Therapeutics
Review: Spacers and nebulizers for delivery of β2-agonists do not differ for clinical outcomes in acute asthma
Cates CJ, Welsh EJ, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2013;(9):CD000052.
Clinical impact ratings: F ★★★★★★✩ E ★★★★★✩✩ h ★★★★★★✩ A ★★★★★✩✩ p ★★★★★✩✩ Question In acute asthma, what is the relative efficacy of holding chambers (spacers) and nebulizers for delivery of β2-agonists?
Review scope Included studies compared nebulizers with metered-dose inhalers using a spacer for delivery of β2-agonists in children and adults who presented to a community setting or emergency department with acute asthma. Studies that included children with a mean age < 2 years were excluded. Studies including patients with chronic obstructive pulmonary disease were included if results of patients with asthma were reported separately. Outcomes included hospitalization, emergency department length of stay, FEV1 (% predicted), and use of steroids.
Review methods Cochrane Airways Group Specialised Register of trials (2008 to Feb 2013), which includes studies identified from Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE/ Excerpta Medica, CINAHL, AMED, PsycINFO, and handsearches of respiratory journals and meeting abstracts; and reference lists were searched for randomized controlled trials (RCTs). Authors were contacted. {Eligible studies published before 2008 were extracted from a previous literature search.}* 39 RCTs, including 1897 children and 729 adults, met the inclusion criteria. Only analyses for adults are reported here. Of the 13 RCTs that reported on adults (range 22 to 122 patients), 6 used multiple treatments at 10- to 30-minute intervals. 6 RCTs adequately reported random sequence generation, 1 adequately reported allocation concealment, 8 reported blinding of participants and personnel, and 9 reported blinding of outcome assessment. Overall evidence was judged to be of moderate quality.
Main results For studies that assessed multiple treatments, spacers and nebulizers did not differ for hospitalizations, use of steroids, emergency department length of stay, or FEV1 (% predicted) (Table). 1 study assessed the effect of single treatments on hospital admissions and found no difference between groups (relative risk increase 67%, 95% CI −52 to 483).
Conclusion Holding chambers (spacers) and nebulizers for delivery of β2agonists do not differ for clinical outcomes in acute asthma. Holding chambers (spacers) vs nebulizers for delivery of β2-agonists in multiple-treatment studies in adults with acute asthma† Outcomes
Number of Weighted RRR (95% CI) trials (n) event rates Spacers Nebulizers
Hospitalization
9 (582)
Use of steroids
2 (88)
9.9% 10%
11% 17%
NNT (CI)
6% (−43 to 39)
NS
29% (−502 to 92)
NS
Mean difference (CI) Emergency department 2 (132) length of stay (min)
1.75 (−23.45 to 26.95)‡
FEV1 (% predicted)
0.96 (−2.54 to 4.46)§
6 (307)
†NS = not significant; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from risk ratios and risk differences in article using a fixed-effect model. ‡Positive difference favors nebulizers. §Positive difference favors spacers.
18 February 2014 | ACP Journal Club | Volume 160 • Number 4
*Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2006;(2):CD000052.
Sources of funding: Garfield Weston Foundation, UK and Canadian Institutes of Health Research. For correspondence: Dr. C.J. Cates, St. George’s University of London, London, England, UK. E-mail [email protected]. ■
Commentary Acute asthma presents with widespread airflow obstruction and bronchoconstriction. Inhaled β2-agonists relieve airway smooth muscle spasm and are thus an effective first-line therapy and recommended in established practice guidelines. Pharmacodynamic studies indicate that spacers and nebulizers deliver similar doses of bronchodilator to the lungs (1). The assumption that nebulizers provide more relief for severe airflow obstruction in acute asthma is based on the theory that the more β2-agonist administered, the better the effect (2). This is incorrect because 1) the dose response of β2-agonists on airway smooth muscle rapidly reaches a plateau beyond which further dosing does not achieve greater smooth muscle relaxation (3); 2) airway smooth muscle spasm is only 1 mechanism of airflow obstruction in acute asthma exacerbations—other mechanisms, including airway edema, mucus secretion, and plugging of small airways, are nonresponsive to β2-agonists; and 3) nebulized aerosol technology, at best, delivers 20% to 35% efficiency of lung deposition, with the rest disappearing as mist into the room or deposited into the oropharynx and swallowed (4). Beyond this dose–response plateau, further benefit is offset by such increasing side effects as tremors, tachycardia, cardiac arrhythmias, and lactic acidosis, probably a result of systemic absorption from the oropharynx and gastrointestinal tract. Another concern is that nebulized aerosols contribute to the nosocomial spread of respiratory viral infections, and a World Health Organization Consultation on human influenza recommended their use only with strict airborne precautions (5). The meta-analysis by Cates and colleagues reinforces that spacers and nebulizers provide equivalent outcomes in acute asthma. Despite this, administration of a misty aerosol nebulizer in acute asthma conveys an intangible “smoke and mirrors” impression of efficacy for patient and physician alike. Institutional change for such an entrenched practice is achievable but requires a MythBusters approach with stakeholders, including patients, emergency physicians, intensivists, and pulmonologists, to promote evidence-based practice (6). Francis Thien, MD Monash University and Eastern Health Melbourne, Victoria, Australia References 1. Mazhar SH, Ismail NE, Newton DA, Chrystyn H. Br J Clin Pharmacol. 2008;65:334-7. 2. Rottier BL, Rubin BK. Paediatr Respir Rev. 2013;14:112-8. 3. Blake K, Madabushi R, Derendorf H, Lima J. Chest. 2008;134:981-9. 4. Selroos O, Pietinalho A, Riska H. BioDrugs (Clinical Immunotherapeutics) 1996;6:273−99. 5. Beigel JH, Farrar J, Han AM, et al; Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. N Engl J Med. 2005;353:1374-85. 6. Salyer JW, DiBlasi RM, Crotwell DN, Cowan CA, Carter ER. Respir Care. 2008;53:338-45. © 2014 American College of Physicians
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JC9
Review: Spacers and nebulizers for delivery of β2-agonists do not differ for clinical outcomes in acute asthma
Cates CJ, Welsh EJ, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2013;(9):CD000052.
Clinical impact ratings: F ★★★★★★✩ E ★★★★★✩✩ h ★★★★★★✩ A ★★★★★✩✩ p ★★★★★✩✩ Question In acute asthma, what is the relative efficacy of holding chambers (spacers) and nebulizers for delivery of β2-agonists?
Review scope Included studies compared nebulizers with metered-dose inhalers using a spacer for delivery of β2-agonists in children and adults who presented to a community setting or emergency department with acute asthma. Studies that included children with a mean age < 2 years were excluded. Studies including patients with chronic obstructive pulmonary disease were included if results of patients with asthma were reported separately. Outcomes included hospitalization, emergency department length of stay, FEV1 (% predicted), and use of steroids.
Review methods Cochrane Airways Group Specialised Register of trials (2008 to Feb 2013), which includes studies identified from Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE/ Excerpta Medica, CINAHL, AMED, PsycINFO, and handsearches of respiratory journals and meeting abstracts; and reference lists were searched for randomized controlled trials (RCTs). Authors were contacted. {Eligible studies published before 2008 were extracted from a previous literature search.}* 39 RCTs, including 1897 children and 729 adults, met the inclusion criteria. Only analyses for adults are reported here. Of the 13 RCTs that reported on adults (range 22 to 122 patients), 6 used multiple treatments at 10- to 30-minute intervals. 6 RCTs adequately reported random sequence generation, 1 adequately reported allocation concealment, 8 reported blinding of participants and personnel, and 9 reported blinding of outcome assessment. Overall evidence was judged to be of moderate quality.
Main results For studies that assessed multiple treatments, spacers and nebulizers did not differ for hospitalizations, use of steroids, emergency department length of stay, or FEV1 (% predicted) (Table). 1 study assessed the effect of single treatments on hospital admissions and found no difference between groups (relative risk increase 67%, 95% CI −52 to 483).
Conclusion Holding chambers (spacers) and nebulizers for delivery of β2agonists do not differ for clinical outcomes in acute asthma. Holding chambers (spacers) vs nebulizers for delivery of β2-agonists in multiple-treatment studies in adults with acute asthma† Outcomes
Number of Weighted RRR (95% CI) trials (n) event rates Spacers Nebulizers
Hospitalization
9 (582)
Use of steroids
2 (88)
9.9% 10%
11% 17%
NNT (CI)
6% (−43 to 39)
NS
29% (−502 to 92)
NS
Mean difference (CI) Emergency department 2 (132) length of stay (min)
1.75 (−23.45 to 26.95)‡
FEV1 (% predicted)
0.96 (−2.54 to 4.46)§
6 (307)
†NS = not significant; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from risk ratios and risk differences in article using a fixed-effect model. ‡Positive difference favors nebulizers. §Positive difference favors spacers.
18 February 2014 | ACP Journal Club | Volume 160 • Number 4
*Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2006;(2):CD000052.
Sources of funding: Garfield Weston Foundation, UK and Canadian Institutes of Health Research. For correspondence: Dr. C.J. Cates, St. George’s University of London, London, England, UK. E-mail [email protected]. ■
Commentary Acute asthma presents with widespread airflow obstruction and bronchoconstriction. Inhaled β2-agonists relieve airway smooth muscle spasm and are thus an effective first-line therapy and recommended in established practice guidelines. Pharmacodynamic studies indicate that spacers and nebulizers deliver similar doses of bronchodilator to the lungs (1). The assumption that nebulizers provide more relief for severe airflow obstruction in acute asthma is based on the theory that the more β2-agonist administered, the better the effect (2). This is incorrect because 1) the dose response of β2-agonists on airway smooth muscle rapidly reaches a plateau beyond which further dosing does not achieve greater smooth muscle relaxation (3); 2) airway smooth muscle spasm is only 1 mechanism of airflow obstruction in acute asthma exacerbations—other mechanisms, including airway edema, mucus secretion, and plugging of small airways, are nonresponsive to β2-agonists; and 3) nebulized aerosol technology, at best, delivers 20% to 35% efficiency of lung deposition, with the rest disappearing as mist into the room or deposited into the oropharynx and swallowed (4). Beyond this dose–response plateau, further benefit is offset by such increasing side effects as tremors, tachycardia, cardiac arrhythmias, and lactic acidosis, probably a result of systemic absorption from the oropharynx and gastrointestinal tract. Another concern is that nebulized aerosols contribute to the nosocomial spread of respiratory viral infections, and a World Health Organization Consultation on human influenza recommended their use only with strict airborne precautions (5). The meta-analysis by Cates and colleagues reinforces that spacers and nebulizers provide equivalent outcomes in acute asthma. Despite this, administration of a misty aerosol nebulizer in acute asthma conveys an intangible “smoke and mirrors” impression of efficacy for patient and physician alike. Institutional change for such an entrenched practice is achievable but requires a MythBusters approach with stakeholders, including patients, emergency physicians, intensivists, and pulmonologists, to promote evidence-based practice (6). Francis Thien, MD Monash University and Eastern Health Melbourne, Victoria, Australia References 1. Mazhar SH, Ismail NE, Newton DA, Chrystyn H. Br J Clin Pharmacol. 2008;65:334-7. 2. Rottier BL, Rubin BK. Paediatr Respir Rev. 2013;14:112-8. 3. Blake K, Madabushi R, Derendorf H, Lima J. Chest. 2008;134:981-9. 4. Selroos O, Pietinalho A, Riska H. BioDrugs (Clinical Immunotherapeutics) 1996;6:273−99. 5. Beigel JH, Farrar J, Han AM, et al; Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. N Engl J Med. 2005;353:1374-85. 6. Salyer JW, DiBlasi RM, Crotwell DN, Cowan CA, Carter ER. Respir Care. 2008;53:338-45. © 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929769/ by a University of California San Diego User on 03/27/2017
JC9
