Salbutamol: A Safety Meta-Analysis
Overview
Salbutamol, a widely used bronchospasm reliever, has been insufficiently scrutinized for potential risks. In a meta-analysis of 58 randomized controlled trials with 12,961 participants, the study unearthed a 34% incidence of total adverse events (AEs). Notably, severe AEs stood at 2%, and treatment discontinuation was 3%. Subgroup analysis revealed higher risks in cases of premature labor and intravenous use, notably associated with palpitations or tachycardia. The findings underscore the necessity for clinical vigilance and ongoing research to optimize the safe administration of salbutamol, a stalwart in managing bronchospastic conditions.
Introduction
Salbutamol, a primary choice for acute airflow obstruction in conditions like asthma and COPD, is extensively used. While previous studies generally deem long-term usage well-tolerated, the Global Initiative for Asthma (GINA) highlights increased short-acting β2-agonist (SABA) usage correlating with heightened risks, including emergency presentations and death. Despite most adverse events being manageable, they significantly impact patients psychologically and physically, inducing symptoms like nervousness, anxiety, palpitations, tachycardia, tremors, and headache. Notably, the safety profiles of salbutamol differ across trials, prompting a comprehensive meta-analysis of randomized controlled trials (RCTs) to delve into the adverse event profiles and offer a more nuanced understanding of salbutamol’s safety implications.
Salbutamol, revered for its efficacy in relieving acute airflow obstruction and symptoms associated with asthma, chronic obstructive pulmonary disease (COPD), and other bronchospasm-related conditions, has a long-standing reputation for being well-tolerated in long-term use. However, the Global Initiative for Asthma (GINA) sheds light on a critical concern – a higher utilization of short-acting β2-agonists (SABA), such as salbutamol, is linked to an elevated risk of adverse clinical outcomes, including emergency department presentations and even mortality.
While many adverse events (AEs) associated with salbutamol are considered manageable and not inherently life-threatening, their impact on patients’ psychological and physical well-being should not be underestimated. These events encompass a spectrum of effects, ranging from heightened nervousness and anxiety to more palpable physical symptoms like palpitations, tachycardia, tremors, and headaches. These manifestations underscore the need for a nuanced understanding of salbutamol’s safety profiles, especially considering the variability observed across different trials.
Surprisingly, despite salbutamol’s extensive use, a comprehensive and systematic meta-analysis addressing the specific adverse event profiles associated with its use has been lacking. In response to this gap, a meticulous exploration was undertaken through a meta-analysis of randomized controlled trials (RCTs). This endeavor seeks to unravel the intricate landscape of adverse events linked to salbutamol usage, providing a more informed perspective on its safety implications. This proactive approach aims to enhance clinical vigilance and contribute to ongoing research efforts, fostering a more optimized and secure usage of salbutamol in various clinical scenarios.
Methods
The study meticulously followed the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), ensuring a robust and transparent methodology. By adhering to these standards, the research aimed to provide a comprehensive and reliable analysis of the available evidence regarding the adverse events associated with salbutamol use.
The inclusion criteria were thoughtfully designed to encompass a broad yet specific range of studies. By focusing exclusively on randomized controlled trials (RCTs), the researchers aimed to establish a solid foundation for their analysis, ensuring a high level of scientific rigor and control. The absence of language restrictions further broadened the scope of the search, contributing to a more inclusive and representative sample of relevant studies.
The comprehensive search strategy employed across major databases, including EmBase, PubMed, and the Cochrane library, attested to the thoroughness of the study’s approach. The choice of specific search terms, such as ‘salbutamol,’ ‘albuterol,’ ‘adverse event,’ ‘adverse effect,’ ‘side effect,’ ‘toxicity,’ ‘clinical trial,’ ‘controlled clinical trial,’ and ‘randomized controlled trial,’ demonstrated a deliberate effort to capture all relevant literature on the subject.
The study’s commitment to data extraction was evident in the meticulous collection of information from each included study. Details ranging from the first author’s name, publication year, and country to more specific data, such as the number of patients in the salbutamol cohort, mean age, indications, and formulation of salbutamol, were systematically gathered. This exhaustive approach aimed to ensure a comprehensive understanding of the studies included in the analysis.
The assessment of the methodological quality of the included studies using the Newcastle-Ottawa Scale (NOS) further attested to the researchers’ commitment to maintaining a high standard of evidence. The three subscales—selection, comparability, and outcome—provided a nuanced evaluation of each study’s quality. This critical appraisal, including the assignment of stars and subsequent scoring, added a layer of transparency to the analysis, allowing readers to gauge the reliability of the included studies.
In the spirit of scholarly collaboration, the study’s approach to resolving disagreements through group discussion until a consensus was established underscored the importance of collective expertise and consensus-building in the research process. This collaborative aspect contributed to the robustness of the final selection of studies and the overall quality of the meta-analysis.
The study’s meticulous adherence to PRISMA guidelines, inclusive yet stringent inclusion criteria, comprehensive search strategy, detailed data extraction, and rigorous quality assessment collectively positioned it as a valuable contribution to the understanding of adverse events associated with salbutamol use.
Statistical Analysis
The meta-analysis focused on pooled incidences of total adverse events (AEs), severe AEs, treatment discontinuation, and specific AEs (tremor, palpitations, headache, nervousness, anxiety, cough, dyspnea, nausea, vomiting) in response to salbutamol treatment. Using a random-effects model, researchers calculated the pooled incidence and corresponding 95% confidence interval, employing I2 and Q statistics to measure heterogeneity. Sensitivity analysis assessed individual trial impact, while subgroup analysis examined variations by indications (premature labor, asthma, COPD) and salbutamol formulations (inhaled, oral, intravenous). Two-sided P-values below 0.05 were deemed statistically significant. Publication bias was evaluated using funnel plots, Egger’s test, and Begg’s test. All analyses utilized STATA 10.0.
Results
The study conducted an extensive search, identifying 8912 potential trials, with 5287 remaining after eliminating duplicates. Through title and abstract scrutiny, 5136 records were excluded, leaving 151 articles for full-text review. Of these, 93 articles were excluded for reasons such as reviews, duplicated cohorts, commentaries, non-randomized or non-human trials, or lacking adverse events (AEs) outcomes. Ultimately, 58 randomized controlled trials (RCTs), encompassing 12,961 patients, were included. The study period spanned from 1978 to 2020, focusing on asthma, COPD, premature labor, and other bronchoconstriction indications. Salbutamol formulations included inhaled (75.9%), oral (7 trials), and intravenous (7 trials). Dosages ranged from 200μg to 30 mg per day, with treatment durations spanning 1 day to 52 weeks. Quality assessment using the Newcastle-Ottawa Scale indicated good quality for 31 studies and fair quality for 27. Funnel plots and statistical tests revealed no publication bias. Incidences of total AEs were reported in 30 trials, yielding a pooled incidence of 34%. Subgroup analysis showed variations by indications and formulations. Incidences of severe AEs were reported in seven trials, resulting in a 2% pooled incidence. Treatment discontinuations were reported in 12 trials, with a pooled incidence of 3%. Specific AEs, such as palpitations or tachycardia, had a pooled incidence of 16%, while various nervous system-related AEs had pooled incidences ranging from 9%.
Conclusion
The comprehensive meta-analysis, involving 58 randomized controlled trials and 12,961 patients, delved into the adverse effects (AEs) of salbutamol across diverse conditions and formulations. The risk of total AEs was notably common, affecting 34% of patients, with severe AEs and treatment discontinuation at 2% and 3%, respectively. Palpitations or tachycardia emerged as the most frequent specific AEs, occurring in 16% of cases. Premature labor users exhibited a higher risk of total AEs (57%). Intravenous salbutamol usage correlated with increased total AEs (51% vs. 33%) and severe AEs (6% vs. 2%) compared to inhaled users. Anxiety (13%) and tremor (9%) were prominent nervous system-related AEs. The study underscores the need for careful consideration in cardiovascular patients and suggests heightened awareness during salbutamol use. While limitations and heterogeneity exist, the findings highlight the imperative for further research to ensure the safe administration of salbutamol in clinical practice.
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