REVIEW
Outpatient Medications Deimplemented by the AAP Bronchiolitis Guidelines: An Umbrella Review of Meta-Analyses
Larry Mellick,
Paul Walsh, Clista Clanton,
Sarathi Kalra,
Shane McKinney,
Corresponding Author
Larry Mellick
Department of Emergency Medicine, Augusta University, Augusta, Georgia, USA
Correspondence: Larry Mellick ([email protected])
Search for more papers by this authorClista Clanton
Charles M. Baugh Biomedical Library, University of South Alabama, Mobile, Alabama, USA
Search for more papers by this authorSarathi Kalra
Memorial Hermann Pearland and South-East Houston, Memorial Hermann Medical Group, Houston, Texas, USA
Search for more papers by this authorShane McKinney
Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
Search for more papers by this authorLarry Mellick,
Paul Walsh, Clista Clanton,
Sarathi Kalra,
Shane McKinney,
Corresponding Author
Larry Mellick
Department of Emergency Medicine, Augusta University, Augusta, Georgia, USA
Correspondence: Larry Mellick ([email protected])
Search for more papers by this authorClista Clanton
Charles M. Baugh Biomedical Library, University of South Alabama, Mobile, Alabama, USA
Search for more papers by this authorSarathi Kalra
Memorial Hermann Pearland and South-East Houston, Memorial Hermann Medical Group, Houston, Texas, USA
Search for more papers by this authorShane McKinney
Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
Search for more papers by this authorABSTRACT
Background
The 2014 AAP Bronchiolitis Guidelines deimplemented or recommended against the routine therapeutic use of albuterol, hypertonic saline, and epinephrine for infants and children presenting in the outpatient setting. Our objective was to perform an umbrella review of all meta-analyses that included outpatient subanalyses or network meta-analyses with medication treatment comparisons to study the clinical benefits of these deimplemented medications in the outpatient (i.e., primary care, urgent care, and emergency department) setting.
Methods
Searches were performed in the databases PubMed and Scopus and the Web search engine Google Scholar on the following three topics: albuterol and bronchiolitis, epinephrine and bronchiolitis, and hypertonic saline and bronchiolitis. Article types were limited to systematic reviews and meta-analyses with outpatient subanalyses, with English language and age restrictions. The search strategy was based on the Population, Intervention, Comparator, Outcomes, Studies (PICOS) framework. The studies were uploaded to Rayyan, a Web-based platform for managing articles of systematic reviews. Citation tracking and manual review of references were performed for the included studies. The meta-analyses and network meta-analyses were reviewed for outpatient subanalyses focused on clinical responses and risk of hospital admission.
Results
A total of 6 meta-analyses for albuterol, 4 meta-analyses for epinephrine, and 11 meta-analyses for hypertonic saline were included. Our review identified evidence from predominantly low and moderate evidence meta-analyses (assessed using GRADE and AMSTAR 2) indicating that all three deimplemented medications exhibit one or more therapeutic effects and benefits for infants with the bronchiolitis syndrome in the outpatient setting. Effect sizes ranged from medium to near medium. These clinical benefits include decreased hospital admissions and lower clinical severity scores.
Conclusions
Given the heterogeneity of patients under the umbrella term “acute bronchiolitis” and the potential for some patients to respond clinically to albuterol, hypertonic saline, and epinephrine, current evidence supports conducting therapeutic trials in infants with acute bronchiolitis in outpatient settings. However, further well-designed and adequately powered randomized controlled trials and high-quality meta-analyses are still needed.
Video Abstract
Outpatient Medications Deimplemented by the AAP Bronchiolitis Guidelines: An Umbrella Review of Meta-Analyses
by Mellick et al.Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The supplementary material for this article can be found online at https://jagworks.southalabama.edu/university_data/6/.
Supporting Information
| Filename | Description |
|---|---|
| ppul27391-sup-0001-SUPPLE_1.DOC22.5 KB | Supporting information. |
| ppul27391-sup-0002-Table_S1_PICOS.docx23.3 KB | Supporting information. |
| ppul27391-sup-0003-TAB2A8_1.DOC60.5 KB | Supporting information. |
| ppul27391-sup-0004-TA50FD_1.DOC54.9 KB | Supporting information. |
| ppul27391-sup-0005-TA9603_1.DOC50.6 KB | Supporting information. |
| ppul27391-sup-0006-TAFF6B_1.DOC21.9 KB | Supporting information. |
| ppul27391-sup-0007-TableS6_EpiAdmit_Data.docx49.8 KB | Supporting information. |
| ppul27391-sup-0008-TableS7_EpiClin_Data.docx57.4 KB | Supporting information. |
| ppul27391-sup-0009-TableS8_HTSAdm_Data.docx135.9 KB | Supporting information. |
| ppul27391-sup-0010-APPEND_1.PDF176.9 KB | Supporting information. |
| ppul27391-sup-0011-APPEND_2.PDF109.9 KB | Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1S. L. Ralston, A. S. Lieberthal, H. C. Meissner, et al., “Clinical Practice Guideline: The Diagnosis, Management, and Prevention of Bronchiolitis,” Pediatrics 134, no. 5 (2014): e1474–e1502, https://doi.org/10.1542/peds.2014-2742.
- 2A. Kirolos, S. Manti, R. Blacow, et al., “A Systematic Review of Clinical Practice Guidelines for the Diagnosis and Management of Bronchiolitis,” Journal of Infectious Diseases 222, no. Suppl_7 (2020): S672–S679, https://doi.org/10.1093/infdis/jiz240.
- 3A. C. Plint, R. Grenon, T. P. Klassen, and D. W. Johnson, “Bronchodilator and Steroid Use for the Management of Bronchiolitis in Canadian Pediatric Emergency Departments,” CJEM 17, no. 1 (2015): 46–53, https://doi.org/10.2310/8000.2013.131325.
- 4C. Ochoa Sangrador and J. González de Dios, “Overuse of Bronchodilators and Steroids in Bronchiolitis of Different Severity,” Allergologia et Immunopathologia 42, no. 4 (2014): 307–315, https://doi.org/10.1016/j.aller.2013.02.010.
- 5E. Barbieri, A. Cantarutti, S. Cavagnis, et al., “Impact of Bronchiolitis Guidelines Publication on Primary Care Prescriptions in the Italian Pediatric Population,” NPJ Primary Care Respiratory Medicine 31, no. 1 (2021): 15, https://doi.org/10.1038/s41533-021-00228-w.
- 6A. Gultekingil, E. Gocer, M. Anil, et al., “Pediatricians' Attitude in Management of Acute Bronchiolitis: Did Guidelines Overcome Practices,” Pediatric Allergy, Immunology, and Pulmonology 33, no. 2 (2020): 57–62, https://doi.org/10.1089/ped.2020.1141.
- 7M. P. Lirette, N. Kuppermann, Y. Finkelstein, et al., “International Variation in Evidence-Based Emergency Department Management of Bronchiolitis: A Retrospective Cohort Study,” BMJ Open 12, no. 12 (2022): e059784, https://doi.org/10.1136/bmjopen-2021-059784.
- 8E. R. Wolf, A. Richards, M. Lavallee, et al., “Patient, Provider, and Health Care System Characteristics Associated With Overuse in Bronchiolitis,” Pediatrics 148, no. 4 (2021): e2021051345, https://doi.org/10.1542/peds.2021-051345.
- 9B. Kusak, E. Grzesik, K. Konarska-Gabryś, Z. Pacek, B. Piwowarczyk, and G. Lis, “Bronchiolitis in Children – Do We Choose Wisely?,” Developmental Period Medicine 22, no. 4 (2018): 323–328, https://doi.org/10.34763/devperiodmed.20182204.323328.
- 10A. V. Rivera-Sepulveda, T. Rebmann, J. Gerard, and R. L. Charney, “Physician Compliance With Bronchiolitis Guidelines in Pediatric Emergency Departments,” Clinical Pediatrics 58, no. 9 (2019): 1008–1018, https://doi.org/10.1177/0009922819850462.
- 11K. Thorlund, G. Imberger, M. Walsh, et al., “The Number of Patients and Events Required to Limit the Risk of Overestimation of Intervention Effects in Meta-Analysis—A Simulation Study,” PLoS One 6, no. 10 (2011): e25491, https://doi.org/10.1371/journal.pone.0025491.
- 12K. S. Button, J. P. A. Ioannidis, C. Mokrysz, et al., “Power Failure: Why Small Sample Size Undermines the Reliability of Neuroscience,” Nature Reviews Neuroscience 14, no. 5 (2013): 365–376, https://doi.org/10.1038/nrn3475.
- 13J. A. Berlin and R. M. Golub, “Meta-Analysis as Evidence: Building a Better Pyramid,” JAMA 312, no. 6 (2014): 603–605, https://doi.org/10.1001/jama.2014.8167.
- 14D. Jackson and R. Turner, “Power Analysis for Random-Effects Meta-Analysis,” Research Synthesis Methods 8, no. 3 (2017): 290–302, https://doi.org/10.1002/jrsm.1240.
- 15T. R. Vetter, “Systematic Review and Meta-Analysis: Sometimes Bigger Is Indeed Better,” Anesthesia & Analgesia 128, no. 3 (2019): 575–583, https://doi.org/10.1213/ANE.0000000000004014.
- 16S. Gopalakrishnan and P. Ganeshkumar, “Systematic Reviews and Meta-Analysis: Understanding the Best Evidence in Primary Healthcare,” Journal of Family Medicine and Primary Care 2, no. 1 (2013): 9–14, https://doi.org/10.4103/2249-4863.109934.
- 17A. P. Siddaway, A. M. Wood, and L. V. Hedges, “How to Do a Systematic Review: A Best Practice Guide for Conducting and Reporting Narrative Reviews, Meta-Analyses, and Meta-Syntheses,” Annual Review of Psychology 70 (2019): 747–770, https://doi.org/10.1146/annurev-psych-010418-102803.
- 18A. Liberati, D. G. Altman, J. Tetzlaff, et al., “The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Healthcare Interventions: Explanation and Elaboration,” BMJ 339 (2009): b2700, https://doi.org/10.1136/bmj.b2700.
- 19PRISMA, 2023, http://www.prisma-statement.org/PRISMAStatement/Checklist.aspx.
- 20PROSPERO Inclusion Guidelines, https://www.crd.york.ac.uk/PROSPERO/#aboutpage.
- 21Google Scholar, https://scholar.google.com.
- 22W. S. Richardson, M. C. Wilson, J. Nishikawa, and R. S. A. Hayward, “The Well-Built Clinical Question: A Key to Evidence-Based Decisions,” ACP Journal Club 123 (1995): A12-3, https://doi.org/10.7326/ACPJC-1995-123-3-A12.
- 23C. Schardt, M. B. Adams, T. Owens, S. Keitz, and P. Fontelo, “Utilization of the PICO Framework to Improve Searching PubMed for Clinical Questions,” BMC Medical Informatics and Decision Making 7, no. 1 (2007): 16, https://doi.org/10.1186/1472-6947-7-16.
- 24C. Kiefer, S. Sturtz, and R. Bender, “Indirect Comparisons and Network Meta-Analyses,” Deutsches Ärzteblatt International 112, no. 47 (2015): 803–808, https://doi.org/10.3238/arztebl.2015.0803.
- 25M. Ouzzani, H. Hammady, Z. Fedorowicz, and A. Elmagarmid, “Rayyan—A Web and Mobile App for Systematic Reviews,” Systematic Reviews 5, no. 1 (2016): 210, https://doi.org/10.1186/s13643-016-0384-4.
- 26G. H. Guyatt, A. D. Oxman, R. Kunz, G. E. Vist, Y. Falck-Ytter, and H. J. Schünemann, “What Is ‘Quality of Evidence’ and Why Is It Important to Clinicians,” BMJ 336, no. 7651 (2008): 995–998, https://doi.org/10.1136/bmj.39490.551019.BE.
- 27G. Guyatt, A. D. Oxman, E. A. Akl, et al., “GRADE Guidelines: 1. Introduction—GRADE Evidence Profiles and Summary of Findings Tables,” Journal of Clinical Epidemiology 64, no. 4 (2011): 383–394, https://doi.org/10.1016/j.jclinepi.2010.04.026.
- 28R. Ryan and S. Hill, How to GRADE the Quality of the Evidence (Melbourne: La Trobe University, 2018), https://doi.org/10.26181/5B57D95632A2C.
- 29A. Nikolakopoulou, J. P. T. Higgins, T. Papakonstantinou, et al., “CINeMA: An Approach for Assessing Confidence in the Results of a Network Meta-Analysis,” PLoS Medicine 17, no. 4 (2020): e1003082, https://doi.org/10.1371/journal.pmed.1003082.
- 30B. J. Shea, B. C. Reeves, G. Wells, et al., “AMSTAR 2: A Critical Appraisal Tool for Systematic Reviews That Include Randomised or Non-Randomised Studies of Healthcare Interventions, or Both,” BMJ 358 (2017): j4008, https://doi.org/10.1136/bmj.j4008.
- 31S. Harrison, H. E. Jones, R. M. Martin, S. J. Lewis, and J. P. T. Higgins, “The Albatross Plot: A Novel Graphical Tool for Presenting Results of Diversely Reported Studies in a Systematic Review,” Research Synthesis Methods 8, no. 3 (2017): 281–289, https://doi.org/10.1002/jrsm.1239.
- 32M. Kossmeier, U. S. Tran, and M. Voracek, “Charting the Landscape of Graphical Displays for Meta-Analysis and Systematic Reviews: A Comprehensive Review, Taxonomy, and Feature Analysis,” BMC Medical Research Methodology 20, no. 1 (2020): 26, https://doi.org/10.1186/s12874-020-0911-9.
- 33S. A. Elliott, L. A. Gaudet, R. M. Fernandes, et al., “Comparative Efficacy of Bronchiolitis Interventions in Acute Care: A Network Meta-Analysis,” Pediatrics 147, no. 5 (2021): e2020040816, https://doi.org/10.1542/peds.2020-040816.
- 34L. Hartling, K. F. Russell, H. Patel, T. P. Klassen, and Y. Liang, “Epinephrine for Bronchiolitis,” Cochrane Database of Systematic Reviews (2004): CD003123, https://doi.org/10.1002/14651858.CD003123.pub2.
- 35L. Hartling, L. M. Bialy, B. Vandermeer, et al., “Epinephrine for Bronchiolitis,” Cochrane Database of Systematic Reviews no. 6 (2011): CD003123, https://doi.org/10.1002/14651858.CD003123.pub3.
- 36L. Hartling, R. M. Fernandes, L. Bialy, et al., “Steroids and Bronchodilators for Acute Bronchiolitis in the First Two Years of Life: Systematic Review and Meta-Analysis,” BMJ 342, no. 2 (2011): d1714, https://doi.org/10.1136/bmj.d1714.
- 37L. Zhang, R. A. Mendoza-Sassi, C. Wainwright, and T. P. Klassen, “Nebulized Hypertonic Saline Solution for Acute Bronchiolitis in Infants,” Cochrane Database of Systematic Reviews 2008 (2008): CD006458, https://doi.org/10.1002/14651858.CD006458.pub2.
10.1002/14651858.CD006458.pub2 Google Scholar
- 38L. Zhang, R. A. Mendoza-Sassi, C. Wainwright, and T. P. Klassen, “Nebulised Hypertonic Saline Solution for Acute Bronchiolitis in Infants,” Cochrane Database of Systematic Reviews (July 2013): CD006458, https://doi.org/10.1002/14651858.CD006458.pub3.
- 39L. Zhang, R. A. Mendoza-Sassi, C. Wainwright, and T. P. Klassen, “Nebulised Hypertonic Saline Solution for Acute Bronchiolitis in Infants,” Cochrane Database of Systematic Reviews 12, no. 12 (2017): CD006458, https://doi.org/10.1002/14651858.CD006458.pub4.
- 40L. Zhang, C. B. Gunther, O. S. Franco, and T. P. Klassen, “Impact of Hypertonic Saline on Hospitalization Rate in Infants With Acute Bronchiolitis: A Meta-Analysis,” Pediatric Pulmonology 53, no. 8 (2018): 1089–1095, https://doi.org/10.1002/ppul.24066.
- 41L. Zhang, R. A. Mendoza-Sassi, C. E. Wainwright, A. Aregbesola, and T. P. Klassen, “Nebulised Hypertonic Saline Solution for Acute Bronchiolitis in Infants,” Cochrane Database of Systematic Reviews 4, no. 4 (2023): CD006458, https://doi.org/10.1002/14651858.CD006458.pub5.
- 42L. Zhang, R. A. Mendoza-Sassi, T. P. Klassen, and C. Wainwright, “Nebulized Hypertonic Saline for Acute Bronchiolitis: A Systematic Review,” Pediatrics 136, no. 4 (2015): 687–701, https://doi.org/10.1542/peds.2015-1914.
- 43J. F. Yu, Y. Zhang, Z. B. Liu, J. Wang, and L. P. Bai, “3% Nebulized Hypertonic Saline Versus Normal Saline for Infants With Acute Bronchiolitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials,” Medicine 101, no. 43 (2022): e31270, https://doi.org/10.1097/MD.0000000000031270.
- 44C. W. Hsieh, C. Chen, H. C. Su, and K. H. Chen, “Exploring the Efficacy of Using Hypertonic Saline for Nebulizing Treatment in Children With Bronchiolitis: A Meta-Analysis of Randomized Controlled Trials,” BMC Pediatrics 20, no. 1 (2020): 434, https://doi.org/10.1186/s12887-020-02314-3.
- 45Y. J. Chen, W. L. Lee, C. M. Wang, and H. H. Chou, “Nebulized Hypertonic Saline Treatment Reduces Both Rate and Duration of Hospitalization for Acute Bronchiolitis in Infants: An Updated Meta-Analysis,” Pediatrics & Neonatology 55, no. 6 (2014): 431–438, https://doi.org/10.1016/j.pedneo.2013.09.013.
- 46P. Heikkilä, M. Renko, and M. Korppi, “Hypertonic Saline Inhalations in Bronchiolitis—A Cumulative Meta-Analysis,” Pediatric Pulmonology 53, no. 2 (2018): 233–242, https://doi.org/10.1002/ppul.23928.
- 47S. Wu, C. Baker, M. E. Lang, et al., “Nebulized Hypertonic Saline for Bronchiolitis: A Randomized Clinical Trial,” JAMA Pediatrics 168, no. 7 (2014): 657–663, https://doi.org/10.1001/jamapediatrics.2014.301.
- 48A. Khanal, A. Sharma, S. Basnet, P. R. Sharma, and F. C. Gami, “Nebulised Hypertonic Saline (3%) Among Children With Mild to Moderately Severe Bronchiolitis—A Double Blind Randomized Controlled Trial,” BMC Pediatrics 15 (2015): 115, https://doi.org/10.1186/s12887-015-0434-4.
- 49F. Angoulvant, X. Bellêttre, K. Milcent, et al., “Effect of Nebulized Hypertonic Saline Treatment in Emergency Departments on the Hospitalization Rate for Acute Bronchiolitis: A Randomized Clinical Trial,” JAMA Pediatrics 171, no. 8 (2017): e171333, https://doi.org/10.1001/jamapediatrics.2017.1333.
- 50I. Rombach, R. Knight, N. Peckham, J. R. Stokes, and J. A. Cook, “Current Practice in Analysing and Reporting Binary Outcome Data—A Review of Randomised Controlled Trial Reports,” BMC Medicine 18, no. 1 (2020): 147, https://doi.org/10.1186/s12916-020-01598-7.
- 51G. Flores and R. I. Horwitz, “Efficacy of Beta2-Agonists in Bronchiolitis: A Reappraisal and Meta-Analysis,” Pediatrics 100, no. 2, Pt. 1 (1997): 233–239, https://doi.org/10.1542/peds.100.2.233.
- 52A. M. Gadomski and A. L. Bhasale, “Bronchodilators for Bronchiolitis,” Cochrane Database of Systematic Reviews (2006): CD001266, https://doi.org/10.1002/14651858.CD001266.pub2.
- 53A. M. Gadomski and M. Brower, “Bronchodilators for Bronchiolitis,” Cochrane Database of Systematic Reviews (2010): CD001266, https://doi.org/10.1002/14651858.CD001266.pub3.
- 54A. M. Gadomski and M. B. Scribani, “Bronchodilators for Bronchiolitis,” Cochrane Database of Systematic Reviews 2014, no. 6 (2014): CD001266, https://doi.org/10.1002/14651858.CD001266.pub4.
- 55J. Kellner, A. Ohlsson, A. Gadomski, and E. Wang, “Bronchodilators for Bronchiolitis,” Cochrane Database of Systematic Reviews (1999): CD001266, https://doi.org/10.1002/14651858.CD001266.
10.1002/14651858.CD001266 Google Scholar
- 56C. Gómez, G. Alarcón, and L. Cifuentes, “Beta-2 Agonists for the Treatment of Bronchiolitis,” Medwave 20, no. 8 (2020): e7945, https://doi.org/10.5867/medwave.2020.08.7947.
- 57P. Walsh and S. J. Rothenberg, “The Recommendation to Not Use Bronchodilators Is Not Supported by the Evidence,” Pediatrics 135, no. 2 (2015): e556, https://doi.org/10.1542/peds.2014-3676A.
- 58P. Walsh, J. Caldwell, K. K. McQuillan, S. Friese, D. Robbins, and S. J. Rothenberg, “Comparison of Nebulized Epinephrine to Albuterol in Bronchiolitis,” Academic Emergency Medicine 15, no. 4 (2008): 305–313, https://doi.org/10.1111/j.1553-2712.2008.00064.x.
- 59J. D. Kellner, “Efficacy of Bronchodilator Therapy in Bronchiolitis: A Meta-Analysis,” Archives of Pediatrics & Adolescent Medicine 150, no. 11 (1996): 1166–1172, https://doi.org/10.1001/archpedi.1996.02170360056009.
- 60L. B. Mellick, “The De-Implementation of Bronchiolitis Medications: Is It Time for a Moratorium,” Pediatric Emergency Care 40 (September 2023): e30–e32, https://doi.org/10.1097/PEC.0000000000003049.
- 61P. J. Schweich, T. L. Hurt, E. I. Walkley, N. Mullen, and L. F. Archibald, “The Use of Nebulized Albuterol in Wheezing Infants,” Pediatric Emergency Care 8, no. 4 (1992): 184–188, https://doi.org/10.1097/00006565-199208000-00003.
- 62I. O. Ipek, E. U. Yalcin, R. G. Sezer, and A. Bozaykut, “The Efficacy of Nebulized Salbutamol, Hypertonic Saline and Salbutamol/Hypertonic Saline Combination in Moderate Bronchiolitis,” Pulmonary Pharmacology & Therapeutics 24, no. 6 (2011): 633–637, https://doi.org/10.1016/j.pupt.2011.09.004.
- 63A. M. Gadomski, G. H. Aref, O. B. el Din, I. H. el Sawy, N. Khallaf, and R. E. Black, “Oral Versus Nebulized Albuterol in the Management of Bronchiolitis in Egypt,” Journal of Pediatrics 124, no. 1 (1994): 131–138, https://doi.org/10.1016/s0022-3476(94)70269-1.
- 64A. M. Gadomski, R. Lichenstein, L. Horton, J. King, V. Keane, and T. Permutt, “Efficacy of Albuterol in the Management of Bronchiolitis,” Pediatrics 93, no. 6, Pt. 1 (1994): 907–912.
- 65P. Gupta, A. Aggarwal, P. Gupta, and K. K. Sharma, “Oral Salbutamol for Symptomatic Relief in Mild Bronchiolitis a Double Blind Randomized Placebo Controlled Trial,” Indian Pediatrics 45, no. 7 (2008): 547–553.
- 66H. Patel, S. Gouin, and R. W. Platt, “Randomized, Double-Blind, Placebo-Controlled Trial of Oral Albuterol in Infants With Mild-to-Moderate Acute Viral Bronchiolitis,” Journal of Pediatrics 142, no. 5 (2003): 509–514, https://doi.org/10.1067/mpd.2003.196.
- 67R. Cengizlier, Y. Saraçlar, G. Adalioǧlu, and A. Tuncer, “Effect of Oral and Inhaled Salbutamol in Infants With Bronchiolitis,” Pediatrics International 39, no. 1 (1997): 61–63, https://doi.org/10.1111/j.1442-200x.1997.tb03557.x.
- 68S. A. House, A. M. Gadomski, and S. L. Ralston, “Evaluating the Placebo Status of Nebulized Normal Saline in Patients With Acute Viral Bronchiolitis: A Systematic Review and Meta-Analysis,” JAMA Pediatrics 174, no. 3 (2020): 250–259, https://doi.org/10.1001/jamapediatrics.2019.5195.
- 69G. Pukai and T. Duke, “Nebulised Normal Saline in Moderate Acute Bronchiolitis and Pneumonia in a Low- to Middle-Income Country: A Randomised Trial in Papua New Guinea,” Paediatrics and International Child Health 40, no. 3 (2020): 171–176, https://doi.org/10.1080/20469047.2020.1725338.
- 70A. B. Anil, M. Anil, A. B. Saglam, N. Cetin, A. Bal, and N. Aksu, “High Volume Normal Saline Alone Is as Effective as Nebulized Salbutamol-Normal Saline, Epinephrine-Normal Saline, and 3% Saline in Mild Bronchiolitis,” Pediatric Pulmonology 45, no. 1 (2010): 41–47, https://doi.org/10.1002/ppul.21108.
- 71A. Mandelberg and I. Amirav, “Hypertonic Saline or High Volume Normal Saline for Viral Bronchiolitis: Mechanisms and Rationale,” Pediatric Pulmonology 45, no. 1 (2010): 36–40, https://doi.org/10.1002/ppul.21185.
- 72A. J. Alario, W. J. Lewander, P. Dennehy, R. Seifer, and A. L. Mansell, “The Efficacy of Nebulized Metaproterenol in Wheezing Infants and Young Children,” American Journal of Diseases of Children 146, no. 4 (1992): 412–418, https://doi.org/10.1001/archpedi.1992.02160160032008.
- 73S. J. Senn, “Covariate Imbalance and Random Allocation in Clinical Trials,” Statistics in Medicine 8, no. 4 (1989): 467–475, https://doi.org/10.1002/sim.4780080410.
- 74S. Senn, “Seven Myths of Randomisation in Clinical Trials,” Statistics in Medicine 32, no. 9 (2013): 1439–1450, https://doi.org/10.1002/sim.5713.
- 75R. J. Lewis and K. Viele, “Revisiting the Analogy Between Clinical Trials and Diagnostic Tests by Interpreting a Negative Trial as a Negative Test for Efficacy,” JAMA 329, no. 23 (2023): 2023–2025, https://doi.org/10.1001/jama.2023.8972.
- 76S. Greenland, “Nonsignificance Plus High Power Does Not Imply Support for the Null Over the Alternative,” Annals of Epidemiology 22, no. 5 (2012): 364–368, https://doi.org/10.1016/j.annepidem.2012.02.007.
- 77J. Leppink, P. O'Sullivan, and K. Winston, “Effect Size – Large, Medium, and Small,” Perspectives on Medical Education 5, no. 6 (2016): 347–349, https://doi.org/10.1007/S40037-016-0308-Y.
- 78C. R. Brydges, “Effect Size Guidelines, Sample Size Calculations, and Statistical Power in Gerontology,” Innovation in Aging 3, no. 4 (2019): igz036, https://doi.org/10.1093/geroni/igz036.
- 79P. P. Glasziou, S. Shepperd, and J. Brassey, “Can We Rely on the Best Trial? A Comparison of Individual Trials and Systematic Reviews,” BMC Medical Research Methodology 10 (2010): 23, https://doi.org/10.1186/1471-2288-10-23.
- 80J. Villar and G. Piaggio, “Large Trials or Meta-Analysis? That Is Not the Question,” Best Practice & Research Clinical Obstetrics & Gynaecology 19, no. 1 (2005): 27–35, https://doi.org/10.1016/j.bpobgyn.2004.10.013.
- 81A. Agarwal, B. Rochwerg, and J. E. Sevransky, “21st Century Evidence: Randomized Controlled Trials Versus Systematic Reviews and Meta-Analyses,” Critical Care Medicine 49, no. 12 (2021): 2001–2002, https://doi.org/10.1097/CCM.0000000000005343.
- 82S. Borzak, “Discordance Between Meta-Analyses and Large-Scale Randomized, Controlled Trials: Examples From the Management of Acute Myocardial Infarction,” Annals of Internal Medicine 123, no. 11 (1995): 873–877, https://doi.org/10.7326/0003-4819-123-11-199512010-00010.
- 83C. M. Scifres, J. D. Iams, M. Klebanoff, and G. A. Macones, “Metaanalysis Vs Large Clinical Trials: Which Should Guide Our Management,” American Journal of Obstetrics and Gynecology 200, no. 5 (2009): 484.e1–484.e5, https://doi.org/10.1016/j.ajog.2008.09.873.
- 84A. Norwood, J. M. Mansbach, S. Clark, M. Waseem, and C. A. Camargo, “Prospective Multicenter Study of Bronchiolitis: Predictors of an Unscheduled Visit After Discharge From the Emergency Department,” Academic Emergency Medicine 17, no. 4 (2010): 376–382, https://doi.org/10.1111/j.1553-2712.2010.00699.x.
- 85W. D. Bennett, A. Burbank, M. Almond, et al., “Acute and Durable Effect of Inhaled Hypertonic Saline on Mucociliary Clearance in Adult Asthma,” ERJ Open Research 7, no. 2 (2021): 00062-2021, https://doi.org/10.1183/23120541.00062-2021.
- 86A. Forouzan, K. Masoumi, A. Delirrooyfard, A. Asgari Darian, and L. Mokhtar Gandomani, “Effect of Nebulized 3% Hypertonic Saline With Salbutamol on Management of Acute Asthma in Outpatient Adults: A Double-Blind, Randomized Clinical Trial in Emergency Department,” Iranian Journal of Allergy, Asthma, and Immunology 16, no. 5 (2017): 370–377.
- 87E. Daviskas, S. Anderson, I. Gonda, et al., “Inhalation of Hypertonic Saline Aerosol Enhances Mucociliary Clearance in Asthmatic and Healthy Subjects,” European Respiratory Journal 9, no. 4 (1996): 725–732, https://doi.org/10.1183/09031936.96.09040725.
- 88T. Kanjanapradap, J. Deerojanawong, S. Sritippayawan, and N. Prapphal, “Does Nebulized Hypertonic Saline Shorten Hospitalization in Young Children With Acute Viral Wheezing,” Pediatric Pulmonology 53, no. 2 (2018): 138–144, https://doi.org/10.1002/ppul.23924.
- 89D. Ater, H. Shai, B. E. Bar, et al., “Hypertonic Saline and Acute Wheezing in Preschool Children,” Pediatrics 129, no. 6 (2012): e1397–e1403, https://doi.org/10.1542/peds.2011-3376.
- 90A. Teper, C. Kofman, J. Alchundia Moreira, T. Köhler, and F. García Bournissen, “Bronchodilator Response to Albuterol Nebulized With Hypertonic Saline in Asthmatic Children,” Pediatric Pulmonology 56, no. 12 (2021): 3714–3719, https://doi.org/10.1002/ppul.25653.
- 91M. R. Elkins, M. Robinson, B. R. Rose, et al., “A Controlled Trial of Long-Term Inhaled Hypertonic Saline in Patients With Cystic Fibrosis,” New England Journal of Medicine 354, no. 3 (2006): 229–240, https://doi.org/10.1056/NEJMoa043900.
- 92S. H. Donaldson, W. D. Bennett, K. L. Zeman, M. R. Knowles, R. Tarran, and R. C. Boucher, “Mucus Clearance and Lung Function in Cystic Fibrosis With Hypertonic Saline,” New England Journal of Medicine 354, no. 3 (2006): 241–250, https://doi.org/10.1056/NEJMoa043891.
- 93S. H. Donaldson, T. Danielle Samulski, C. LaFave, et al., “A Four Week Trial of Hypertonic Saline in Children With Mild Cystic Fibrosis Lung Disease: Effect on Mucociliary Clearance and Clinical Outcomes,” Journal of Cystic Fibrosis 19, no. 6 (2020): 942–948, https://doi.org/10.1016/j.jcf.2020.07.009.
- 94V. Terlizzi, E. Masi, M. Francalanci, G. Taccetti, and D. Innocenti, “Hypertonic Saline in People With Cystic Fibrosis: Review of Comparative Studies and Clinical Practice,” Italian Journal of Pediatrics 47, no. 1 (2021): 168, https://doi.org/10.1186/s13052-021-01117-1.
- 95M. Stahl, M. O. Wielpütz, I. Ricklefs, et al., “Preventive Inhalation of Hypertonic Saline in Infants With Cystic Fibrosis (PRESIS). A Randomized, Double-Blind, Controlled Study,” American Journal of Respiratory and Critical Care Medicine 199, no. 10 (2019): 1238–1248, https://doi.org/10.1164/rccm.201807-1203OC.
- 96O. Dumas, J. M. Mansbach, T. Jartti, et al., “A Clustering Approach to Identify Severe Bronchiolitis Profiles in Children,” Thorax 71, no. 8 (2016): 712–718, https://doi.org/10.1136/thoraxjnl-2016-208535.
- 97K. Hasegawa, O. Dumas, T. V. Hartert, and C. A. Camargo, “Advancing Our Understanding of Infant Bronchiolitis Through Phenotyping and Endotyping: Clinical and Molecular Approaches,” Expert Review of Respiratory Medicine 10, no. 8 (2016): 891–899, https://doi.org/10.1080/17476348.2016.1190647.
- 98J. Merckx, F. M. Ducharme, C. Martineau, et al., “Respiratory Viruses and Treatment Failure in Children With Asthma Exacerbation,” Pediatrics 142, no. 1 (2018): e20174105, https://doi.org/10.1542/peds.2017-4105.
- 99K. K. De Santis, D. Pieper, R. C. Lorenz, U. Wegewitz, W. Siemens, and K. Matthias, “User Experience of Applying AMSTAR 2 to Appraise Systematic Reviews of Healthcare Interventions: A Commentary,” BMC Medical Research Methodology 23, no. 1 (2023): 63, https://doi.org/10.1186/s12874-023-01879-8.
- 100M. Pollock, R. M. Fernandes, A. S. Newton, S. D. Scott, and L. Hartling, “The Impact of Different Inclusion Decisions on the Comprehensiveness and Complexity of Overviews of Reviews of Healthcare Interventions,” Systematic Reviews 8, no. 1 (2019): 18, https://doi.org/10.1186/s13643-018-0914-3.
- 101C. Lunny, D. Pieper, P. Thabet, and S. Kanji, “Managing Overlap of Primary Study Results Across Systematic Reviews: Practical Considerations for Authors of Overviews of Reviews,” BMC Medical Research Methodology 21, no. 1 (2021): 140, https://doi.org/10.1186/s12874-021-01269-y.
- 102L. Belbasis, V. Bellou, and J. P. A. Ioannidis, “Conducting Umbrella Reviews,” BMJ Medicine 1, no. 1 (2022): e000071, https://doi.org/10.1136/bmjmed-2021-000071.
- 103S. A. House, J. R. Marin, M. Hall, and S. L. Ralston, “Trends Over Time in Use of Nonrecommended Tests and Treatments Since Publication of the American Academy of Pediatrics Bronchiolitis Guideline,” JAMA Network Open 4, no. 2 (2021): e2037356, https://doi.org/10.1001/jamanetworkopen.2020.37356.
- 104E. McCoy and M. Chumpia, “Decreasing Racemic Epinephrine for Bronchiolitis in an Academic Children's Hospital,” Hospital Pediatrics 8, no. 10 (2018): 651–657, https://doi.org/10.1542/hpeds.2017-0214.
- 105C. E. McDaniel, S. A. House, and S. L. Ralston, “Behavioral and Psychological Aspects of the Physician Experience With Deimplementation,” Pediatric Quality & Safety 7, no. 1 (2022): e524, https://doi.org/10.1097/pq9.0000000000000524.
- 106M. Montejo, N. Paniagua, C. Saiz-Hernando, L. Martinez-Indart, S. Mintegi, and J. Benito, “Initiatives to Reduce Treatments in Bronchiolitis in the Emergency Department and Primary Care,” Archives of Disease in Childhood 106, no. 3 (2021): 294–300, https://doi.org/10.1136/archdischild-2019-318085.
- 107M. J. Lipshaw and T. A. Florin, “‘Don't Just Do Something, Stand There’: Embracing Deimplementation of Bronchiolitis Therapeutics,” Pediatrics 147, no. 5 (2021): e2020048645, https://doi.org/10.1542/peds.2020-048645.
- 108L. Haskell, E. J. Tavender, C. L. Wilson, et al., “Effectiveness of Targeted Interventions on Treatment of Infants With Bronchiolitis: A Randomized Clinical Trial,” JAMA Pediatrics 175, no. 8 (2021): 797–806, https://doi.org/10.1001/jamapediatrics.2021.0295.
- 109E. Sprecher, G. Chi, A. Ozonoff, J. Cox, N. Patel, and K. Conroy, “Use of Social Psychology to Improve Adherence to National Bronchiolitis Guidelines,” Pediatrics 143, no. 1 (2019): e20174156, https://doi.org/10.1542/peds.2017-4156.
- 110M. L. Borland, S. O'Brien, E. Tavender, et al., “Evaluation of Targeted Implementation Interventions for Reducing Investigations and Therapies in Infants With Bronchiolitis,” Acta Paediatrica 112, no. 8 (2023): 1747–1754, https://doi.org/10.1111/apa.16786.
- 111G. M. Mussman, M. Lossius, F. Wasif, et al., “Multisite Emergency Department Inpatient Collaborative to Reduce Unnecessary Bronchiolitis Care,” Pediatrics 141, no. 2 (2018): e20170830, https://doi.org/10.1542/peds.2017-0830.
- 112S. L. Ralston, E. C. Atwood, M. D. Garber, and A. V. Holmes, “What Works to Reduce Unnecessary Care for Bronchiolitis? A Qualitative Analysis of a National Collaborative,” Academic Pediatrics 17, no. 2 (2017): 198–204, https://doi.org/10.1016/j.acap.2016.07.001.
- 113P. Walsh, “Even the Thinnest Salami Contains Some Meat,” Western Journal of Emergency Medicine 19, no. 3 (2018): 484–486, https://doi.org/10.5811/westjem.2018.4.38408.
- 114J. N. Friedman, M. J. Rieder, and J. M. Walton, “Bronchiolitis: Recommendations for Diagnosis, Monitoring and Management of Children One to 24 Months of Age,” Paediatrics & Child Health 19, no. 9 (2014): 485–491, https://doi.org/10.1093/pch/19.9.485.
Citing Literature
