is for pediatric use.

 

The aim of this review is to emphasize the role of nebulized corticosteroids in acute asthma management by systematically reviewing the best evidence available, represented by RCT. Because the review has focused on RCTs, this makes the evidence quite robust with minimal biases, hence more reliable. The inclusion of different studies across a wide age spectrum improves the external validity of nebulized corticosteroid efficacy for both adults and children.

Considering these strengths, some limitations should be considered. The heterogeneity of treatment protocols concerning different medications, dosages, and co-administered medication across studies complicates comparing results, at least in adults. Secondly, sample sizes of some of the included studies were rather small, which may reduce the generalizability of findings. Lastly, regional differences concerning nebulized corticosteroid availability in clinical practice and differences in healthcare practice might further restrict the generalization of these findings to larger populations.

Conclusion

Nebulized corticosteroids, more specifically budesonide, are a promising treatment option for acute asthma exacerbation and, in particular, in children because of its equal efficacy as compared to systemic steroids with less adverse effects. Corticosteroids may enhance outcomes when used in combination with other interventions in adults; as an isolated intervention, however, the outcome remains uncertain. Further large-scale and standardized studies are necessary to establish the full potential of nebulized corticosteroids both in pediatric and adult populations.

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