Evaluating the Placebo Status of Nebulized Normal Saline in Patients with Acute Viral Bronchiolitis: A Systematic Review and Meta-analysis

Importance: In therapeutic trials for acute viral bronchiolitis, consistent clinical improvement in groups that received nebulized normal saline (NS) as placebo raises the question of whether nebulized NS acts as a treatment rather than a placebo. Objective: To measure the short-term association of nebulized NS with physiologic measures of respiratory status in children with bronchiolitis by analyzing the changes in these measures between the use of nebulized NS and the use of other placebos and the changes before and after nebulized NS treatment. Data Sources: MEDLINE and Scopus were searched through March 2019, as were bibliographies of included studies and relevant systematic reviews, for randomized clinical trials evaluating nebulized therapies in bronchiolitis. Study Selection: Randomized clinical trials comparing children 2 years or younger with bronchiolitis who were treated with nebulized NS were included. Studies enrolling a treatment group receiving an alternative placebo were included for comparison of NS with other placebos. Data Extraction and Synthesis: Data abstraction was performed per PRISMA guidelines. Fixed- and random-effects, variance-weighted meta-analytic models were used. Main Outcomes and Measures: Pooled estimates of the association with respiratory scores, respiratory rates, and oxygen saturation within 60 minutes of treatment were generated for nebulized NS vs another placebo and for change before and after receiving nebulized NS. Results: A total of 29 studies including 1583 patients were included. Standardized mean differences in respiratory scores for nebulized NS vs other placebo (3 studies) favored nebulized NS by -0.9 points (95% CI, -1.2 to -0.6 points) at 60 minutes after treatment (P <.001). There were no differences in respiratory rate or oxygen saturation comparing nebulized NS with other placebo. The standardized mean difference in respiratory score (25 studies) after nebulized NS was -0.7 (95% CI, -0.7 to -0.6; I² = 62%). The weighted mean difference in respiratory scores using a consistent scale (13 studies) after nebulized NS was -1.6 points (95% CI, -1.9 to -1.3 points; I² = 72%). The weighted mean difference in respiratory rate (17 studies) after nebulized NS was -5.5 breaths per minute (95% CI, -6.3 to -4.6 breaths per minute; I² = 24%). The weighted mean difference in oxygen saturation (23 studies) after nebulized NS was -0.4% (95% CI, -0.6% to -0.2%; I² = 79%). Conclusions and Relevance: Nebulized NS may be an active treatment for acute viral bronchiolitis. Further evaluation should occur to establish whether it is a true placebo..