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TÍTULO; Agentes anticolinérgicos de acción prolongada en pacientes con asma no controlada: revisión sistemática y metanálisis
AÑO Y TIPO DES ESTUDIO: 2014, Metaanálisis de ECA
RESULTADOS:Se analizaron cinco estudios con 1635 pacientes. En comparación con un placebo o una dosis doble de corticosteroides inhalados, la adición de tiotropio aumentó el volumen espiratorio forzado mínimo y máximo medio en 1 segundo en 97 ml (IC del 95%: 71-122) y 103 ml (IC del 95%: 42-163), respectivamente. Las diferencias medias en el flujo espiratorio máximo matutino fueron de 19,2 l / min (IC del 95%: 11,8-26,6). El tiotropio también redujo el riesgo de exacerbación aguda grave (OR 0,73; IC del 95%: 0,56 a 0,96) y mejoró la puntuación del Cuestionario de calidad de vida para el asma de forma significativa en 0,10 (IC del 95%: 0,04 a 0,16). No hubo diferencias en los eventos adversos graves.
CONCLUSIONES: La adición de tiotropio puede ser beneficiosa para los pacientes con asma mal controlada, aunque los problemas de exacerbación o seguridad deben aclararse en ensayos a largo plazo antes de su uso generalizado en el asma.

https://pubmed.ncbi.nlm.nih.gov/25517806/

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Affiliations

¹ Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

² Institute for Evidence-based Medicine, Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Korea.

³ Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea.

⁴ Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea.

⁵ Department of Pulmonology and Critical Care Medicine, Won Kwang University Sanbon Hospital, Sanbon, Korea.

⁶ Division of Pulmonology, Department of Internal Medicine, Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea.

⁷ Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.

⁸ Division of Pulmonology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

⁹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Ewha Medical Center and Ewha Medical Research Institute, Ewha Womans University, School of Medicine, Mokdong Hospital, Seoul, Korea.

¹⁰ Department of Pulmonary and Critical Care Medicine, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee University, Seoul, Korea.

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

² Institute for Evidence-based Medicine, Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Korea.

³ Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea.

⁴ Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea.

⁵ Department of Pulmonology and Critical Care Medicine, Won Kwang University Sanbon Hospital, Sanbon, Korea.

⁶ Division of Pulmonology, Department of Internal Medicine, Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea.

⁷ Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.

⁸ Division of Pulmonology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

⁹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Ewha Medical Center and Ewha Medical Research Institute, Ewha Womans University, School of Medicine, Mokdong Hospital, Seoul, Korea.

¹⁰ Department of Pulmonary and Critical Care Medicine, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee University, Seoul, Korea.

Abstract

Setting: A novel effective treatment is necessary for severe asthma.

Objective: To review clinical trials examining the role of tiotropium in patients with poorly controlled asthma despite inhaled corticosteroid use with or without long-acting β₂-agonists.

Design: A computerised search of electronic databases (Medline, EMBASE and Cochrane Central Register) was performed. Randomised controlled trials of at least a 4-week treatment duration with findings published in English were included.

Results: Five studies involving 1635 patients were analysed. Compared with a placebo or a double dose of inhaled corticosteroids, the addition of tiotropium increased mean trough and peak forced expiratory volume in 1 second by 97 ml (95%CI 71-122) and 103 ml (95%CI 42-163), respectively. The mean differences in morning peak expiratory flow were 19.2 l/min (95%CI 11.8-26.6). Tiotropium also reduced the risk of severe acute exacerbation (OR 0.73, 95%CI 0.56-0.96) and improved Asthma Quality-of-Life Questionnaire score significantly by 0.10 (95%CI 0.04-0.16). There were no differences in serious adverse events.

Conclusion: The addition of tiotropium may be beneficial for patients with poorly controlled asthma, although exacerbation or safety issues should be clarified in long-term trials before its wide use in asthma.

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Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, Boushey HA, Calhoun WJ, Castro M, Cherniack RM, Craig T, Denlinger L, Engle LL, DiMango EA, Fahy JV, Israel E, Jarjour N, Kazani SD, Kraft M, Lazarus SC, Lemanske RF Jr, Lugogo N, Martin RJ, Meyers DA, Ramsdell J, Sorkness CA, Sutherland ER, Szefler SJ, Wasserman SI, Walter MJ, Wechsler ME, Chinchilli VM, Bleecker ER; National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Peters SP, et al. N Engl J Med. 2010 Oct 28;363(18):1715-26. doi: 10.1056/NEJMoa1008770. Epub 2010 Sep 19. N Engl J Med. 2010. PMID: 20979471 Free PMC article. Clinical Trial.

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anti-asthmatic agents / therapeutic use*

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bronchodilator agents / therapeutic use*

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cholinergic antagonists / adverse effects

# data[].attributes.attachment_link.keywords[]
cholinergic antagonists / therapeutic use*

# data[].attributes.attachment_link.keywords[]
scopolamine derivatives / adverse effects

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scopolamine derivatives / therapeutic use*

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national center for biotechnology information

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Long-acting anticholinergic agents in patients with uncontrolled asthma: a systematic review and meta-analysis - PubMed

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1 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. 2 Institute for Evidence-based Medicine, Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Korea. 3 Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea.

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Título del estudio:

Eficacia relativa y seguridad de los corticosteroides inhalados en pacientes con asma

Autor y año de publicación: Chipps, B; 2020
Tipo de estudio: Meta-análisis y revisión sistemática
Resultado: El tratamiento varió de 4 a 39 semanas. Se seleccionaron 31 ECAs donde se incluía tratamiento con corticoides inhalados y se encontró una mejoría en los síntomas durante la noche tras el uso de esta medicación. Hubo una mejora en el cambio en el volumen espiratorio forzado en 1 segundo y flujo espiratorio máximo matutino.
Conclusiones: Dosis altas de corticoides inhalados no tienen ningún beneficio adicional en la mayor cantidad de parámetros evaluados en eficacia si se enfrenta con dosis bajas o moderadas del mismo medicamento para controlar el asma moderada-grave; sin embargo, se reconoce a estos medicamentos como controladores de primera línea, pero se debe realizar mayor investigación para evaluar los problemas de seguridad potenciales.

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TITULO: Eficacia de los corticosteroides inhalados en bebés y niños en edad preescolar con sibilancias recurrentes y asma
TIPO DE ESTUDIO: Revisión sistemática con metaanálisis
AÑO: 2009
RESULTADO: De ochenta y nueve estudios identificados, 29 (N = 3592 sujetos) cumplieron los criterios de inclusión. Los pacientes que recibieron corticosteroides inhalados tuvieron significativamente menos sibilancias / exacerbaciones del asma que los que recibieron placebo (18,0% frente a 32,1%);
COCNCLUSION: Los bebés y los niños en edad preescolar con sibilancias o asma recurrentes tienen menos sibilancias / exacerbaciones del asma y mejoran sus síntomas y la función pulmonar durante el tratamiento con corticosteroides inhalados.

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Abstract

Objective: To compare the efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing or asthma.

Methods: Randomized, prospective, controlled trials published January 1996 to March 2008 with a minimum of 4 weeks of inhaled corticosteroids versus placebo were retrieved through Medline, Embase, and Central databases. The primary outcome was wheezing/asthma exacerbations; secondary outcomes were withdrawal caused by wheezing/asthma exacerbations, changes in symptoms score, pulmonary function (peak expiratory flow and forced expiratory volume in 1 second), or albuterol use.

Results: Of eighty-nine studies identified, 29 (N = 3592 subjects) met the criteria for inclusion. Patients who received inhaled corticosteroids had significantly less wheezing/asthma exacerbations than those on placebo (18.0% vs 32.1%); posthoc subgroup analysis suggests that this effect was higher in those with a diagnosis of asthma than wheeze but was independent of age (infants versus preschoolers), atopic condition, type of inhaled corticosteroid (budesonide metered-dose inhaler versus fluticasone metered-dose inhaler), mode of delivery (metered-dose inhaler versus nebulizer), and study quality (Jadad score: <4 vs >/=4) and duration (<12 vs >/=12 weeks). In addition, children treated with inhaled corticosteroids had significantly fewer withdrawals caused by wheezing/asthma exacerbations, less albuterol use, and more clinical and functional improvement than those on placebo.

Conclusions: Infants and preschoolers with recurrent wheezing or asthma had less wheezing/asthma exacerbations and improve their symptoms and lung function during treatment with inhaled corticosteroids.

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Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: A systematic review.

Castro-Rodriguez JA, Rodriguez-Martinez CE, Ducharme FM. Castro-Rodriguez JA, et al. Pediatr Pulmonol. 2018 Dec;53(12):1670-1677. doi: 10.1002/ppul.24176. Epub 2018 Nov 5. Pediatr Pulmonol. 2018. PMID: 30394700

Preschool Wheezing: Trajectories and Long-Term Treatment.

Fainardi V, Santoro A, Caffarelli C. Fainardi V, et al. Front Pediatr. 2020 May 12;8:240. doi: 10.3389/fped.2020.00240. eCollection 2020. Front Pediatr. 2020. PMID: 32478019 Free PMC article. Review.

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adrenal cortex hormones / administration & dosage*

# data[].attributes.attachment_link.keywords[]
androstadienes / administration & dosage

# data[].attributes.attachment_link.keywords[]
beclomethasone / administration & dosage

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis - PubMed

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Objective: To compare the efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing or asthma. Methods: Randomized, prospective, controlled trials published January 1996 to March 2008 with a minimum of 4 weeks of inhaled corticosteroids versus placebo were retrieved through Medline, Embase, and Central databases.

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Anticolinérgicos inhalados y agonistas beta (2) de acción corta versus agonistas beta2 de acción corta solos para niños con asma aguda en el hospital

AÑO DE ESTUDIO: 2014 - Metanalisis
OBJETIVO: Evaluar la eficacia y seguridad de los anticolinérgicos agregados a los agonistas β2 como terapia inhalada o nebulizada en niños hospitalizados por una exacerbación aguda del asma.

CONCLUSION: Se respalda las recomendaciones nacionales e internacionales actuales que indican que los médicos deben abstenerse de usar anticolinérgicos en niños hospitalizados por asma aguda.

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Abstract

Background: Inhaled anticholinergics given in addition to β2-agonists are effective in reducing hospital admissions in children presenting to the emergency department with a moderate to severe asthma exacerbation. It seems logical to assume a similar beneficial effect in children hospitalised for an acute asthma exacerbation.

Objectives: To assess the efficacy and safety of anticholinergics added to β2-agonists as inhaled or nebulised therapy in children hospitalised for an acute asthma exacerbation. To investigate the characteristics of patients or therapy, if any, that would influence the magnitude of response attributable to the addition of anticholinergics.

Search methods: We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO and through handsearching of respiratory journals and meeting abstracts. The search is current to November 2013.

Selection criteria: Randomised trials comparing the combination of inhaled or nebulised anticholinergics and short-acting β2-agonists versus short-acting β2-agonists alone in children one to 18 years of age hospitalised for an acute asthma exacerbation were eligible.

Data collection and analysis: Two review authors independently assessed the methodological quality of trials and extracted data; disagreement was resolved by consensus or with the input of a third review author, when needed. Primary outcomes were duration of hospital stay and serious adverse events. Secondary outcomes included admission and duration of stay in the intensive care unit (ICU), ventilation assistance, time to short-acting β2-agonists spaced at four hours or longer, supplemental asthma therapy, duration of supplemental oxygen, change from baseline in asthma severity, relapse after discharge, adverse health effects and withdrawals.

Main results: Seven randomised trials were included, four of which reported usable data on 472 children with asthma one to 18 years of age who were admitted to paediatric wards. No trials included patients admitted to the ICU. The anticholinergic used, ipratropium bromide 250 μg, was given every one to eight hours over a period from four hours to the entire length of the hospital stay. Two of four trials (50%) contributing data were deemed of high methodological quality. The addition of anticholinergics to β2-agonists showed no evidence of effect on the duration of hospital admission (mean difference (MD) -0.28 hours, 95% confidence interval (CI) -5.07 to 4.52, 3 studies, 327 participants, moderate quality evidence) and no serious or non-serious adverse events were reported in any included trials. As a result of the similarity of trials, we could not explore the influence of age, admission site, intensity of anticholinergic treatment and co-interventions on primary outcomes. No statistically significant group difference was noted in other secondary outcomes, including the need for supplemental asthma therapy, time to short-acting β2-agonists spaced at four hours or longer, asthma clinical scores, lung function and overall withdrawals for any reason.

Authors' conclusions: In children hospitalised for an acute asthma exacerbation, no evidence of benefit for length of hospital stay and other markers of response to therapy was noted when nebulised anticholinergics were added to short-acting β2-agonists. No adverse health effects were reported, yet the small number of trials combined with inadequate reporting prevent firm reassurance regarding the safety of anticholinergics. In the absence of trials conducted in ICUs, no conclusion can be drawn regarding children with impending respiratory failure. These findings support current national and international recommendations indicating that healthcare practitioners should refrain from using anticholinergics in children hospitalised for acute asthma.

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# data[].attributes.attachment_link.keywords[]
adrenergic beta-2 receptor agonists / administration & dosage*

# data[].attributes.attachment_link.keywords[]
anti-asthmatic agents / administration & dosage*

# data[].attributes.attachment_link.keywords[]
cholinergic antagonists / administration & dosage*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Inhaled anticholinergics and short-acting beta(2)-agonists versus short-acting beta2-agonists alone for children with acute asthma in hospital - PubMed

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In children hospitalised for an acute asthma exacerbation, no evidence of benefit for length of hospital stay and other markers of response to therapy was noted when nebulised anticholinergics were added to short-acting β2-agonists. No adverse health effects were reported, yet the small number of tr ...

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Titulo: Eficacia a corto plazo de la beclometasona nebulizada en episodios de sibilancias leves a moderadas en niños en edad preescolar

Tipo de estudio: ECA
Año: 2011
Resultado: Los participantes mostraron una mejoría (caída) en la frecuencia respiratoria de 7,7 respiraciones por minuto después del salbutamol en comparación con 2,6 respiraciones por minuto después del placebo, una diferencia de ‐5,1 respiraciones por minuto. Hubo una mejoría en la puntuación de los síntomas (que evaluó la frecuencia cardíaca, la frecuencia respiratoria, las sibilancias y los músculos accesorios en una escala de cero a tres) de 2,9 puntos después del salbutamol versus 0,4 puntos después del placebo (diferencia ‐2,5; IC del 95%: ‐3,88 a ‐1,12). Hubo una mejoría en la saturación de oxígeno del 1,3% después del salbutamol en comparación con un deterioro del ‐0,3% después del placebo (diferencia 1,6, IC del 95%: 0,33 a 2,87).
Conclusión:
Un tratamiento de 1 semana con BDP nebulizado y prn (pro re nata) salbutamol es eficaz para aumentar los SFD (% de días sin síntomas) y mejorar la tos en los niños con sibilancias, lo que proporciona una justificación clínica para el uso a corto plazo de ICS en las exacerbaciones episódicas de las sibilancias en niños en edad preescolar.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170583/

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Short term efficacy of nebulized beclomethasone in mild-to-moderate wheezing episodes in pre-school children

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Few data are available on the usefulness of short term treatment with low-medium dose of inhaled corticosteroids (ICS) in pre-school children with wheezing exacerbations.To compare the efficacy of one week treatment with 400 μg b.i.d. nebulized ...

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AUTOR: Hongzhen Xu, et al.
TITULO:

Combinación de bromuro de ipratropio y salbutamol en niños y adolescentes con asma: un metanálisis

TIPO DE ESTUDIO: Metaanálisis
AÑO: 2021
RESULTADOS:  IB + salbutamol redujo significativamente el riesgo de ingreso hospitalario en comparación con salbutamol solo (cociente de riesgo [RR] 0,79; IC del 95%: 0,66-0,95; p = 0,01; I2 = 40%). El análisis de subgrupos solo mostró una diferencia significativa en el riesgo de ingreso hospitalario en los participantes con exacerbación del asma grave (RR 0,73; IC del 95%: 0,60 a 0,88; p = 0,0009; I2 = 4%) y exacerbación de moderada a grave (RR 0,69; 95 % IC 0,50-0,96; p = 0,03; I2 = 3%)
CONCLUSION:  IB + salbutamol puede ser más eficaz que el salbutamol solo para el tratamiento del asma en niños y adolescentes, especialmente en aquellos con exacerbación del asma severa y moderada a severa.

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Affiliations

¹ Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

² Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

Free PMC article

Free PMC article

Affiliations

¹ Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

² Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

Abstract

Background: A combination of ipratropium bromide (IB) and salbutamol is commonly used to treat asthma in children and adolescents; however, there has been a lack of consistency in its usage in clinical practice.

Objective: To evaluate the efficacy and safety of IB + salbutamol in the treatment of asthma in children and adolescents.

Methods: The MEDLINE, Embase, and Cochrane Library as well as other Chinese biomedical databases (including China Biological Medicine Database, Chinese National Knowledge Infrastructure, Chongqing VIP, and Wanfang Chinese language bibliographic database) were systematically searched from the earliest record date to September 2020 for randomized controlled trials in children and adolescents (≤18 years) with asthma who received IB + salbutamol or salbutamol alone. The primary outcomes included hospital admission and adverse events. A random effects model with a 95% confidence interval (CI) was used. Subgroup analysis was performed according to age, severity of asthma, and co-interventions with other asthma controllers. This study was registered with PROSPERO.

Results: Of the 1061 studies that were identified, 55 met the inclusion criteria and involved 6396 participants. IB + salbutamol significantly reduced the risk of hospital admission compared with salbutamol alone (risk ratio [RR] 0.79; 95% CI 0.66-0.95; p = 0.01; I2 = 40%). Subgroup analysis only showed significant difference in the risk of hospital admission in participants with severe asthma exacerbation (RR 0.73; 95% CI 0.60-0.88; p = 0.0009; I2 = 4%) and moderate-to-severe exacerbation (RR 0.69; 95% CI 0.50-0.96; p = 0.03; I2 = 3%). There were no significant differences in the risk of adverse events between IB + salbutamol group and salbutamol alone group (RR 1.77; 95% CI 0.63-4.98).

Conclusion: IB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. The very low to high quality of evidence indicated that future well-designed double-blind RCTs with large sample are needed for research on evaluating the effectiveness of IB + salbutamol treatment for asthma in children and adolescents.

Conflict of interest statement

The authors have declared that no competing interests exist.

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Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma.

Kirkland SW, Vandenberghe C, Voaklander B, Nikel T, Campbell S, Rowe BH. Kirkland SW, et al. Cochrane Database Syst Rev. 2017 Jan 11;1(1):CD001284. doi: 10.1002/14651858.CD001284.pub2. Cochrane Database Syst Rev. 2017. PMID: 28076656 Free PMC article. Review.

References

Masoli M, Fabian D, Holt S, Beasley R, Program GIfA. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59(5):469-78. 10.1111/j.1398-9995.2004.00526.x - DOI - PubMed

Zhou X, Hong J. Pediatric Asthma Management in China: Current and Future Challenges. Paediatr Drugs. 2018;20(2):105-10. 10.1007/s40272-017-0276-7 - DOI - PubMed

Kamble S, Bharmal M. Incremental direct expenditure of treating asthma in the United States. J Asthma. 2009;46(1):73-80. 10.1080/02770900802503107 - DOI - PubMed

Asher I, Pearce N. Global burden of asthma among children. Int J Tuberc Lung Dis. 2014;18(11):1269-78. 10.5588/ijtld.14.0170 - DOI - PubMed

Bao Y, Chen Z, Liu E, Xiang L, Zhao D, Hong J. Risk Factors in Preschool Children for Predicting Asthma During the Preschool Age and the Early School Age: a Systematic Review and Meta-Analysis. Curr Allergy Asthma Rep. 2017;17(12):85 10.1007/s11882-017-0753-7 - DOI - PubMed

Grant support

The author(s) received no specific funding for this work.

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national center for biotechnology information

# data[].attributes.attachment_link.title
Combination of ipratropium bromide and salbutamol in children and adolescents with asthma: A meta-analysis - PubMed

# data[].attributes.attachment_link.description
IB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. The very low to high quality of evidence indicated that future well-designed double-blind RCTs with large s ...

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TITULO:

Eficacia y seguridad de budesonida / formoterol en comparación con salbutamol en el tratamiento del asma aguda

TIPO DE ESTUDIO:
Ensayo controlado aleatorio

AÑO:
2006

RESULTADOS:
No se observaron diferencias de tratamiento para otros signos vitales, incluido el ECG. La budesonida / formoterol en dosis altas fue eficaz y bien tolerada para el tratamiento del asma aguda, con un inicio rápido de la eficacia y un perfil de seguridad durante 3 h similar al salbutamol en dosis altas. La frecuencia media del pulso durante 3 h fue significativamente mayor en el grupo de salbutamol que en el grupo de budesonida / formoterol. No se observaron diferencias de tratamiento para otros signos vitales, incluido el ECG.

CONCLUSIONES:
La budesonida / formoterol en dosis altas fue eficaz y bien tolerada para el tratamiento del asma aguda, con un inicio rápido de la eficacia y un perfil de seguridad durante 3 h similar al salbutamol en dosis altas

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Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma - PubMed

# data[].attributes.attachment_link.description
This study compared the efficacy and safety of budesonide/formoterol (Symbicort) Turbuhaler)) with salbutamol pressurized metered-dose inhaler (pMDI) with spacer for relief of acute bronchoconstriction in patients with asthma. In this randomized, double-blind, parallel-group study, patients (n = 104…

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Antecedentes: Los corticosteroides inhalados (CSI) son el pilar del tratamiento de control diario para el asma persistente y no controlada. Sin embargo, muchos médicos desconfían de los ICS por motivos de seguridad. Los médicos necesitan conocer los datos de eficacia subyacentes que respaldan el uso de ICS para sopesar la eficacia con la seguridad.

Objetivo: discutir los datos de eficacia de los ensayos fundamentales para ayudar a los médicos en sus decisiones de utilizar ICS.

Métodos: Se seleccionaron estudios clave de eficacia para aumentar la discusión.

Resultados: Los estudios clínicos han revelado que los CSI son eficaces para reducir el riesgo de exacerbaciones tanto en niños como en adultos. Los ICS también reducen el riesgo de hospitalización y muerte relacionada con el asma, mejoran los síntomas del asma y mejoran la calidad de vida. Además, los CSI mejoran la función pulmonar y la capacidad de respuesta de las vías respiratorias y reducen la inflamación y remodelación de las vías respiratorias. En los niños pequeños, los CSI mejoran los síntomas diurnos y nocturnos, mejoran la función pulmonar, reducen el riesgo de exacerbaciones y reducen la necesidad de medicamentos de rescate. Hasta la fecha, la evidencia es contradictoria acerca de si el tratamiento intermitente con CSI es tan efectivo como el tratamiento diario con CSI. Es necesario sopesar la posibilidad de una menor eficacia de la terapia intermitente frente a un riesgo reducido de crecimiento lento en los niños.

Conclusión: Los CSI reducen eficazmente el riesgo de exacerbaciones, hospitalizaciones y muerte relacionada con el asma y mejoran los síntomas del asma, la calidad de vida, la función pulmonar y la capacidad de respuesta de las vías respiratorias. Los ICS también reducen la inflamación y remodelación de las vías respiratorias. Es posible que la terapia intermitente no sea tan eficaz como la terapia diaria, y los médicos deben sopesar la eficacia reducida frente a la reducción del riesgo de efectos adversos, en particular la ralentización del crecimiento en los niños.
https://pubmed.ncbi.nlm.nih.gov/27979013/

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Abstract

Background: Inhaled corticosteroids (ICSs) are the mainstay of daily controller treatment for persistent and uncontrolled asthma. However, many clinicians are wary of ICSs because of safety concerns. Clinicians need to know the underlying efficacy data that support the use of ICSs to weigh efficacy against safety.

Objective: To discuss efficacy data from pivotal trials to aid clinicians in their decisions to use ICSs.

Methods: Key efficacy studies were selected to augment discussion.

Results: Clinical studies have revealed that ICSs are effective in reducing the risk of exacerbations in both children and adults. ICSs also reduce the risk of hospitalization and asthma-related death, improve asthma symptoms, and improve quality of life. In addition, ICSs improve lung function and airway responsiveness and reduce airway inflammation and remodeling. In young children, ICSs improve daytime and nighttime symptoms, improve lung function, reduce the risk of exacerbations, and reduce the need for rescue medications. To date, evidence is conflicting about whether intermittent ICS treatment is as effective as daily ICS treatment. The possibility of lower efficacy of intermittent therapy needs to be weighed against a reduced risk of slowed growth in children.

Conclusion: ICSs effectively reduce the risk of exacerbations, hospitalizations, and asthma-related death and improve asthma symptoms, quality of life, lung function, and airway responsiveness. ICSs also reduce airway inflammation and remodeling. Intermittent therapy may not be as effective as daily therapy, and clinicians should weigh reduced efficacy against reduced risk of adverse effects, particularly slowed growth in children.

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Relative efficacy and safety of inhaled corticosteroids in patients with asthma: Systematic review and network meta-analysis.

Chipps B, Taylor B, Bayer V, Shaikh A, Mosnaim G, Trevor J, Rogers S, Del Aguila M, Paek D, Wechsler ME. Chipps B, et al. Ann Allergy Asthma Immunol. 2020 Aug;125(2):163-170.e3. doi: 10.1016/j.anai.2020.04.006. Epub 2020 Apr 14. Ann Allergy Asthma Immunol. 2020. PMID: 32302768

The effectiveness of inhaled corticosteroids in the emergency department treatment of acute asthma: a meta-analysis.

Edmonds ML, Camargo CA Jr, Pollack CV Jr, Rowe BH. Edmonds ML, et al. Ann Emerg Med. 2002 Aug;40(2):145-54. doi: 10.1067/mem.2002.124753. Ann Emerg Med. 2002. PMID: 12140492

A pilot school-based health center intervention to improve asthma chronic care in high-poverty schools.

Holmes LC, Orom H, Lehman HK, Lampkin S, Halterman JS, Akiki V, Supernault-Sarker AA, Butler SB, Piechowski D, Sorrentino PM, Chen Z, Wilding GE. Holmes LC, et al. J Asthma. 2021 Jan 6:1-18. doi: 10.1080/02770903.2020.1864823. Online ahead of print. J Asthma. 2021. PMID: 33322963

Pharmacogenetic Factors Affecting Asthma Treatment Response. Potential Implications for Drug Therapy.

García-Menaya JM, Cordobés-Durán C, García-Martín E, Agúndez JAG. García-Menaya JM, et al. Front Pharmacol. 2019 May 21;10:520. doi: 10.3389/fphar.2019.00520. eCollection 2019. Front Pharmacol. 2019. PMID: 31178722 Free PMC article. Review.

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adrenal cortex hormones / administration & dosage

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adrenal cortex hormones / adverse effects

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adrenal cortex hormones / therapeutic use*

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anti-asthmatic agents / administration & dosage

# data[].attributes.attachment_link.keywords[]
anti-asthmatic agents / therapeutic use*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Pivotal efficacy trials of inhaled corticosteroids in asthma - PubMed

# data[].attributes.attachment_link.description
ICSs effectively reduce the risk of exacerbations, hospitalizations, and asthma-related death and improve asthma symptoms, quality of life, lung function, and airway responsiveness. ICSs also reduce airway inflammation and remodeling. Intermittent therapy may not be as effective as daily therapy, an ...

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https://pubmed.ncbi.nlm.nih.gov/15189956/
TÌTULO:

Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis

AUTOR Y AÑO DE PUBLICACIÓN: Salpeter, S et al.; 2004.
TIPO DE ESTUDIO: Meta-Análisis
RESULTADOS: En el estudio se incluyeron trece ensayos de dosis única y 20 ensayos de mayor duración. Una dosis única de beta (2) -agonista aumentó la frecuencia cardíaca en 9,12 latidos / min (intervalo de confianza [IC] del 95%, 5,32 a 12,92) y redujo la concentración de potasio en 0,36 mmol / L (IC del 95%, 0,18 a 0,54 ), en comparación con placebo. Para los ensayos que duraron de 3 días a 1 año, el tratamiento con agonistas beta (2) aumentó significativamente el riesgo de un evento cardiovascular (riesgo relativo [RR], 2,54; IC del 95%, 1,59 a 4,05) en comparación con placebo. El RR para la taquicardia sinusal sola fue de 3,06 (IC del 95%, 1,70 a 5,50) y para todos los demás eventos fue de 1,66 (IC del 95%, 0,76 a 3,6).
CONCLUSIONES: El uso de beta (2) -agonistas en pacientes con enfermedad obstructiva de las vías respiratorias aumenta el riesgo de eventos cardiovasculares adversos. El inicio del tratamiento aumenta la frecuencia cardíaca y reduce las concentraciones de potasio en comparación con el placebo. Podría ser a través de estos mecanismos, y otros efectos de la estimulación beta-adrenérgica, que los agonistas beta (2) pueden precipitar isquemia, insuficiencia cardíaca congestiva, arritmias y muerte súbita.

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Abstract

Background: beta-Adrenergic agonists exert physiologic effects that are the opposite of those of beta-blockers. beta-Blockers are known to reduce morbidity and mortality in patients with cardiac disease. beta(2)-Agonist use in patients with obstructive airway disease has been associated with an increased risk for myocardial infarction, congestive heart failure, cardiac arrest, and acute cardiac death.

Objectives: To assess the cardiovascular safety of beta(2)-agonist use in patients with obstructive airway disease, defined as asthma or COPD.

Methods: A meta-analysis of randomized placebo-controlled trials of beta(2)-agonist treatment in patients with obstructive airway disease was performed, to evaluate the short-term effect on heart rate and potassium concentrations, and the long-term effect on adverse cardiovascular events. Longer duration trials were included in the analysis if they reported at least one adverse event. Adverse events included sinus and ventricular tachycardia, syncope, atrial fibrillation, congestive heart failure, myocardial infarction, cardiac arrest, or sudden death.

Results: Thirteen single-dose trials and 20 longer duration trials were included in the study. A single dose of beta(2)-agonist increased the heart rate by 9.12 beats/min (95% confidence interval [CI], 5.32 to 12.92) and reduced the potassium concentration by 0.36 mmol/L (95% CI, 0.18 to 0.54), compared to placebo. For trials lasting from 3 days to 1 year, beta(2)-agonist treatment significantly increased the risk for a cardiovascular event (relative risk [RR], 2.54; 95% CI, 1.59 to 4.05) compared to placebo. The RR for sinus tachycardia alone was 3.06 (95% CI, 1.70 to 5.50), and for all other events it was 1.66 (95% CI, 0.76 to 3.6).

Conclusion: beta(2)-Agonist use in patients with obstructive airway disease increases the risk for adverse cardiovascular events. The initiation of treatment increases heart rate and reduces potassium concentrations compared to placebo. It could be through these mechanisms, and other effects of beta-adrenergic stimulation, that beta(2)-agonists may precipitate ischemia, congestive heart failure, arrhythmias, and sudden death.

[Cardiac arrest under special circumstances].

Lott C, Truhlář A, Alfonzo A, Barelli A, González-Salvado V, Hinkelbein J, Nolan JP, Paal P, Perkins GD, Thies KC, Yeung J, Zideman DA, Soar J. Lott C, et al. Notf Rett Med. 2021 Jun 10:1-77. doi: 10.1007/s10049-021-00891-z. Online ahead of print. Notf Rett Med. 2021. PMID: 34127910 Free PMC article. Review. German.

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adrenergic beta-agonists / adverse effects*

# data[].attributes.attachment_link.keywords[]
adrenergic beta-agonists / therapeutic use

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis - PubMed

# data[].attributes.attachment_link.description
beta(2)-Agonist use in patients with obstructive airway disease increases the risk for adverse cardiovascular events. The initiation of treatment increases heart rate and reduces potassium concentrations compared to placebo. It could be through these mechanisms, and other effects of beta-adrenergic ...

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https://www.bmj.com/content/326/7390/621.1

TITULO: Glucocorticoides inhalados versus antagonistas de los receptores de leucotrienos como agente único para el tratamiento del asma: revisión sistemática de la evidencia actual

TIPO DE ESTUDIO: revisión sistemática de ensayos controlados aleatorios
RESULTADOS: Se observó una mejora de 130 ml mayor (80 ml a 170 ml) en el volumen espiratorio forzado en un segundo y un aumento mayor de 19 l / min (14 la 24 l) en la tasa de flujo espiratorio máximo matutino a favor de los glucocorticoides inhalados. También se observaron diferencias a favor de los glucocorticoides inhalados para los despertares nocturnos, uso de rescate β ₂agonistas y días sin síntomas.
CONCLUSIÓN: Dosis de glucocorticoides inhalados equivalentes a 400 μg / día de beclometasona son más eficaces que los antagonistas de los receptores de leucotrienos en el tratamiento de adultos con asma leve o moderada.

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Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma treatment: systematic review of current evidence

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Objective: To compare the safety and efficacy of anti-leukotrienes and inhaled glucocorticoids as monotherapy in people with asthma. Design: Systematic review of randomised controlled trials comparing anti-leukotrienes with inhaled glucocorticoids for 28 days or more in children and adults. Main o…

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TITULO:El salbutamol y el ipratropio por inhalación es superior al nebulizador en niños con exacerbación aguda grave del asma TIPO DE ESTUDIOS: Ensayo clínico aleatorizado
AÑO: 2019
OBJETIVO: Comparar la eficacia del salbutamol y el bromuro de ipratropio por MDI versus NEB en las exacerbaciones graves del asma.
RESULTADOS: Cincuenta y dos niños recibieron MDI-SIB y 51 NEB-SIB. Después de la cuarta hora, los niños con MDI-SIB tuvieron una tasa de ingreso hospitalario significativamente menor (P = 0,003) que con NEB-SIB (5,8% frente a 27,5%, RR: 0,21 [0,06-0,69], respectivamente). De manera similar, se observó una mejora significativa en la puntuación clínica después de 60 min y un aumento en la saturación de oxígeno después de 90 min de tratamiento en el grupo MDI-SIB versus NEB-SIB (4.46 ± 0.7 vs 5.76 ± 0.65, P <0.00001; y 90.5 ± 1.7 vs 88.43 1 ± 1, P <0,00001, respectivamente).
CONCLUSIÓN: Se concluye que incluso en las exacerbaciones graves del asma, la administración de salbutamol e ipratropio por MDI con cámara de sujeción con válvula y mascarilla junto con oxígeno mediante una cánula por separado fue más eficaz que mediante un nebulizador.
https://pubmed.ncbi.nlm.nih.gov/32257877/

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Affiliations

¹ Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, No.155, Sec.2, Linong St, Beitou Dist, Taipei City, Taiwan.

² Taiwan Association for Traditional Chinese Medicine of Family, 9F, No.105, Yusheng St, Shilin Dist, Taipei City, Taiwan.

³ Institute of Public Health, National Yang-Ming University, No.155, Sec.2, Linong St, Beitou Dist, Taipei City, Taiwan.

⁴ Department of Chinese Medicine, Taipei City Hospital, Renai Branch, No.10, Sec.4, Renai Rd, Daan Dist, Taipei City, Taiwan.

⁵ School of Chinese Medicine, College of Chinese Medicine, China Medical University, No.91 Hsueh-Shih Road, North Dist, Taichung, Taiwan.

⁶ Department of Chinese Medicine, China Medical University Hospital, No.2, Yude Rd, Taichung City, Taiwan.

Free PMC article

Free PMC article

Affiliations

¹ Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, No.155, Sec.2, Linong St, Beitou Dist, Taipei City, Taiwan.

² Taiwan Association for Traditional Chinese Medicine of Family, 9F, No.105, Yusheng St, Shilin Dist, Taipei City, Taiwan.

³ Institute of Public Health, National Yang-Ming University, No.155, Sec.2, Linong St, Beitou Dist, Taipei City, Taiwan.

⁴ Department of Chinese Medicine, Taipei City Hospital, Renai Branch, No.10, Sec.4, Renai Rd, Daan Dist, Taipei City, Taiwan.

⁵ School of Chinese Medicine, College of Chinese Medicine, China Medical University, No.91 Hsueh-Shih Road, North Dist, Taichung, Taiwan.

⁶ Department of Chinese Medicine, China Medical University Hospital, No.2, Yude Rd, Taichung City, Taiwan.

Abstract

Background: Clinical trials have indicated some traditional Chinese medicine formulas reduce airway hyperresponsiveness and relieve asthma symptoms. This study investigated Chinese herbal Medicine (CHM) for childhood asthma and clarified the relationship between CHM use and consequent asthma hospitalization by a population-based cohort study.

Methods: We used the data of one million individuals randomly selected from Registry of Beneficiaries of the National Health Insurance Research Database. Patients aged less than 18 years and diagnosed as asthma were followed from 2000 to 2012 and divided into the CHM group and the non-CHM group. Cox proportional hazard regression model was conducted to estimate the adjusted hazard ratio (aHR) of the two groups, and the Kaplan-Meier survival curve was used to determine the association between CHM cumulative days and consequent asthma hospitalization.

Results: Of the total of 33,865 patients, 14,783 (43.6%) were included in the CHM group, and 19,082 (56.4%) were included in the non-CHM group. After adjustment for gender, age, comorbidities, and total numbers of asthma medication, CHM users had a lower risk of asthma hospitalization than non-CHM users (aHR: 0.90, 95% confidence interval [CI]: 0.83-0.95). Children older than 6 years who used CHM therapy for more than 180 days exhibited a reduction of 29% for the risk of consequent asthma hospitalization (aHR: 0.71, 95% CI: 0.51-0.98).

Conclusion: Children aged 6-18 years who used more than 6 months CHM therapy reduced the risk of consequent asthma hospitalization. Long-term CHM therapy has benefit in school-age children with asthma.

Keywords: Asthma; Childhood asthma; Chinese herbal medicine; National health insurance research database (NHIRD); Traditional Chinese medicine.

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Complementary Chinese herbal medicine therapy improves survival of patients with gastric cancer in Taiwan: A nationwide retrospective matched-cohort study.

Hung KF, Hsu CP, Chiang JH, Lin HJ, Kuo YT, Sun MF, Yen HR. Hung KF, et al. J Ethnopharmacol. 2017 Mar 6;199:168-174. doi: 10.1016/j.jep.2017.02.004. Epub 2017 Feb 3. J Ethnopharmacol. 2017. PMID: 28163114

Chinese herbal medicine for endometriosis.

Flower A, Liu JP, Chen S, Lewith G, Little P. Flower A, et al. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD006568. doi: 10.1002/14651858.CD006568.pub2. Cochrane Database Syst Rev. 2009. PMID: 19588398 Updated. Review.

How can the concurrent use of conventional medicine and Korean medicine be defined in the National Health Insurance Service database?

Hyun MK. Hyun MK. Integr Med Res. 2021 Jun;10(2):100485. doi: 10.1016/j.imr.2020.100485. Epub 2020 Jul 24. Integr Med Res. 2021. PMID: 33145165 Free PMC article. No abstract available.

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national center for biotechnology information

# data[].attributes.attachment_link.title
Long-term use of Chinese herbal medicine therapy reduced the risk of asthma hospitalization in school-age children: A nationwide population-based cohort study in Taiwan - PubMed

# data[].attributes.attachment_link.description
1 Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, No.155, Sec.2, Linong St, Beitou Dist, Taipei City, Taiwan. 2 Taiwan Association for Traditional Chinese Medicine of Family, 9F, No.105, Yusheng St, Shilin Dist, Taipei City, Taiwan. 3 Institute of Public Health, National Yang-Ming University, No.155, Sec.2, Linong St, Beitou Dist, Taipei City, Taiwan.

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titulo: Evaluación de la efectividad de los corticosteroides sistémicos para mitigar la recaída en niños evaluados y tratados por asma aguda: un metanálisis en red

año: 2019
tipo de estudio: metanalisis

Resultados: Se incluyeron quince estudios. En 3 estudios que compararon SCS con placebo, la recaída del asma se redujo significativamente (RR = 0,10; IC del 95%: 0,01, 0,77; I ² = 0%). Un análisis de red identificó una reducción significativa en la recaída en niños tratados con corticosteroides intramusculares (OR = 0,038; 95% CrI: 0,001, 0,397), prednisona oral de corta duración (OR = 0,054; 95% CrI: 0,002, 0,451) y oral dexametasona (OR = 0,071; 95% CrI: 0,002, 0,733) en comparación con placebo.

Conclusión: Esta revisión encontró pruebas de que la CEC reduce la recaída en los niños después del tratamiento para el asma aguda, aunque se basa en un número limitado de estudios. Se necesitan estudios adicionales para evaluar el efecto diferencial de las dosis de SCS y la duración del tratamiento para prevenir la recaída en los niños después del alta por asma aguda.
https://pubmed.ncbi.nlm.nih.gov/29693459/

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Affiliations

¹ a Department of Emergency Medicine , University of Alberta , Edmonton , AB , Canada.

² b Department of Pediatrics, Alberta Research Centre for Health Evidence , University of Alberta, Edmonton Clinic Health Academy , Edmonton , AB , Canada.

³ c J.W. Scott Health Sciences Library , University of Alberta , Walter C. Mackenzie Health Sciences Centre, Edmonton , AB , Canada.

⁴ d Department of Pediatrics , University of Alberta , Edmonton , AB , Canada.

⁵ e Departments of Pediatrics and of Social and Preventive Medicine , University of Montreal , Montreal , Quebec , Canada.

⁶ f School of Public Health, University of Alberta , Edmonton Clinic Health Academy , Edmonton , AB , Canada.

Affiliations

¹ a Department of Emergency Medicine , University of Alberta , Edmonton , AB , Canada.

² b Department of Pediatrics, Alberta Research Centre for Health Evidence , University of Alberta, Edmonton Clinic Health Academy , Edmonton , AB , Canada.

³ c J.W. Scott Health Sciences Library , University of Alberta , Walter C. Mackenzie Health Sciences Centre, Edmonton , AB , Canada.

⁴ d Department of Pediatrics , University of Alberta , Edmonton , AB , Canada.

⁵ e Departments of Pediatrics and of Social and Preventive Medicine , University of Montreal , Montreal , Quebec , Canada.

⁶ f School of Public Health, University of Alberta , Edmonton Clinic Health Academy , Edmonton , AB , Canada.

Abstract

Objective: The objective of this systematic review was to explore the effectiveness of various systemic corticosteroid (SCS) regimens to mitigate relapse in children with asthma discharged from an acute care setting.

Data sources: Medline, EMBASE, Global Health, International Pharmaceutical Abstracts, EMB ALL, CINAHL, SCOPUS, Proquest Dissertations and Theses Global, and LILACS were searched using controlled vocabulary and key words. Additional citations were searched via clinical trial registries, Google Scholar, bibliographies, a SCOPUS forward search of a sentinel paper, and hand searching conference abstracts.

Study selection: No limitations based on language, publication status, or year of publication were applied. Two independent reviewers searched to identify randomized controlled trials comparing the effectiveness of SCS regimens to prevent relapse in children following treatment for acute asthma.

Results: Fifteen studies were included. In 3 studies comparing SCS to placebo, asthma relapse was significantly reduced (RR = 0.10; 95% CI: 0.01, 0.77; I ² = 0%). A network analysis identified a significant reduction in relapse in children treated with intramuscular corticosteroids (OR = 0.038; 95% CrI: 0.001, 0.397), short-course oral prednisone (OR = 0.054; 95% CrI: 0.002, 0.451), and oral dexamethasone (OR = 0.071; 95% CrI: 0.002, 0.733) compared to placebo.

Conclusion: This review found evidence that SCS reduces relapse in children following treatment for acute asthma, albeit based on a limited number of studies. Additional studies are required to assess the differential effect of SCS doses and treatment duration to prevent relapse in children following discharge for acute asthma.

Keywords: Dexamethasone; emergency department; prednisone; randomized controlled trials; systematic review.

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Intramuscular versus oral corticosteroids to reduce relapses following discharge from the emergency department for acute asthma.

Kirkland SW, Cross E, Campbell S, Villa-Roel C, Rowe BH. Kirkland SW, et al. Cochrane Database Syst Rev. 2018 Jun 2;6(6):CD012629. doi: 10.1002/14651858.CD012629.pub2. Cochrane Database Syst Rev. 2018. PMID: 29859017 Free PMC article. Review.

Corticosteroids for preventing relapse following acute exacerbations of asthma.

Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW. Rowe BH, et al. Cochrane Database Syst Rev. 2000;(2):CD000195. doi: 10.1002/14651858.CD000195. Cochrane Database Syst Rev. 2000. PMID: 10796506 Updated. Review.

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adrenal cortex hormones / administration & dosage*

# data[].attributes.attachment_link.keywords[]
dexamethasone / administration & dosage*

# data[].attributes.attachment_link.keywords[]
glucocorticoids / administration & dosage*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Evaluating the effectiveness of systemic corticosteroids to mitigate relapse in children assessed and treated for acute asthma: A network meta-analysis - PubMed

# data[].attributes.attachment_link.description
This review found evidence that SCS reduces relapse in children following treatment for acute asthma, albeit based on a limited number of studies. Additional studies are required to assess the differential effect of SCS doses and treatment duration to prevent relapse in children following discharge ...

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[OPTIMIZACIÓN DEL TRATAMIENTO BRONCODILATADOR PARA NIÑOS DURANTE LA EXACERBACIÓN DEL ASMA TENIENDO EN CUENTA EL RIESGO DE DESARROLLO DE TRASTORNOS CARDIOHEMODINÁMICOS] - PubMed (nih.gov)

TÍTULO: OPTIMIZACIÓN DEL TRATAMIENTO BRONCODILATADOR PARA NIÑOS DURANTE LA EXACERBACIÓN DEL ASMA TENIENDO EN CUENTA EL RIESGO DE DESARROLLO DE TRASTORNOS CARDIOHEMODINÁMICOS

AÑO Y TIPO DEE STUDIO : 2015 Y ECA
RESULTADOS : Se establece que la elección incorrecta del broncodilatador influye más significativamente en los parámetros de presión arterial y la tasa de flujo sanguíneo en la arteria pulmonar, las válvulas mitral y tricúspide, y también contribuye a la aparición de signos de disfunción diastólica de los ventrículos derecho e izquierdo.
CONCLUSIÓN: Utilizando el tratamiento adecuado ( broncodilatador )del asma aguda en niños  previene la formación de futuras complicaciones del sistema cardiovascular.

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Abstract

We have studied the effect of bronchodilator drugs representing three groups--b2-adrenomimetic (fenoterol), anticholinergic (ipratropium bromide), and combined preparation (fenoterol/ipratropium bromide)--on cardiohemodynamics in children with acute asthma exacerbation. It is established that incorrect choice of bronchodilator most significantly influences the parameters of blood pressure and blood flow rate in the pulmonary artery, mitral and tricuspid valves, and also contributes to the appearance of signs of diastolic dysfunction of the right and left ventricles. A model predicting the risk of cardiohemodynamic violations was created using the multiple regression method, which allows the probability of negative changes in the cardiovascular system on the background of bronchodilator therapy to be calculated within several minutes using data on the medical prehistory and the results of objective and instrumental examination of a patient. Using this model it is possible to optimize the bronchodilator treatment of acute asthma in children and also to prevent the formation of future complications of the cardiovascular system.

Similar articles

Comparison of nebulized ipratropium bromide with salbutamol vs salbutamol alone in acute asthma exacerbation in children.

Watanasomsiri A, Phipatanakul W. Watanasomsiri A, et al. Ann Allergy Asthma Immunol. 2006 May;96(5):701-6. doi: 10.1016/S1081-1206(10)61068-X. Ann Allergy Asthma Immunol. 2006. PMID: 16729783 Clinical Trial.

[Evaluation of the bronchodilatory activity of berodual and its components: fenoterol and ipratropium bromide in children with bronchial asthma].

Jedrys U, Kurzawa R, Hałuszka J, Smieszek J, Doniec Z, Willim G. Jedrys U, et al. Pneumonol Alergol Pol. 1994;62(11-12):615-22. Pneumonol Alergol Pol. 1994. PMID: 7719261 Clinical Trial. Polish.

[Comparative study of the bronchodilating action of fenoterol and ipratropium bromide administered by aerosols in acute attacks of asthma].

Della Toffola A, Ardizzi A, Giorgis GE, Galietti F, Massaglia GM, Onoscuri E. Della Toffola A, et al. Minerva Med. 1986 May 31;77(22-23):1005-8. Minerva Med. 1986. PMID: 2941697 Clinical Trial. Italian.

[A trial of ipratropium bromide dose optimalization in patients with atopic asthma].

Karwat K. Karwat K. Pneumonol Alergol Pol. 1995;63(9-10):539-43. Pneumonol Alergol Pol. 1995. PMID: 8620176 Polish.

Combined anticholinergic therapy in the management of acute asthma.

# data[].attributes.attachment_link.keywords[]
bronchodilator agents / administration & dosage*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
[OPTIMIZATION OF BRONCHODILATOR THERAPY FOR CHILDREN DURING ASTHMA EXACERBATION WITH ALLOWANCE FOR THE RISK OF DEVELOPMENT OF CARDIOHEMODYNAMIC DISORDERS] - PubMed

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We have studied the effect of bronchodilator drugs representing three groups--b2-adrenomimetic (fenoterol), anticholinergic (ipratropium bromide), and combined preparation (fenoterol/ipratropium bromide)--on cardiohemodynamics in children with acute asthma exacerbation. It is established that incorrect choice of bronchodilator most significantly influences the parameters of blood pressure and blood flow rate in the pulmonary artery, mitral and tricuspid valves, and also contributes to the appearance of signs of diastolic dysfunction of the right and left ventricles.

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TITULO:

El salbutamol y el ipratropio por inhalación es superior al nebulizador en niños con exacerbación aguda grave del asma: ensayo clínico aleatorizado

AÑO Y TIPO DE ESTUDIO: 2019; ECA.
RESULTADOS: Cincuenta y dos niños recibieron MDI-SIB y 51 NEB-SIB. Después de la cuarta hora, los niños con MDI-SIB tuvieron una tasa de ingreso hospitalario significativamente menor (P = 0,003) que con NEB-SIB (5,8% frente a 27,5%, RR: 0,21 [0,06-0,69], respectivamente). De manera similar, se observó una mejora significativa en la puntuación clínica después de 60 min y un aumento en la saturación de oxígeno después de 90 min de tratamiento en el grupo MDI-SIB versus NEB-SIB (4.46 ± 0.7 vs 5.76 ± 0.65, P <0.00001; y 90.5 ± 1.7 vs 88.43 1 ± 1, P <0,00001, respectivamente).
CONCLUSIONES: Incluso en las exacerbaciones graves del asma, la administración de salbutamol e ipratropio por MDI con cámara de sujeción con válvula y mascarilla junto con oxígeno mediante una cánula por separado fue más eficaz que mediante un nebulizador.

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Affiliations

¹ Division of Pediatrics, Emergency Department, Clinical Hospital, National University of Asunción, Asunción, Paraguay.

² Emergency Department, Private Childreńs Institute Asunción, Asunción, Paraguay.

³ Division of Pediatrics, Department of Pediatric Respiratory and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Randomized Controlled Trial

Affiliations

¹ Division of Pediatrics, Emergency Department, Clinical Hospital, National University of Asunción, Asunción, Paraguay.

² Emergency Department, Private Childreńs Institute Asunción, Asunción, Paraguay.

³ Division of Pediatrics, Department of Pediatric Respiratory and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Abstract

Introduction: In moderate-severe asthma exacerbation, salbutamol by inhaler (MDI) is superior to salbutamol delivered by nebulizer (NEB); however, to our knowledge, no studies in children with exclusively severe exacerbations were performed.

Objective: To compare the efficacy of salbutamol and ipratropium bromide by MDI versus by NEB in severe asthma exacerbations.

Methods: We performed a clinical trial enrolling 103 children (2-14 years of age) with severe asthma exacerbations (defined by the Pulmonary Score ≥ 7) seen at the emergency room in Asuncion, Paraguay. One group received salbutamol and ipratropium (two puff every 10 min for 2 h and then every 30 min for 2 h more) by MDI with a valved-holding chamber and mask along with oxygen by a cannula separately (MDI-SIB); and the other received nebulization with oxygen (NEB-SIB) of salbutamol and ipratropium (1 every 20 min for 2 h and then every 30 min for 2 h more). Primary outcome was the rate of hospitalization (Pulmonary Score ≥ 7) after 4 h and secondary outcome was oxygen saturation.

Results: Fifty two children received MDI-SIB and 51 NEB-SIB. After the 4th hour, children on MDI-SIB had significantly (P = 0.003) lower rate of hospital admission than on NEB-SIB (5.8% vs 27.5%, RR: 0.21 [0.06-0.69], respectively). Similarly, a significant improved clinical score after 60 min and increase in oxygen saturation after 90 min of treatment was observed in MDI-SIB versus NEB-SIB group (4.46 ± 0.7 vs 5.76 ± 0.65, P < 0.00001; and 90.5 ± 1.7 vs 88.43 1 ± 1, P < 0.00001, respectively).

Conclusion: Even in severe asthma exacerbations administration of salbutamol and ipratropium by MDI with valved-holding chamber and mask along with oxygen by a cannula separately was more effective than by a nebulizer.

Keywords: MDI; children; ipratropium; nebulizer; salbutamol; severe acute asthma.

[Paediatric Life Support].

Van de Voorde P, Turner NM, Djakow J, de Lucas N, Martinez-Mejias A, Biarent D, Bingham R, Brissaud O, Hoffmann F, Johannesdottir GB, Lauritsen T, Maconochie I. Van de Voorde P, et al. Notf Rett Med. 2021 Jun 2:1-70. doi: 10.1007/s10049-021-00887-9. Online ahead of print. Notf Rett Med. 2021. PMID: 34093080 Free PMC article. Review. German.

Asthma and COVID-19 in children - a systematic review and call for data.

Castro-Rodriguez JA, Forno E. Castro-Rodriguez JA, et al. medRxiv. 2020 May 8:2020.05.04.20090845. doi: 10.1101/2020.05.04.20090845. Preprint. medRxiv. 2020. PMID: 32511474 Free PMC article. Updated.

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bronchodilator agents / administration & dosage*

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national center for biotechnology information

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Salbutamol and ipratropium by inhaler is superior to nebulizer in children with severe acute asthma exacerbation: Randomized clinical trial - PubMed

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1 Division of Pediatrics, Emergency Department, Clinical Hospital, National University of Asunción, Asunción, Paraguay. 2 Emergency Department, Private Childreńs Institute Asunción, Asunción, Paraguay. 3 Division of Pediatrics, Department of Pediatric Respiratory and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

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https://www.ingentaconnect.com/content/iuatld/ijtld/2014/00000018/00000012/art00008;jsessionid=wu5pthghj3nv.x-ic-live-03

Título: Agentes anticolinérgicos de acción prolongada en pacientes con asma no controlada: revisión sistemática y metanálisis

Tipo de estudio: revisión sistemática y metanálisis
Año: 2014
Resultados: Se analizaron cinco estudios con 1635 pacientes. En comparación con un placebo o una dosis doble de corticosteroides inhalados, la adición de tiotropio aumentó el volumen espiratorio forzado mínimo y máximo medio en 1 segundo en 97 ml (IC del 95%: 71-122) y 103 ml (IC del 95%: 42-163), respectivamente. Las diferencias medias en el flujo espiratorio máximo matutino fueron de 19,2 l / min (IC del 95%: 11,8-26,6). El tiotropio también redujo el riesgo de exacerbación aguda grave (OR 0,73; IC del 95%: 0,56 a 0,96) y mejoró la puntuación del Cuestionario de calidad de vida para el asma significativamente en 0,10 (IC del 95%: 0,04 a 0,16). No hubo diferencias en los eventos adversos graves.
Conclusión: La adición de tiotropio puede ser beneficiosa para los pacientes con asma mal controlada, aunque los problemas de exacerbación o seguridad deben aclararse en ensayos a largo plazo antes de su uso generalizado en el asma.

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Download Article:

SETTING: A novel effective treatment is necessary for severe asthma.
OBJECTIVE: To review clinical trials examining the role of tiotropium in patients with poorly controlled asthma despite inhaled corticosteroid use with or without long-acting β ₂-agonists.
DESIGN: A computerised search of electronic databases (Medline, EMBASE and Cochrane Central Register) was performed. Randomised controlled trials of at least a 4-week treatment duration with findings published in English were included.
RESULTS: Five studies involving 1635 patients were analysed. Compared with a placebo or a double dose of inhaled corticosteroids, the addition of tiotropium increased mean trough and peak forced expiratory volume in 1 second by 97 ml (95%CI 71-122) and 103 ml (95%CI 42-163), respectively. The mean differences in morning peak expiratory flow were 19.2 l/min (95%CI 11.8-26.6). Tiotropium also reduced the risk of severe acute exacerbation (OR 0.73, 95%CI 0.56-0.96) and improved Asthma Quality-of-Life Questionnaire score significantly by 0.10 (95%CI 0.04-0.16). There were no differences in serious adverse events.
CONCLUSION: The addition of tiotropium may be beneficial for patients with poorly controlled asthma, although exacerbation or safety issues should be clarified in long-term trials before its wide use in asthma.

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Keywords: anticholinergics; asthma; tiotropium

Document Type: Research Article

Affiliations: 1: Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul 2: Institute for Evidence-based Medicine, Department of Preventive Medicine, College of Medicine, Korea University, Seoul 3: Department of Internal Medicine, Konkuk University School of Medicine, Seoul 4: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul 5: Department of Pulmonology and Critical Care Medicine, Won Kwang University Sanbon Hospital, Sanbon 6: Division of Pulmonology, Department of Internal Medicine, Severance Hospital, Yonsei University, College of Medicine, Seoul 7: *Department of Internal Medicine, Hanyang University College of Medicine, Seoul 8: Division of Pulmonology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 9: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Ewha Medical Center and Ewha Medical Research Institute, Ewha Womans University, School of Medicine, Mokdong Hospital, Seoul 10: Department of Pulmonary and Critical Care Medicine, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee University, Seoul, Korea

Publication date: 01 December 2014

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Long-acting anticholinergic agents in patients with uncontrolled ...: Ingenta Connect

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Download Article: SETTING: A novel effective treatment is necessary for severe asthma.OBJECTIVE: To review clinical trials examining the role of tiotropium in patients with poorly controlled asthma despite inhaled corticosteroid use with or without long-acting β 2-agonists.DESIGN: A computerised search of electronic databases (Medline, EMBASE and Cochrane Central Register) was performed.

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Titulo:

Agonistas beta-2 de acción corta para las sibilancias recurrentes en niños menores de dos años

Año y tipo de estudio: Metanalisis de ECA 2002
Se utilizaron dos activaciones de salbutamol (200 mcg) tres veces al día durante cuatro o seis semanas. se usó jarabe de salbutamol, 1 mg, tres veces al día durante cinco días y luego según fue necesario durante nueve días. Los cinco estudios restantes siguieron una estrategia de dosis única, dos usaron dos dosis de salbutamol nebulizado a una dosis de 0,15 mg / kg, uno una dosis nebulizada única de 2,5 mg, uno una dosis inhalada de 800 mcg y uno de 600 mcg por inhalador y espaciador.
Resultados:Los participantes mostraron una mejoría (caída) en la frecuencia respiratoria de 7,7 respiraciones por minuto después del salbutamol en comparación con 2,6 respiraciones por minuto después del placebo, una diferencia de ‐5,1 respiraciones por minuto. Hubo una mejoría en la puntuación de los síntomas (que evaluó la frecuencia cardíaca, la frecuencia respiratoria, las sibilancias y los músculos accesorios en una escala de cero a tres) de 2,9 puntos después del salbutamol versus 0,4 puntos
Conclusion:No existe un efecto beneficioso claro del uso de los agonistas b-2 en el tratamiento de las sibilancias recurrentes en los dos primeros años de vida, aunque hay evidencia contradictoria.

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Los beta-agonistas, como el salbutamol, son los medicamentos prescritos con más frecuencia para el alivio del asma. Funcionan bien en adultos y niños, pero su efectividad en los lactantes está menos clara. Se revisaron ocho ensayos con 229 pacientes en cuatro contextos diferentes. Aunque los lactantes tienen la capacidad de responder al salbutamol, el alivio de los síntomas agudos es limitado cuando se administra a pacientes con enfermedad aguda. Esto no repercutió en la necesidad de ingreso hospitalario ni en la duración de la estancia hospitalaria. No se ha demostrado que el salbutamol habitual ofrezca protección contra el desarrollo de los síntomas.

Conclusiones de los autores:

No existe un efecto beneficioso claro del uso de los agonistas b-2 en el tratamiento de las sibilancias recurrentes en los dos primeros años de vida, aunque hay evidencia contradictoria. En la actualidad, sólo se deberían realizar más estudios si se puede definir claramente el grupo de pacientes y si existe un parámetro de desenlace adecuado capaz de medir una respuesta.

Leer el resumen completo...

La traducción de las revisiones Cochrane ha sido realizada bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad del Gobierno de España. Si detecta algún problema con la traducción, por favor, contacte con comunica@cochrane.es.

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Agonistas beta-2 de acción corta para las sibilancias recurrentes en niños menores de dos años

# data[].attributes.attachment_link.description
Los beta-agonistas, como el salbutamol, son los medicamentos prescritos con más frecuencia para el alivio del asma. Funcionan bien en adultos y niños, pero su efectividad en los lactantes está menos clara. Se revisaron ocho ensayos con 229 pacientes en cuatro contextos diferentes.

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TÍTULO:

Eficacia y efectos secundarios de la teofilina intravenosa en el asma aguda: revisión sistemática y metaanálisis.

AÑO: 2018
TIPO DE ESTUDIO: Revisión sistemática y metaanálisis.
RESULTADOS: Se incluyeron 52 brazos de estudio de 42 ensayos individuales. De estos, 29 brazos del estudio incluyeron un control activo, como adrenalina, agonistas beta-2 o antagonistas del receptor de leucotrienos, y 23 brazos del estudio compararon teofilina (con o sin etilendiamina) con placebo o ningún fármaco. La teofilina redujo significativamente la frecuencia cardíaca en comparación con el control activo ( p = 0,01) y la duración total de la estancia ( p = 0,002), pero los agonistas beta-2 fueron superiores a la teofilina para mejorar el volumen espiratorio forzado en un segundo (FEV1) ( p= 0,002). La teofilina no fue significativamente diferente de otros fármacos en sus efectos sobre la frecuencia respiratoria, la capacidad vital forzada (FVC), la tasa de flujo espiratorio máximo, la tasa de admisión, el uso de medicación de rescate, la saturación de oxígeno o la puntuación de los síntomas.
CONCLUSIONES: Dado el bajo costo de la teofilina y su eficacia y tasa de efectos secundarios similares en comparación con otros medicamentos, sugerimos que la teofilina, cuando se administra con broncodilatadores con o sin esteroides, es una opción rentable y segura para las exacerbaciones agudas del asma.

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Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis

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Theophylline has been used for decades to treat both acute and chronic asthma. Despite its longevity in the practitioner’s formulary, no detailed meta-analysis has been performed to determine the conditions, including concomitant medications, ...

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Resultados: De los 139 pacientes inscritos, 105 fueron asignados al azar para recibir una de las cuatro secuencias de tratamiento. La respuesta máxima del FEV1 (0-3 h) para tiotropio 5 μg fue significativamente mayor que el placebo (p = 0,0043). Las respuestas mínimas del FEV1 fueron significativamente mayores para tiotropio 5 μg (p <0,00001) y 1,25 μg (p = 0,0134) frente a placebo, pero no para 2,5 μg (p = 0,0975), mientras que las respuestas del área bajo la curva del FEV1 (0-3 h) fueron significativo para todas las dosis (p = 0,00001-0,0398). La incidencia general de eventos adversos se equilibró entre los grupos de tratamiento, sin observaciones dependientes de la dosis. La mayoría de los eventos adversos fueron de intensidad leve a moderada.

Conclusión: Este primer estudio de tiotropio en adolescentes con asma sintomática demuestra que el tiotropio es bien tolerado y eficaz como complemento del tratamiento de mantenimiento con CSI.

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Affiliations

¹ Technische Universität Dresden, University Hospital Carl Gustav Carus, Department of Pediatric Pneumology and Allergology, Fetscherstraße 74, 01307 Dresden, Germany. Electronic address: christian.vogelberg@uniklinikum-dresden.de.

² Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Straße 173, 55218 Ingelheim am Rhein, Germany.

³ Vilnius University Hospital, Santariskiu 7, Vilnius LT-08406, Lithuania.

⁴ Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88400 Biberach an der Riss, Germany.

⁵ Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, Ridgefield, CT 06877, USA.

⁶ Private Practice, 18th Street November 21, Rēzekne LV4601, Latvia.

⁷ Clinical Research of the Ozarks, 601 W Nifong Blvd, Suite 2A, Columbia, MO 65203, USA.

Free article

Free article

Affiliations

¹ Technische Universität Dresden, University Hospital Carl Gustav Carus, Department of Pediatric Pneumology and Allergology, Fetscherstraße 74, 01307 Dresden, Germany. Electronic address: christian.vogelberg@uniklinikum-dresden.de.

² Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Straße 173, 55218 Ingelheim am Rhein, Germany.

³ Vilnius University Hospital, Santariskiu 7, Vilnius LT-08406, Lithuania.

⁴ Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88400 Biberach an der Riss, Germany.

⁵ Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, Ridgefield, CT 06877, USA.

⁶ Private Practice, 18th Street November 21, Rēzekne LV4601, Latvia.

⁷ Clinical Research of the Ozarks, 601 W Nifong Blvd, Suite 2A, Columbia, MO 65203, USA.

Abstract

Introduction: Tiotropium, a once-daily long-acting anticholinergic agent, has been shown to be an efficacious and safe add-on treatment for adults with symptomatic asthma, despite treatment with inhaled corticosteroids (ICS). A large proportion of asthmatic adolescents have symptomatic disease despite a wide range of therapeutic options. We investigated the efficacy and safety of three doses of tiotropium, administered in the evening (via Respimat(®) SoftMist™ inhaler), versus placebo in asthmatic adolescents symptomatic despite ICS treatment.

Methods: This randomised, double-blind, placebo-controlled, incomplete crossover study evaluated once-daily tiotropium 5 μg, 2.5 μg and 1.25 μg versus placebo in three 4-week treatment periods. Primary efficacy end point was change in peak forced expiratory volume in 1 s within 3 h post-dose from baseline (peak FEV1(0-3h)).

Results: From 139 enrolled patients, 105 were randomised to receive one of four treatment sequences. Peak FEV1(0-3h) response for tiotropium 5 μg was significantly greater versus placebo (p = 0.0043). Trough FEV1 responses were significantly greater for tiotropium 5 μg (p < 0.00001) and 1.25 μg (p = 0.0134) versus placebo, but not for 2.5 μg (p = 0.0975), while FEV1 area under the curve(0-3h) responses were significant for all doses (p = 0.00001-0.0398). Overall incidence of adverse events was balanced across treatment groups, with no dose-dependent observations. The majority of adverse events were mild to moderate in intensity.

Conclusion: This first study of tiotropium in adolescents with symptomatic asthma demonstrates that tiotropium is well tolerated and efficacious as add-on to maintenance treatment with ICS. ClinicalTrials.gov identifier; NCT01122680.

Keywords: Adolescents; Anticholinergic; Asthma; Bronchodilator; Inhaled corticosteroids; Tiotropium.

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bronchodilator agents / administration & dosage*

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cholinergic antagonists / administration & dosage*

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cholinergic antagonists / adverse effects

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cholinergic antagonists / therapeutic use

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peak expiratory flow rate / drug effects

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scopolamine derivatives / administration & dosage*

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scopolamine derivatives / adverse effects

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scopolamine derivatives / therapeutic use

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national center for biotechnology information

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Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: a randomised dose-ranging study - PubMed

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1 Technische Universität Dresden, University Hospital Carl Gustav Carus, Department of Pediatric Pneumology and Allergology, Fetscherstraße 74, 01307 Dresden, Germany. Electronic address: christian.vogelberg@uniklinikum-dresden.de. 2 Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Straße 173, 55218 Ingelheim am Rhein, Germany. 3 Vilnius University Hospital, Santariskiu 7, Vilnius LT-08406, Lithuania.

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TITULO: Respuesta al salbutamol nebulizado versus combinación con bromuro de ipratropio en niños con asma aguda grave

AÑO Y TIPO DE ESTUDIO: 2016, ECA

RESULTADOS: Hubo dos grupos de 100 (50%) pacientes cada uno. La edad media en el Grupo A fue de 9,1 ± 3 años y de 9,3 ± 2,8 años en el Grupo B. La relación hombre-mujer en el Grupo A fue de 1,5: 1 y en el Grupo B fue de 1,2: 1. En el Grupo B, 93 (93%) niños mostraron una mejoría en la puntuación clínica (puntuación <10) mientras que fue 84 (84%) en el Grupo A. Hubo una mejor respuesta en la puntuación clínica en el Grupo A que en el Grupo B, pero no fue significativo (p> 0.05).

CONCLUSIÓN: La combinación de salbutamol nebulizado junto con bromuro de ipratropio en el tratamiento de la exacerbación aguda del asma no fue superior al salbutamol solo.

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Abstract

Objective: To compare the efficacy of nebulised salbutamol alone and in combination with ipratropium bromide in acute severe asthma in children.

Methods: The randomised controlled trial was conducted at the National Institute of Child Health, Karachi, from October 2012 to March 2013, and comprised patients with acute severe asthma who were randomised into two equal groups. Group A patients received 3 doses of nebulised salbutamol alone (0.03 ml/kg/dose) at 15-minute intervals and Group B received 3 similar doses of salbutamol along with ipratropium (250 ug/dose). Acute severe asthma was categorised as serve exacerbation (clinical score >10) and moderate (5-10 score) based on Bentur Modification. Efficacy was measured after 5minutes of the last dose by change in severity score from severe exacerbation (baseline) to low score. SPSS 10 was used for statistical analysis.

Results: There were two groups of 100(50%) patients each. The mean age in Group A was 9.1±3 years and 9.3±2.8 years in Group B. Male-Female ratio in Group A was 1.5:1 and in Group B it was 1.2:1. In Group B, 93(93%) children showed improvement in clinical score (<10 score) while it was 84(84%) in Group A. There was better response in clinical score in Group A than Group B, but it was not significant (p>0.05).

Conclusions: The combination of nebulised salbutamol along with ipratropium bromide in the treatment of acute asthma exacerbation was not superior to salbutamol alone.

Keywords: Acute severe asthma, Bentur Modification, Salbutamol, Ipratropium, Neublization..

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Does adding ipratropium to salbutamol (albuterol) help children with asthma?

Patel N, Phillips B. Patel N, et al. Arch Dis Child. 2001 Nov;85(5):432-3. Arch Dis Child. 2001. PMID: 12035817 Review. No abstract available.

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bronchodilator agents / therapeutic use*

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national center for biotechnology information

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Response to nebulized salbutamol versus combination with ipratropium bromide in children with acute severe asthma - PubMed

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Objective: To compare the efficacy of nebulised salbutamol alone and in combination with ipratropium bromide in acute severe asthma in children. Methods: The randomised controlled trial was conducted at the National Institute of Child Health, Karachi, from October 2012 to March 2013, and comprised patients with acute severe asthma who were randomised into two equal groups.

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TÍTULO; Agentes antileucotrienos comparados con corticosteroides inhalados en el tratamiento del asma recurrente y / o crónica en adultos y niños
AÑO Y TIPO DES ESTUDIO: 2012, Metaanálisis de ECA
RESULTADOS: El tratamiento con antileucotrienos se asoció con un mayor riesgo de retiros debido a un control deficiente del asma (N = 7669 participantes; RR 2,56; IC del 95%: 2,01 a 3,27). Por cada treinta y un (IC del 95%: 22 a 47) pacientes tratados con antileucotrienos en lugar de corticosteroides inhalados, hubo un retiro adicional debido a un control deficiente. . El tratamiento con antileucotrienos se asoció con un mayor riesgo de retiros debido a un control deficiente del asma (N = 7669 participantes; RR 2,56; IC del 95%: 2,01 a 3,27).

https://pubmed.ncbi.nlm.nih.gov/22592685/

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Abstract

Background: Anti-leukotrienes (5-lipoxygenase inhibitors and leukotriene receptors antagonists) serve as alternative monotherapy to inhaled corticosteroids (ICS) in the management of recurrent and/or chronic asthma in adults and children.

Objectives: To determine the safety and efficacy of anti-leukotrienes compared to inhaled corticosteroids as monotherapy in adults and children with asthma and to provide better insight into the influence of patient and treatment characteristics on the magnitude of effects.

Search methods: We searched MEDLINE (1966 to Dec 2010), EMBASE (1980 to Dec 2010), CINAHL (1982 to Dec 2010), the Cochrane Airways Group trials register, and the Cochrane Central Register of Controlled Trials (Dec 2010), abstract books, and reference lists of review articles and trials. We contacted colleagues and the international headquarters of anti-leukotrienes producers.

Selection criteria: We included randomised trials that compared anti-leukotrienes with inhaled corticosteroids as monotherapy for a minimum period of four weeks in patients with asthma aged two years and older.

Data collection and analysis: Two review authors independently assessed the methodological quality of trials and extracted data. The primary outcome was the number of patients with at least one exacerbation requiring systemic corticosteroids. Secondary outcomes included patients with at least one exacerbation requiring hospital admission, lung function tests, indices of chronic asthma control, adverse effects, withdrawal rates and biological inflammatory markers.

Main results: Sixty-five trials met the inclusion criteria for this review. Fifty-six trials (19 paediatric trials) contributed data (representing total of 10,005 adults and 3,333 children); 21 trials were of high methodological quality; 44 were published in full-text. All trials pertained to patients with mild or moderate persistent asthma. Trial durations varied from four to 52 weeks. The median dose of inhaled corticosteroids was quite homogeneous at 200 µg/day of microfine hydrofluoroalkane-propelled beclomethasone or equivalent (HFA-BDP eq). Patients treated with anti-leukotrienes were more likely to suffer an exacerbation requiring systemic corticosteroids (N = 6077 participants; risk ratio (RR) 1.51, 95% confidence interval (CI) 1.17, 1.96). For every 28 (95% CI 15 to 82) patients treated with anti-leukotrienes instead of inhaled corticosteroids, there was one additional patient with an exacerbation requiring rescue systemic corticosteroids. The magnitude of effect was significantly greater in patients with moderate compared with those with mild airway obstruction (RR 2.03, 95% CI 1.41, 2.91 versus RR 1.25, 95% CI 0.97, 1.61), but was not significantly influenced by age group (children representing 23% of the weight versus adults), anti-leukotriene used, duration of intervention, methodological quality, and funding source. Significant group differences favouring inhaled corticosteroids were noted in most secondary outcomes including patients with at least one exacerbation requiring hospital admission (N = 2715 participants; RR 3.33; 95% CI 1.02 to 10.94), the change from baseline FEV(1) (N = 7128 participants; mean group difference (MD) 110 mL, 95% CI 140 to 80) as well as other lung function parameters, asthma symptoms, nocturnal awakenings, rescue medication use, symptom-free days, the quality of life, parents' and physicians' satisfaction. Anti-leukotriene therapy was associated with increased risk of withdrawals due to poor asthma control (N = 7669 participants; RR 2.56; 95% CI 2.01 to 3.27). For every thirty one (95% CI 22 to 47) patients treated with anti-leukotrienes instead of inhaled corticosteroids, there was one additional withdrawal due to poor control. Risk of side effects was not significantly different between both groups.

Authors' conclusions: As monotherapy, inhaled corticosteroids display superior efficacy to anti-leukotrienes in adults and children with persistent asthma; the superiority is particularly marked in patients with moderate airway obstruction. On the basis of efficacy, the results support the current guidelines' recommendation that inhaled corticosteroids remain the preferred monotherapy.

Conflict of interest statement

Bhupendrasinh Chauhan ‐ none known.

Prof. Francine Ducharme has received travel support, research funds and fees for speaking from Glaxo SmithKline, Novartis, Nycomed, and Merck Frosst Inc.

Controller Medication Use and Exacerbations for Children and Adults With Asthma in High-Deductible Health Plans.

Galbraith AA, Ross-Degnan D, Zhang F, Wu AC, Sinaiko A, Peltz A, Xu X, Wallace J, Wharam JF. Galbraith AA, et al. JAMA Pediatr. 2021 Aug 1;175(8):807-816. doi: 10.1001/jamapediatrics.2021.0747. JAMA Pediatr. 2021. PMID: 33970186

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anti-asthmatic agents / therapeutic use*

# data[].attributes.attachment_link.keywords[]
anti-inflammatory agents / administration & dosage

# data[].attributes.attachment_link.keywords[]
anti-inflammatory agents / therapeutic use*

# data[].attributes.attachment_link.keywords[]
leukotriene antagonists / therapeutic use*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children - PubMed

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As monotherapy, inhaled corticosteroids display superior efficacy to anti-leukotrienes in adults and children with persistent asthma; the superiority is particularly marked in patients with moderate airway obstruction. On the basis of efficacy, the results support the current guidelines' recommendat ...

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Título:

Eficacia de un nuevo agonista adrenérgico β2 intravenoso (bedoradrina, MN-221) para pacientes con una exacerbación aguda del asma

Objetivo: Evaluar la  eficacia de la bedoradrina intravenosa (MN-221), un agonista adrenérgico β2 altamente selectivo, como complemento de la terapia estándar en el tratamiento de pacientes con exacerbación aguda del asma que no respondieron al tratamiento estándar.
Año: 2015
Tipo de estudio:  Ensayo clínico
Resultados: No hubo diferencia significativa en el% FEV1 a las 3 h entre los 2 grupos. Las puntuaciones de disnea mejoraron significativamente en los pacientes tratados con bedoradrina en comparación con el placebo.
Conclusión: La bedoradrina intravenosa, además de la terapia estándar, no aumentó significativamente el% FEV1 a las 3 h, pero se asoció con puntuaciones de disnea significativamente mejoradas.

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Affiliations

¹ Division of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. Electronic address: houses@wustl.edu.

² MediciNova, Inc., San Diego, CA, USA.

³ Division of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

⁴ Olive View-UCLA Medical Center, Sylmar, CA, USA.

Free article

Free article

Affiliations

¹ Division of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. Electronic address: houses@wustl.edu.

² MediciNova, Inc., San Diego, CA, USA.

³ Division of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

⁴ Olive View-UCLA Medical Center, Sylmar, CA, USA.

Abstract

Background: Many patients with acute exacerbation of asthma are non-responders to inhaled β-adrenergic agonists. The goal of this study was to evaluate the safety and efficacy of intravenous bedoradrine (MN-221), a highly selective β2-adrenergic agonist, as adjunct to standard therapy in the management of patients with acute exacerbation of asthma who did not respond to standard therapy.

Methods: Patients (N = 167) received standard therapy and were randomized to either bedoradrine (1200 μg) or placebo. Safety and efficacy parameters were monitored hourly for 3 h, followed by a 24-h follow-up visit and an 8-day follow-up phone call. Change in %FEV1 from baseline to Hour 3 was the primary outcome. Secondary outcome measures included change in %FEV1 at 1 and 2 h, change in dyspnea score at 1, 2, and 3 h, treatment failure rate, defined as a combination of hospitalization on the index visit or return to the emergency department within 1 week, and safety monitoring.

Results: There was no significant difference in %FEV1 at 3 h between the 2 groups. The dyspnea scores were significantly improved for patients treated with bedoradrine compared to placebo (AUC0-2 hP < 0.005, AUC0-3 hP < 0.05). The safety profile for those treated with bedoradrine was consistent with the known mechanism of action of β-adrenergic agonists, and included both cardiovascular and metabolic effects.

Conclusions: Intravenous bedoradrine, in addition to standard therapy, did not significantly increase %FEV1 at 3 h, but it was associated with significantly improved dyspnea scores.

Trial registration: Clinicaltrials.gov; study name: MN-221-CL-007, registration number: NCT00838591; www.clinical trials.gov.

Keywords: Asthma; Beta agonists; Emergency medicine; Pharmacotherapy.

G Protein-Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action.

Wendell SG, Fan H, Zhang C. Wendell SG, et al. Pharmacol Rev. 2020 Jan;72(1):1-49. doi: 10.1124/pr.118.016899. Pharmacol Rev. 2020. PMID: 31767622 Free PMC article. Review.

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adrenergic beta-2 receptor agonists / administration & dosage*

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adrenergic beta-2 receptor agonists / adverse effects

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bronchodilator agents / administration & dosage

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glucocorticoids / administration & dosage

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

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Efficacy of a new intravenous β2-adrenergic agonist (bedoradrine, MN-221) for patients with an acute exacerbation of asthma - PubMed

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1 Division of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. Electronic address: houses@wustl.edu. 2 MediciNova, Inc., San Diego, CA, USA. 3 Division of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. 4 Olive View-UCLA Medical Center, Sylmar, CA, USA.

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https://pubmed.ncbi.nlm.nih.gov/30394700/
TITULO: Corticosteroides inhalados diarios o montelukast para niños en edad preescolar con asma o sibilancias recurrentes: una revisión sistemática

OBJETIVO: comparar la eficacia de los corticosteroides inhalados (CSI) diarios frente a los antagonistas de los receptores de leucotrienos (ARLT) en niños en edad preescolar con asma o sibilancias recurrentes.

TIPO DE ESTUDIO:  Revisión sistemática

AÑO:2018

RESULTADOS: 3204 pacientes, 62% hombres, cumplieron con los criterios de inclusión; los corticosteroides inhalados (CSI) se asoció con un mejor control de los síntomas y menos exacerbaciones que los antagonistas de los receptores de leucotrienos (ARLT). Y también menos necesidad de rescate SC. Los datos insuficientes de alta calidad impidieron establecer conclusiones firmes sobre otros resultados secundarios.

CONCLUSION: En niños en edad preescolar con asma o sibilancias recurrentes, los CSI diarios parecen más efectivos que los ARLT diarios para mejorar el control de los síntomas y disminuir las exacerbaciones, en particular las que requieren CS de rescate, aunque la magnitud del beneficio aún no se ha cuantificado.

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Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: A systematic review - PubMed

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In preschoolers with asthma or recurrent wheezing, daily ICS appears more effective than daily LTRA for improving symptom control and decreasing exacerbations, particularly those requiring rescue SC, although the magnitude of benefit remains to be quantified.

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Título del estudio  Eficacia y seguridad de la administración intravenosa de teofilina para el tratamiento de la exacerbación aguda leve del asma bronquial
e los resúmenes de 2008 que se examinaron, 50 ensayos cumplieron con los criterios de elegibilidad. Los metanálisis de efectos aleatorios de seis ensayos de monoterapia con ARLT mostraron que los ARLT reducían el riesgo de exacerbación (cociente de riesgo resumido [RR], 0,60 [IC del 95%, 0,44 a 0,81]). En cuatro ensayos de ARLT como tratamiento adicional a los corticosteroides inhalados, el RR resumido para la exacerbación fue 0,80 (IC, 0,60 a 1,07). Los antagonistas de los receptores de leucotrienos, ya sea como monoterapia o como terapia complementaria a los corticosteroides inhalados, aumentaron el FEV1, mientras que el porcentaje de FEV1 de los valores predichos mejoró solo en los ensayos de monoterapia con LTRA. Las tasas de eventos adversos fueron similares en los grupos de intervención y de comparación.Los antagonistas de los receptores de leucotrienos como monoterapia mejoraron el control del asma en comparación con el placebo, pero no está claro qué pacientes tienen más probabilidades de responder al tratamiento con ARLT.
https://pubmed.ncbi.nlm.nih.gov/26390230/

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Leukotriene-receptor antagonists versus placebo in the treatment of asthma in adults and adolescents: a systematic review and meta-analysis - PubMed

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Título: El salbutamol y el ipratropio por inhalación es superior al nebulizador en niños con exacerbación aguda grave del asma: ensayo clínico aleatorizado
Año y Tipo de Estudio: 2019, ECA
Número de  pacientes: 103
Resultados: Cincuenta y dos niños recibieron MDI-SIB y 51 NEB-SIB. Después de la cuarta hora, los niños con MDI-SIB tuvieron una tasa de ingreso hospitalario significativamente menor (P = 0,003) que con NEB-SIB (5,8% frente a 27,5%, RR: 0,21 [0,06-0,69], respectivamente). De manera similar, se observó una mejora significativa en la puntuación clínica después de 60 min y un aumento en la saturación de oxígeno después de 90 min de tratamiento en el grupo MDI-SIB versus NEB-SIB (4.46 ± 0.7 vs 5.76 ± 0.65, P <0.00001; y 90.5 ± 1.7 vs 88.43 1 ± 1, P <0,00001, respectivamente).
Conclusión: Incluso en las exacerbaciones graves del asma, la administración de salbutamol e ipratropio por MDI con cámara de sujeción con válvula y mascarilla junto con oxígeno mediante una cánula por separado fue más eficaz que mediante un nebulizador.
https://pubmed.ncbi.nlm.nih.gov/30672140/

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Affiliations

¹ Division of Pediatrics, Emergency Department, Clinical Hospital, National University of Asunción, Asunción, Paraguay.

² Emergency Department, Private Childreńs Institute Asunción, Asunción, Paraguay.

³ Division of Pediatrics, Department of Pediatric Respiratory and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Randomized Controlled Trial

Affiliations

¹ Division of Pediatrics, Emergency Department, Clinical Hospital, National University of Asunción, Asunción, Paraguay.

² Emergency Department, Private Childreńs Institute Asunción, Asunción, Paraguay.

³ Division of Pediatrics, Department of Pediatric Respiratory and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Abstract

Introduction: In moderate-severe asthma exacerbation, salbutamol by inhaler (MDI) is superior to salbutamol delivered by nebulizer (NEB); however, to our knowledge, no studies in children with exclusively severe exacerbations were performed.

Objective: To compare the efficacy of salbutamol and ipratropium bromide by MDI versus by NEB in severe asthma exacerbations.

Methods: We performed a clinical trial enrolling 103 children (2-14 years of age) with severe asthma exacerbations (defined by the Pulmonary Score ≥ 7) seen at the emergency room in Asuncion, Paraguay. One group received salbutamol and ipratropium (two puff every 10 min for 2 h and then every 30 min for 2 h more) by MDI with a valved-holding chamber and mask along with oxygen by a cannula separately (MDI-SIB); and the other received nebulization with oxygen (NEB-SIB) of salbutamol and ipratropium (1 every 20 min for 2 h and then every 30 min for 2 h more). Primary outcome was the rate of hospitalization (Pulmonary Score ≥ 7) after 4 h and secondary outcome was oxygen saturation.

Results: Fifty two children received MDI-SIB and 51 NEB-SIB. After the 4th hour, children on MDI-SIB had significantly (P = 0.003) lower rate of hospital admission than on NEB-SIB (5.8% vs 27.5%, RR: 0.21 [0.06-0.69], respectively). Similarly, a significant improved clinical score after 60 min and increase in oxygen saturation after 90 min of treatment was observed in MDI-SIB versus NEB-SIB group (4.46 ± 0.7 vs 5.76 ± 0.65, P < 0.00001; and 90.5 ± 1.7 vs 88.43 1 ± 1, P < 0.00001, respectively).

Conclusion: Even in severe asthma exacerbations administration of salbutamol and ipratropium by MDI with valved-holding chamber and mask along with oxygen by a cannula separately was more effective than by a nebulizer.

Keywords: MDI; children; ipratropium; nebulizer; salbutamol; severe acute asthma.

[Paediatric Life Support].

Van de Voorde P, Turner NM, Djakow J, de Lucas N, Martinez-Mejias A, Biarent D, Bingham R, Brissaud O, Hoffmann F, Johannesdottir GB, Lauritsen T, Maconochie I. Van de Voorde P, et al. Notf Rett Med. 2021 Jun 2:1-70. doi: 10.1007/s10049-021-00887-9. Online ahead of print. Notf Rett Med. 2021. PMID: 34093080 Free PMC article. Review. German.

Asthma and COVID-19 in children - a systematic review and call for data.

Castro-Rodriguez JA, Forno E. Castro-Rodriguez JA, et al. medRxiv. 2020 May 8:2020.05.04.20090845. doi: 10.1101/2020.05.04.20090845. Preprint. medRxiv. 2020. PMID: 32511474 Free PMC article. Updated.

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bronchodilator agents / administration & dosage*

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national center for biotechnology information

# data[].attributes.attachment_link.title
Salbutamol and ipratropium by inhaler is superior to nebulizer in children with severe acute asthma exacerbation: Randomized clinical trial - PubMed

# data[].attributes.attachment_link.description
1 Division of Pediatrics, Emergency Department, Clinical Hospital, National University of Asunción, Asunción, Paraguay. 2 Emergency Department, Private Childreńs Institute Asunción, Asunción, Paraguay. 3 Division of Pediatrics, Department of Pediatric Respiratory and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

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https://pubmed.ncbi.nlm.nih.gov/9027267/
Titulo:

Eficacia del antagonista del receptor de leucotrienos zafirlukast para el asma leve a moderada. Un ensayo aleatorizado, doble ciego y controlado con placebo.

Tipo de estudio: Ensayo aleatorizado, doble ciego y controlado con placebo.

Objetivo:  Evaluar la efectividad clínica y económica de zafirlukast, un antagonista de los receptores de leucotrienos, en pacientes con asma leve a moderada que podrían beneficiarse de un tratamiento antiinflamatorio regular.

Resultado: El grupo de zafirlukast tuvo un 89% más de días sin síntomas (tasas ajustadas, 7,0 en comparación con 3,7 días por mes; P = 0,03), un 89% más de días sin uso de agonistas beta (tasas ajustadas, 11,3 en comparación con 6,0 días por mes ; P = 0,001) y un 98% más de días sin episodios de asma (tasas ajustadas, 10,1 en comparación con 5,1 días por mes; P = 0,003).
Conclusiones: Un régimen diario de zafirlukast agregado a los beta-agonistas inhalados según sea necesario es más eficaz que los beta-agonistas solos para tratar el asma leve a moderada.

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Abstract

Background: The increasing costs of managing asthma are due in part to the introduction of new medications, such as leukotriene receptor antagonists. These antagonists interfere with the action of leukotrienes, which are implicated in bronchoconstriction and the formation of airway edema in patients with asthma. Leukotriene receptor antagonists must be shown to be clinically and economically effective for their clinical use to be justified.

Objective: To assess the clinical and economic effectiveness of zafirlukast, a leukotriene receptor antagonist, in patients with mild-to-moderate asthma who might benefit from regular anti-inflammatory therapy.

Design: Randomized, double-blind, multicenter, placebo-controlled trial.

Setting: 28 outpatient clinics.

Patients: 146 patients with mild-to-moderate asthma who were 12 years of age or older, had not smoked cigarettes in the previous 6 months, had a smoking history of less than 10 pack-years, had an FEV1 at least 55% of the predicted value with no upper limit, had demonstrated bronchial hyperresponsiveness, and were symptomatic during the 7-day run-in period. All patients were seen every 2 to 3 weeks for 13 weeks.

Intervention: 103 patients received zafirlukast (20 mg twice daily), and 43 patients received placebo (twice daily). All patients received inhaled beta-agonists as needed.

Measurements: Data were obtained from medical examinations, patient questionnaires, and daily diaries. The clinical effectiveness outcomes were days per month without asthma symptoms, limitation of activity, use of beta-agonists, sleep disturbance, and episodes of asthma (the latter was a composite measure made up of the first four outcomes plus the occurrence of adverse events). The economic effectiveness outcomes were frequency and type of unscheduled health care contacts, use of beta-agonist inhalers, consumption of nonasthma medications, and days of absence from work or school.

Results: The zafirlukast group had 89% more days without symptoms (adjusted rates, 7.0 compared with 3.7 days per month; P = 0.03), 89% more days without use of beta-agonists (adjusted rates, 11.3 compared with 6.0 days per month; P = 0.001), and 98% more days without episodes of asthma (adjusted rates, 10.1 compared with 5.1 days per month; P = 0.003). They also had 55% (95% CI, 19% to 74%) fewer health care contacts (18.5 compared with 40.7 per 100 per month; P = 0.007) and 55% (CI, 3% to 79%) fewer days of absence from work or school (15.6 compared with 35.0 per 100 per month; P = 0.04). They used 17% fewer canisters of inhaled beta-agonists (P = 0.17) and 19% less nonasthma medication (P < 0.2).

Conclusions: A daily regimen of zafirlukast added to as-needed inhaled beta-agonists is more effective than beta-agonists alone in treating mild-to-moderate asthma. The clinical and economic effectiveness of zafirlukast, a potential alternative to inhaled corticosteroids, provides further impetus to use regular "preventive" therapy in patients with mild-to-moderate asthma.

Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway.

Moore GY, Pidgeon GP. Moore GY, et al. Int J Mol Sci. 2017 Jan 24;18(2):236. doi: 10.3390/ijms18020236. Int J Mol Sci. 2017. PMID: 28125014 Free PMC article. Review.

Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.

Thompson MD, Capra V, Clunes MT, Rovati GE, Stankova J, Maj MC, Duffy DL. Thompson MD, et al. Front Pharmacol. 2016 Dec 1;7:299. doi: 10.3389/fphar.2016.00299. eCollection 2016. Front Pharmacol. 2016. PMID: 27990118 Free PMC article. Review.

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anti-asthmatic agents / therapeutic use*

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health services / statistics & numerical data

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sleep wake disorders / chemically induced

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national center for biotechnology information

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Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. A randomized, double-blind, placebo-controlled trial - PubMed

# data[].attributes.attachment_link.description
A daily regimen of zafirlukast added to as-needed inhaled beta-agonists is more effective than beta-agonists alone in treating mild-to-moderate asthma. The clinical and economic effectiveness of zafirlukast, a potential alternative to inhaled corticosteroids, provides further impetus to use regular ...

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TÍTULO: Corticosteroides inhalados extrafinos versus corticosteroides finos en relación con el control del asma: una revisión sistemática y un metanálisis de estudios observacionales de la vida real.
AÑO: 2018
TIPO DE ESTUDIO: Metaanálisis
OBJETIVO: Comparar la efectividad de los CSI extrafinos (diámetro aerodinámico medio de masa, <2 μm) versus los CSI de partículas finas administrados como monoterapia con CSI o como terapia combinada de corticosteroides β-agonistas de acción prolongada con CSI mediante la realización de un metanálisis de observaciones de la vida real estudios de asma para estimar el efecto del tratamiento con corticosteroides inhalados extrafinos.
RESULTADO: Siete estudios con 33 453 sujetos de entre 5 y 80 años cumplieron los criterios de elegibilidad para la inclusión. Seis estudios utilizaron propionato de beclometasona extrafino y un estudio utilizó propionato de beclometasona extrafino y ciclesonida extrafina como comparadores con CSI de partículas finas. Las probabilidades generales de lograr el control del asma fueron significativamente mayores para los CSI extrafinos en comparación con los CSI de partículas finas (razón de probabilidades, 1,34; IC del 95%, 1,22-1,46). Los índices generales de exacerbación (0,84; IC del 95%, 0,73-0,97) y la dosis de ICS (diferencia de medias ponderada, -170 μg; IC del 95%, -222 a -118 μg) fueron significativamente menores para los ICS extrafinos en comparación con los ICS de partículas finas .
CONCLUSIÓN: Este metanálisis demuestra que los CSI extrafinos tienen probabilidades significativamente más altas de lograr el control del asma con tasas de exacerbación más bajas en dosis prescritas significativamente más bajas que los CSI de partículas finas.

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Affiliations

¹ Observational and Pragmatic Research Institute Pte Ltd, Singapore; Department of Respiratory Paediatrics, Rainbow Children's Hospital, Bengaluru, India.

² University of Colorado Denver, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Denver, Colo.

³ Department of Pulmonary Medicine and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

⁴ National Jewish Health and the University of Colorado Denver, Denver, Colo.

⁵ Respiratory and Intensive Care Medicine, Cochin Hospital (APHP), University Paris Descartes (EA2511), Paris, France.

⁶ Blizard Institute, Queen Mary University London, London, United Kingdom.

⁷ Division of Pulmonology Medicine, Cincinnati Children's Hospital & Medical Center, Cincinnati, Ohio.

⁸ Department of Respiratory Medicine, Mater Dei Hospital, Msida, Malta.

⁹ Department of Medicine, Federal University of Santa Catarina, Santa Catarina, Brazil.

¹⁰ Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

¹¹ Department of Pediatrics, Boston Children's Hospital, Boston, Mass.

¹² Respiratory Effectiveness Group, Oakington, Cambridge, United Kingdom.

¹³ Montreal Chest Institute, Meakins-Christie Laboratories and the McGill University Health Centre Research Institute, McGill University, Montreal, Canada.

¹⁴ Family Physician Airways Group of Canada, University of Toronto, Toronto, Ontario, Canada.

¹⁵ Pulmonary and Critical Care Division, Brigham & Women's Hospital, Harvard Medical School, Boston, Mass.

¹⁶ Department of Respiratory Medicine, University Hospital S. Anna, Ferrara, Italy.

¹⁷ Department of Pediatric Respiratory Diseases, Emma Children's Hospital AMC, Amsterdam, The Netherlands.

¹⁸ National Heart and Lung Institute, Imperial College London & Royal Brompton Hospital, London, United Kingdom.

¹⁹ Observational and Pragmatic Research Institute Pte Ltd, Singapore; Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom. Electronic address: dprice@opri.sg.

Free article

Free article

Affiliations

¹ Observational and Pragmatic Research Institute Pte Ltd, Singapore; Department of Respiratory Paediatrics, Rainbow Children's Hospital, Bengaluru, India.

² University of Colorado Denver, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Denver, Colo.

³ Department of Pulmonary Medicine and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

⁴ National Jewish Health and the University of Colorado Denver, Denver, Colo.

⁵ Respiratory and Intensive Care Medicine, Cochin Hospital (APHP), University Paris Descartes (EA2511), Paris, France.

⁶ Blizard Institute, Queen Mary University London, London, United Kingdom.

⁷ Division of Pulmonology Medicine, Cincinnati Children's Hospital & Medical Center, Cincinnati, Ohio.

⁸ Department of Respiratory Medicine, Mater Dei Hospital, Msida, Malta.

⁹ Department of Medicine, Federal University of Santa Catarina, Santa Catarina, Brazil.

¹⁰ Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

¹¹ Department of Pediatrics, Boston Children's Hospital, Boston, Mass.

¹² Respiratory Effectiveness Group, Oakington, Cambridge, United Kingdom.

¹³ Montreal Chest Institute, Meakins-Christie Laboratories and the McGill University Health Centre Research Institute, McGill University, Montreal, Canada.

¹⁴ Family Physician Airways Group of Canada, University of Toronto, Toronto, Ontario, Canada.

¹⁵ Pulmonary and Critical Care Division, Brigham & Women's Hospital, Harvard Medical School, Boston, Mass.

¹⁶ Department of Respiratory Medicine, University Hospital S. Anna, Ferrara, Italy.

¹⁷ Department of Pediatric Respiratory Diseases, Emma Children's Hospital AMC, Amsterdam, The Netherlands.

¹⁸ National Heart and Lung Institute, Imperial College London & Royal Brompton Hospital, London, United Kingdom.

¹⁹ Observational and Pragmatic Research Institute Pte Ltd, Singapore; Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom. Electronic address: dprice@opri.sg.

Abstract

Background: The particle size of inhaled corticosteroids (ICSs) may affect airway drug deposition and effectiveness.

Objective: To compare the effectiveness of extrafine ICSs (mass median aerodynamic diameter, <2 μm) versus fine-particle ICSs administered as ICS monotherapy or ICS-long-acting β-agonist combination therapy by conducting a meta-analysis of observational real-life asthma studies to estimate the treatment effect of extrafine ICSs.

Methods: MEDLINE and EMBASE databases were reviewed for asthma observational comparative effectiveness studies from January 2004 to June 2016. Studies were included if they reported odds and relative risk ratios and met all inclusion criteria (Respiratory Effectiveness Group/European Academy of Allergy and Clinical Immunology quality standards, comparison of extrafine ICSs with same or different ICS molecule, ≥12-month follow-up). End-point data (asthma control, exacerbations, prescribed ICS dose) were pooled. Random-effects meta-analysis modeling was used. The study protocol is published in the PROSPERO register CRD42016039137.

Results: Seven studies with 33,453 subjects aged 5 to 80 years met eligibility criteria for inclusion. Six studies used extrafine beclometasone propionate and 1 study used both extrafine beclometasone propionate and extrafine ciclesonide as comparators with fine-particle ICSs. The overall odds of achieving asthma control were significantly higher for extrafine ICSs compared with fine-particle ICSs (odds ratio, 1.34; 95% CI, 1.22-1.46). Overall exacerbation rate ratios (0.84; 95% CI, 0.73-0.97) and ICS dose (weighted mean difference, -170 μg; 95% CI, -222 to -118 μg) were significantly lower for extrafine ICSs compared with fine-particle ICSs.

Conclusions: This meta-analysis demonstrates that extrafine ICSs have significantly higher odds of achieving asthma control with lower exacerbation rates at significantly lower prescribed doses than fine-particle ICSs.

Keywords: Asthma control; Conventional ICS; Extrafine beclometasone dipropionate; Extrafine ciclesonide; Extrafine-particle ICS; Fine-particle ICS; Inhaled corticosteroids; Observational studies; Real-life.

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Real-Life Outcomes for Patients with Asthma Prescribed Spacers for Use with Either Extrafine- or Fine-Particle Inhaled Corticosteroids.

Guilbert TW, Colice G, Grigg J, van Aalderen W, Martin RJ, Israel E, Postma DS, Roche N, Phipatanakul W, Hillyer EV, Evans JM, Dolovich MB, Price DB; Respiratory Effectiveness Group. Guilbert TW, et al. J Allergy Clin Immunol Pract. 2017 Jul-Aug;5(4):1040-1049.e4. doi: 10.1016/j.jaip.2016.11.026. Epub 2017 Jan 18. J Allergy Clin Immunol Pract. 2017. PMID: 28110057

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adrenal cortex hormones / therapeutic use*

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anti-asthmatic agents / therapeutic use*

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national center for biotechnology information

# data[].attributes.attachment_link.title
Extrafine Versus Fine Inhaled Corticosteroids in Relation to Asthma Control: A Systematic Review and Meta-Analysis of Observational Real-Life Studies - PubMed

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1 Observational and Pragmatic Research Institute Pte Ltd, Singapore; Department of Respiratory Paediatrics, Rainbow Children's Hospital, Bengaluru, India. 2 University of Colorado Denver, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Denver, Colo. 3 Department of Pulmonary Medicine and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

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TITULO:

Mejoría comparativa de los síntomas del asma y los flujos espiratorios después del tratamiento con corticosteroides: ¿un método para evaluar el efecto de los corticosteroides en las vías respiratorias grandes y pequeñas?

TIPO DE ESTUDIO: Metaanálisis
AÑO: 2006
RESULTADOS: La relación de mejoría de la disnea, sibilancias, alteraciones del sueño, tos y opresión torácica sobre los siguientes parámetros fisiológicos: volumen espiratorio forzado en 1s (FEV1), FEF (25/75%), flujo espiratorio máximo matutino y FVC, desde el valor inicial hasta el último conjunto de medidas en el estudio, mientras toma la medicación del estudio.
CONCLUSION: la proporción de mejoría de RS / FE se distribuye normalmente en un rango estrecho, mostrando una correlación generalmente buena entre las mejoras en la FE y los síntomas del asma; sin embargo, fue similar para las dos moléculas de BDP probadas.

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Abstract

The magnitude of improvement of respiratory symptoms (RS) and expiratory flows (EF) following corticosteroid treatment may vary from one asthmatic patient to another. The distribution of ratio of improvement of the above parameters was assessed in 937 patients with asthma of variable severity who took part in three clinical trials comparing the effects of chlorofluorocarbon-propelled beclomethasone dipropionate (CFC-BDP) with similar (n:316) or half-doses (n:581) of extrafine hydrofluoroalkane-propelled (HFA-BDP) on asthma control. We calculated the ratio of improvement of shortness of breath, wheezing, sleep disturbance, cough, and chest tightness over the following physiological parameters: forced expiratory volume in 1s (FEV1), FEF(25/75%), morning peak expiratory flow, and FVC, from the baseline value to the last set of measures in the study, while on the study medication. We hypothesized that the ratio of RS/EF would have a normal distribution and would be higher with extrafine HFA-BDP compared with CFC-BDP, which has a larger particle size, when FEV1 is used, as it mostly assesses large airways. Ratios of improvement were normally distributed for both drugs and no significant shift in its distribution curve was found for HFA-BDP. The ratio of changes in FEF(25/75%)/FEV1 was similar in the two groups. In conclusion, the ratio of improvement of RS/EF is normally distributed over a narrow range, showing a generally good correlation between improvements in EF and symptoms in asthma; it was, however, similar for the two BDP molecules tested. This may suggest that this ratio is not useful for evaluating the effect of corticosteroids on small airways, or that extrafine HFA-BDP acts at the level of large- to moderate-caliber airways to produce most of its beneficial effect.

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Barnes N, Price D, Colice G, Chisholm A, Dorinsky P, Hillyer EV, Burden A, Lee AJ, Martin RJ, Roche N, von Ziegenweidt J, Israel E. Barnes N, et al. Clin Exp Allergy. 2011 Nov;41(11):1521-32. doi: 10.1111/j.1365-2222.2011.03820.x. Epub 2011 Jul 14. Clin Exp Allergy. 2011. PMID: 21752116

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Fireman P, Prenner BM, Vincken W, Demedts M, Mol SJ, Cohen RM. Fireman P, et al. Ann Allergy Asthma Immunol. 2001 May;86(5):557-65. doi: 10.1016/S1081-1206(10)62905-5. Ann Allergy Asthma Immunol. 2001. PMID: 11379808 Clinical Trial.

Improvements in delivery with an extra fine beclomethasone aerosol.

Davies R. Davies R. Int J Clin Pract Suppl. 1998 Sep;96:28-32. Int J Clin Pract Suppl. 1998. PMID: 10344031 Review.

Inhaled beclomethasone versus placebo for chronic asthma.

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anti-asthmatic agents / administration & dosage*

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beclomethasone / administration & dosage*

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glucocorticoids / administration & dosage*

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national center for biotechnology information

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Comparative improvement of asthma symptoms and expiratory flows after corticosteroid treatment: a method to assess the effect of corticosteroids on large vs. small airways? - PubMed

# data[].attributes.attachment_link.description
The magnitude of improvement of respiratory symptoms (RS) and expiratory flows (EF) following corticosteroid treatment may vary from one asthmatic patient to another. The distribution of ratio of improvement of the above parameters was assessed in 937 patients with asthma of variable severity who to ...

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TÍTULO: Eficacia comparativa de una vez al día ciclesonida y budesonida en el tratamiento del asma persistente.

TIPO DE ESTUDIO: Revisión sistemática con metaanálisis
AÑO: 2006
RESULTADOS: En total, se aleatorizaron 359 pacientes. El FEV1 y la capacidad vital forzada (FVC) disminuyeron en 0,18 y 0,12 L, respectivamente, en el grupo de ciclesonida, y en 0,23 y 0,21 L en el grupo de budesonida. Para el FEV1, la ciclesonida no fue inferior y numéricamente superior a la budesonida. Para la FVC, la ciclesonida fue estadísticamente superior a la budesonida (P = 0,010).
CONCLUSIÓN: La ciclesonida 320 microg una vez al día por HFA-MDI sin un espaciador fue al menos tan eficaz como la budesonida 320 microg una vez al día en el asma persistente.

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Comparative efficacy of once-daily ciclesonide and budesonide in the treatment of persistent asthma - PubMed

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Ciclesonide 320 microg once daily by HFA-MDI without a spacer was at least as effective as budesonide 320 microg once daily in persistent asthma.

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https://www.dovepress.com/clinical-efficacy-and-safety-of-anticholinergic-therapies-in-pediatric-peer-reviewed-fulltext-article-TCRM
Titulo: Eficacia clínica y seguridad de las terapias anticolinérgicas en pacientes pediátricos
Tipo de estudio: Metanaanalisis ECA
Año: 2018
Resultados: Los ensayos clínicos de tiotropio en el asma pediátrica resumidos en esta revisión apoyan la seguridad y eficacia del tiotropio en niños y adolescentes, independientemente de la gravedad y el fenotipo de la enfermedad.
Conclusión: El tiotropio Respimat ® está aprobado en el asma para pacientes adultos (con 18 años) en Singapur, los pacientes de 15 o más años en Japón y, más recientemente, aprobados para pacientes de edad ≥ 6 años en los EE.UU. y la UE.

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Stanley Goldstein

Allergy and Asthma Care of Long Island, Rockville Centre, New York, NY, USA

Abstract: The burden of uncontrolled asthma in children and adolescents is high. Treatment options for pediatric patients (aged under 18 years) with asthma are largely influenced by the Global Initiative for Asthma recommendations. Algorithms for adolescents (12-18 years) and adults are identical, but recommendations for children aged under 6 years and 6-11 years differ. Although the goals of treatment for pediatric patients with asthma are similar to those for adults, relatively few new therapies have been approved for this patient population within the last decade. Designing clinical trials involving children presents several challenges, notably that children are often less able to perform lung function tests, and traditional endpoints used in clinical trials with adults, such as forced expiratory volume in 1 second, asthma exacerbations and questionnaires, have limitations associated with their use in children. There are also ethical considerations related to the performance of longer placebo-controlled exacerbation trials. This review considers additional clinical endpoints to those traditionally reported, including forced expiratory flow at 25%-75% of forced vital capacity, which may help shed light on which treatments are most effective for use in pediatric patients with asthma. The pros and cons of specific and potentially clinically relevant endpoints are considered, along with device considerations and patient preferences that may enhance adherence and quality of life. Recent advances in the management of children and adolescents, including the US Food and Drug Administration and European Medicines Agency approval of tiotropium in patients with asthma aged 6 years and over, are also discussed.

Keywords: asthma, anticholinergic, tiotropium, pediatric, children, adolescents

Introduction

Asthma remains one of the most common chronic diseases of childhood and adolescence. Much of the understanding of the epidemiology of pediatric asthma is derived from data collected in the International Study of Asthma and Allergies in Childhood (ISAAC). Phase III of ISAAC involved around 1.2 million children from 233 centers in 98 countries, and found that the global prevalence of asthma was 14% and 12% in 13- to 14-year-olds and 6- to 7-year-olds, respectively. ISACC has, however, reported substantial differences (of up to 13-fold) between countries in the prevalence of asthma symptoms (specifically wheeze in the past 12 months) in children. The 2014 Global Asthma Report described an increase in the frequency of asthma symptoms in children in many low- and middle-income countries between 1993 and 2003, while prevalence remained the same or decreased in high-income countries.

The burden associated with asthma in children and adolescents is considerable. In 2010, asthma was the eighth highest ranked cause of disability-adjusted life years in children aged 5-9 years and the third highest for children aged 10-14 years worldwide. Recurrent symptoms such as wheeze, cough and shortness of breath can also have a marked negative impact on the quality of life of children. Furthermore, asthma exacerbations are the leading cause of hospitalization in children and of the children who attend an emergency department with an asthma exacerbation, more than half are aged between 2 and 7 years old. These findings make asthma a leading cause of childhood morbidity from chronic diseases. The global socioeconomic burden of pediatric asthma is further increased by school absences and the relatively high cost of asthma care.

Alarmingly, it is estimated that asthma control is inadequate in more than half of pediatric patients with asthma despite currently available treatment and guidelines. Clearly, there is a pressing need to alleviate the burden of uncontrolled asthma in pediatric patients, and effective treatment is paramount to achieving this. As will be discussed, treatment recommendations outlined by the Global Initiative for Asthma (GINA) consist of an inhaled corticosteroid (ICS) backbone with or without additional reliever therapy. Evidence has recently emerged supporting the use of anticholinergics in asthma, and tiotropium has become the first long-acting muscarinic receptor antagonist (LAMA) to be approved for the treatment of asthma. The aim of this review is to report on the use of anticholinergic therapies in pediatric patients with asthma and to discuss the difficulties in investigating new therapies for this population.

GINA Report recommendations

The GINA Report is intended to be a useful resource for the management of asthma, and provides recommendations that should be adjusted in line with local practices and available health care resources. The principle aims of these treatment recommendations are control of asthma symptoms and the minimization of future risk of exacerbations, fixed airflow limitation and treatment side effects. In pediatric patients, additional consideration is given to avoiding reduced lung growth and minimizing adverse effects, given the potential capacity of ICS treatment to negatively impact development. The GINA strategy recommends a stepwise approach towards asthma treatment, building on a framework of ICS controller medication with or without a reliever therapy.

Algorithms for treatment of adult and adolescent (12-18 years) patients with asthma are the same ( Figure 1A). For adolescents, the current GINA recommendations are low-dose ICS treatment followed by a stepwise increase in ICS dose and/or additional (or a second class of) maintenance therapy, such as a long-acting β ₂-agonist (LABA) or leukotriene receptor antagonist (LTRA), if control has not been achieved. Add-on treatment (eg, with tiotropium) is then suggested if control is still not attained. There are key differences in the recommendations for children. In children aged 6-11 years, increasing the ICS dose is preferred over combination ICS/LABA. If this is ineffective, then it is suggested that the child be referred for expert assessment and advice. In children under 6 years of age, the preferred asthma control medication is low-dose ICS, such as 200 μg budesonide or equivalent ( Figure 1B). Due to lack of data, treatment options are limited in children under 6 years of age whose asthma symptoms are poorly controlled with ICS monotherapy. Therefore, data for additional second-line controller medications, such as theophylline, oral corticosteroids and anticholinergics, are particularly valuable to this patient subset.

While the GINA Report and its recommendations are regularly updated (most recently in 2018), there have been no updated recommendations from the National Heart, Lung and Blood Institute on asthma diagnosis/management since 2007.

Anticholinergic therapies

Anticholinergic agents target the function of acetylcholine, a neurotransmitter that plays a key role in the pathophysiology of asthma by way of driving bronchial smooth muscle contraction, mucus secretion, vasodilation and increasing airway tone. Further, cholinergic activity is believed to be the predominant driver of bronchoconstriction. There are two categories of acetylcholine receptors: nicotinic and muscarinic. Of these, the muscarinic M ₁, M ₂ and M ₃ subtypes are believed to be primarily involved in regulating bronchoconstriction. Better understanding of muscarinic receptor agonists over the past two decades has led to investigation of both short- and long-acting anticholinergics in asthma. Several studies in children with severe asthma exacerbations suggest that the addition of the short-acting anticholinergic agent ipratropium to a β ₂-agonist may reduce hospital admissions and improve lung function. A 2012 meta-analysis of short-acting anticholinergics as bronchodilators in children aged ≥2 years with acute asthma exacerbations suggested that short-acting anticholinergics were less efficacious than β ₂-agonists. However, the safety of anticholinergics in children, combined with the lack of additional controller medications licensed for this population, has sustained an interest in developing anticholinergics for use in this patient population.

In recent years, evidence has emerged supporting the use of long-acting anticholinergic agents. Of note, not all LAMAs have equivalent potency as bronchodilators due to their differential effects on the muscarinic receptor subtypes M ₁-M ₃. The different biological functions of M ₁-M ₃ receptors in the airways distinguish their potential as therapeutic targets in asthma. M ₃ is the primary receptor subtype involved in bronchial and tracheal muscle contraction, and acts alongside M ₁ to increase smooth muscle tone in the airways. Conversely, M ₂ receptors inhibit the release of acetylcholine from parasympathetic nerves and decrease smooth muscle tone. Consequently, LAMAs that primarily mediate blockade of the M ₁ and M ₃ receptors are the most attractive candidate therapies for asthma treatment.

Tiotropium for pediatric asthma

Evidence of tiotropium efficacy in pediatric patients with asthma

Tiotropium is a once-daily LAMA that has been approved for the treatment of chronic obstructive pulmonary disease for over a decade. Of note, tiotropium dissociates slowly from the M ₁ and M ₃ muscarinic receptors, but does so rapidly from the M ₂ receptor, making it a highly potent bronchodilator. A number of Phase III clinical trials in adult patients with symptomatic asthma recently led to tiotropium becoming the first LAMA to be approved for the treatment of asthma. These studies demonstrated that tiotropium improves lung function and asthma control in patients with a range of asthma severities, with a safety profile similar to that of placebo. The 2018 GINA Report recommends tiotropium as an add-on therapy in patients aged ≥12 years with a history of asthma exacerbations at Steps 4 and 5 of the stepwise approach ( Figure 1A).

Further investigation of tiotropium in asthma has demonstrated the effectiveness of tiotropium add-on therapy across all age groups. In Phase II dose-escalation studies of tiotropium in children and adolescents with symptomatic asthma, similar safety and tolerability profiles to placebo were observed, with early indications of efficacy. As a consequence of these positive early findings, five Phase III, randomized, double-blind, placebo-controlled, parallel-group trials in children and adolescents have recently investigated the efficacy and safety of once-daily tiotropium as an add-on therapy to ICS with or without other controllers ( Table 1).

Two of these trials were performed in adolescents aged 12-17 years ( Table 1). The first of these, RubaTinA-asthma ® (NCT01257230), was performed in patients with moderate symptomatic asthma. Here, the efficacy and safety of once-daily tiotropium (5 or 2.5 μg) or placebo administered via Respimat ® (Boehringer Ingelheim Pharma, Ingelheim am Rhein, Germany) were assessed as an add-on therapy to ICS (200-800 μg or 400-800 μg budesonide or equivalent/day for patients aged 12-14 years or 15-17 years, respectively) with or without an LTRA over 48 weeks. Both doses of tiotropium were safe and well tolerated, and conferred a significantly greater improvement in peak forced expiratory volume in 1 second (FEV ₁) within 3 hours after dosing (FEV 1(0-3h)) at Week 24 compared with placebo. At Week 24, both doses were associated with significant improvements in forced expiratory flow between 25% and 75% of forced vital capacity (FEF ₂₅₋₇₅) compared with placebo at most time points.

PensieTinA-asthma ® (NCT01277523) was a Phase III study in adolescent patients with severe symptomatic asthma. Once-daily tiotropium (5 or 2.5 μg) or placebo, both administered by the Respimat ®, was added to high-dose ICS (>400 μg or 800-1,600 μg budesonide or equivalent/day for patients aged 12-14 years or 15-17 years, respectively) plus at least one controller therapy (LABA or LTRA) or medium-dose ICS (200-400 μg budesonide or equivalent in patients aged 12-14 years and 400-800 μg budesonide or equivalent in patients aged 15-17 years) plus two or more other controller therapies (LABA and/or LTRA and/or sustained-release theophylline) over 12 weeks. In this study of adolescents with severe asthma, numerical improvements in measures of lung function and asthma control were reported with once-daily tiotropium add-on therapy, while the safety and tolerability of tiotropium were comparable with those of placebo.

Two Phase III trials were performed in children aged 6-11 years ( Table 1). In the first of these, VivaTinA-asthma ® (NCT01634152), participants had severe symptomatic asthma. The efficacy and safety of tiotropium (5 or 2.5 μg) or placebo, both administered via the Respimat ®, were assessed as an add-on therapy to high-dose ICS (>400 μg budesonide or equivalent per day) with one or more controller medications (LABA or LTRA) or medium-dose ICS (200-400 μg budesonide or equivalent per day) with two or more controller medications (LABA and/or LTRA and/or sustained-release theophylline) over 12 weeks. Compared with placebo, 5 μg tiotropium had a similar safety and tolerability profile and significantly improved peak FEV 1(0-3h) at Week 12; both doses were associated with a significant improvement in FEF ₂₅₋₇₅ at Weeks 12 and 24. Add-on tiotropium in children aged 6-11 years was also evaluated in moderate symptomatic asthma in the CanoTinA-asthma ® trial. Tiotropium (5 or 2.5 μg) versus placebo, both delivered via the Respimat ®, was evaluated as an add-on therapy to medium-dose ICS (200-400 μg budesonide or equivalent/day) with or without an LTRA over 48 weeks. Both doses of tiotropium were well tolerated, and the 5 μg dose conferred a statistically significant improvement in FEV 1(0-3h) at Week 24; both doses were associated with a significant improvement in FEF ₂₅₋₇₅ at the majority of time points throughout the 48-week study period. Finally, the NinoTinA-asthma ® (NCT01634113) trial was conducted in preschool children aged 1-5 years with persistent asthma symptoms ( Table 1). Once-daily tiotropium (5 or 2.5 μg) or placebo, delivered via the Respimat ®, was given as an add-on therapy to ICS at a stable dose with or without additional controller medication for 12 weeks. In this study, tiotropium was shown to be safe and reduced the risk of asthma exacerbations reported as adverse events by more than 50% in very young patients.

Overall, these studies demonstrate tiotropium to be efficacious in children and adolescents with asthma, irrespective of disease severity. In support of this, a pooled analysis of the RubaTinA-asthma ® and CanoTinA-asthma ® studies supported the use of tiotropium as an add-on therapy to the usual background medication of pediatric patients aged 6-11 years with symptomatic persistent asthma. Furthermore, in a systematic review of three studies of tiotropium in school-age symptomatic asthmatics, tiotropium was associated with significant improvements in FEV ₁ peak responses and a reduction in asthma exacerbation frequency compared with placebo. This review concluded tiotropium to be an efficacious and well-tolerated add-on to ICS plus one or more controller medications in this population.

Efficacy of tiotropium in allergic asthma

Allergic asthma is the most common asthma phenotype. In childhood, asthma is frequently associated with atopy, a condition that predisposes individuals to develop immunoglobulin E (IgE) against specific allergens. Studies have been performed to investigate whether baseline IgE levels or blood eosinophil counts can influence response to tiotropium add-on therapy in patients aged 6-17 years with asthma. Data were pooled from moderate symptomatic patients in the CanoTinA-asthma ®38 and RubaTinA-asthma ®37 trials and from severe symptomatic patients in the VivaTinA-asthma ®39 and PensieTinA-asthma ®41 trials. In these pooled studies, tiotropium improved lung function irrespective of baseline IgE levels and blood eosinophil counts. Overall, these data demonstrate that tiotropium is effective in children and adolescents without the need for phenotyping of allergic status according to IgE levels and blood eosinophil counts.

Pharmacokinetics and pharmacogenomics of tiotropium

Age and developmental status are major influences on numerous factors, including anatomy, physiology and pathology, that could affect pharmacodynamics, kinetics and drug metabolism. Therefore, it is pertinent to compare the pharmacokinetics of tiotropium when administered to patients with asthma from different age groups. The pharmacokinetic properties of tiotropium are well established in adult patients with symptomatic asthma. Pharmacokinetic parameters of tiotropium demonstrate its fast absorption and long elimination time, with maximum plasma concentrations reached within 5 minutes of post-inhalation and a half-life of approximately 30 hours. Furthermore, pharmacokinetics of tiotropium in adult patients with asthma are dose proportional up to 5 μg once daily.

Plasma and urine samples from subsets of symptomatic patients with asthma aged 6-11 years and 12-17 years treated with tiotropium in Phase II trials were used to evaluate the pharmacokinetic properties of tiotropium in these age groups. These studies found the pattern of absorption, exposure and clearance of tiotropium at steady state to be consistent with those reported in adults. The pharmacokinetic characteristics of tiotropium in children aged 1-5 years were also studied in the Phase III NinoTinA-asthma ® study. Here, exposure to tiotropium, when normalized for body surface area, was comparable to older age groups based on urinary excretion data.

Tiotropium pharmacokinetic data from patients with asthma of different ages were summarized in a clinical pharmacology review carried out by the US Food and Drug Administration ( Table 2). In agreements with the aforementioned analyses, exposure of tiotropium in urine and plasma samples from patients with asthma is comparable in children aged 6-11 years, adolescents and adults.

Although no formal drug interaction studies have been conducted, tiotropium has been used with other drugs without clinical evidence of interactions. Concomitant treatment with other asthma medications such as LABA, ICS+LABA, oral corticosteroids and leukotriene modifiers does not affect exposure to tiotropium.

Pharmacogenomics is another factor that may impact response to therapy. In this respect, a study performed in adults with severe asthma found that the presence of Arg16Gly in ADRB2 may predict response to tiotropium. However, similar studies are yet to be performed in children and adolescents.

Clinical trials with other LAMAs in asthma

Of the clinical trials assessing the safety and efficacy of LAMAs in the treatment of asthma, the tiotropium program has thus far been the most advanced across all age groups. A number of studies evaluating the potential of umeclidinium bromide and glycopyrronium in adult asthma have been completed or are ongoing ( Table 3), although neither agent is approved for the treatment of asthma. Aside from tiotropium, other LAMAs are yet to be studied in children or adolescents with asthma. These pediatric trials are unlikely to be conducted unless their efficacy and safety are first demonstrated in adults. At the time of this publication, no studies are known to be completed or ongoing with aclidinium bromide in asthma.

Umeclidinium is a potent anticholinergic that demonstrates slow functional reversibility at the human M ₃ muscarinic receptor compared with the M ₂ receptor. Once-daily umeclidinium bromide combined with fluticasone furoate, administered via a dual-strip dry powder inhaler (DPI), has been investigated in adults with asthma who were symptomatic despite maintenance ICS treatment. This study reported significant increases in trough FEV ₁ in response to combination treatment, but not with fluticasone furoate alone. Furthermore, umeclidinium monotherapy (delivered via DPI) in patients with asthma not requiring ICS treatment did not provide a therapeutic benefit, given that it conferred modest, inconsistent, dose-independent improvements in trough FEV ₁. Other ongoing and completed studies in adult patients are summarized in Table 3.

As with tiotropium, glycopyrronium is an anticholinergic with higher selectivity for M ₃ receptors than for M ₂ receptors, and dissociates more slowly from the M ₃ receptors than from the M ₂ receptors. The only study of glycopyrronium to be published thus far compared the effects of glycopyrronium (administered via Breezhaler) and tiotropium (administered via Respimat ®) on methacholine-induced bronchoconstriction in adults with symptomatic asthma. Here, tiotropium provided statistically superior bronchoprotection at both 24 and 72 hours compared with glycopyrronium. An additional study of glycopyrronium in adults has been completed and results are awaited ( Table 3).

Challenges for future clinical trials in pediatric asthma

Several challenges are posed by the design of clinical trials in asthma involving children as participants, particularly the choice of endpoints to measure clinical efficacy. The endpoints traditionally used to measure drug efficacy in clinical trials of asthma in adults may not be the most appropriate for use with pediatric patients. These challenges need to be carefully considered in future trials in pediatric patients with asthma.

Clinical trial endpoints

The three attainable objectives of drug development across all age groups in asthma are 1) prevention and treatment of symptoms, 2) exacerbations, and 3) further complications. Clinical trials to investigate candidate drugs therefore have endpoints designed to quantify achievement of these goals ( Table 4). To demonstrate the symptom-modifying effect of a reliever drug, there must be an improvement in an objective measure of airflow. For a drug to be registered as a symptom-preventing agent, there must be a demonstration of benefit in symptomatology, disease control, lung function, exacerbations and/or quality of life.

It is widely recognized that clinical research in asthma lacks standardization in outcomes. To address this, an Asthma Outcomes workshop was convened with the specific purpose of stratifying core, supplemental and emerging asthma outcomes. Importantly, this workshop differentiated between recommended endpoints in adult and pediatric patients. As will be discussed, measures of asthma outcomes frequently used in adult patients are often less appropriate for use in pediatric patients. Alternative endpoints to those traditionally reported in clinical trials may help to shed light on which treatments are most effective in children. More details on these traditional and alternative endpoints are provided in the following text and in Table 4.

Traditional endpoints

Objective measurements such as FEV ₁ and peak expiratory flow (PEF) play an important role in the evaluation of airflow in patients with asthma during clinical trials. In the assessment of efficacy of potential bronchodilators, FEV ₁ is the gold standard measurement of lung function. Although FEV ₁ has numerous advantages, including robustness, repeatability, standardization and ease of measurement, there are limitations to its use as a clinical endpoint. For example, FEV ₁ does not always confer a complete representation of the disease processes that occur in asthma, such as hyperinflation and airway plugging. In clinical trials with pediatric patients, the suitability of FEV ₁ as an endpoint has been questioned given that FEV ₁ does not correlate with asthma severity in children. In fact, FEV ₁ values fall within the normal range in the majority of pediatric patients with asthma, even when patients are markedly symptomatic. Also, efficient and reliable spirometry testing can be difficult in preschool children, especially in the younger age groups. In a study involving 355 children aged 3-5 years, only around half were able to perform effective spirometry. Another traditional endpoint - PEF - has also been shown not to correlate with asthma severity in children. Instead, PEF correlates with FEV ₁, suggesting this test may also have limitations as an asthma outcome measurement in children with asthma. In addition, portable PEF meters allow for self-monitoring at home, which can be beneficial for children, although all patients need to be observed carefully, as it has been reported that many patients, both adults and children, do not use the PEF meters correctly.

Frequency of asthma exacerbations is a commonly used subjective measurement, and is recommended as both a core and supplemental asthma outcome in children. These episodes of airway narrowing are most common in infants and young children. Of note in children, their recurrence in early years is associated with progressive loss of lung function, making the prevention of exacerbations an especially important aspect of asthma control. However, the exact definition of what constitutes an exacerbation in a clinical trial has remained elusive. Most clinicians are able to identify asthma exacerbations through the observation of symptoms and medication changes, but the subjective nature of this assessment can lead to variations between studies and investigators. To rectify this issue, experts in the Asthma Outcomes workshop coined a cross-age definition of asthma exacerbations as "worsening of asthma requiring the use of systemic corticosteroids to prevent serious outcomes". There are also ethical considerations around the use of exacerbations as an endpoint in placebo-controlled trials conducted in children. The chance of being assigned to the placebo group could deter parents from enrolling their child onto such a trial.

Questionnaires also play a role in asthma control by quantifying composite scores for outcome measures. The Asthma Control Questionnaire (ACQ) and Asthma Control Test (ACT) are commonly employed to assess asthma control. There are obvious difficulties in completion of questionnaires by children, and assistance given by caregivers can prevent a true representation of the patient's disease state. The episodic nature of asthma in young children also confounds the use of questionnaires. There are no core questionnaires recommended for efficacy studies in children. The Childhood ACT (cACT), completed by children and caregivers, is recommended for baseline characterization of children aged 4-11 years. cACT was recommended by the Asthma Outcomes workshop both as a core baseline and observational outcome, and as a supplemental outcome for efficacy. Further questionnaires for use in pediatric patients with asthma, such as the Test for Respiratory and Asthma Control in Kids instrument for infants aged 0-4 years, are in development but face ongoing challenges associated with language and the capabilities of the respondent. An interviewer-administered ACQ test has been used in some studies with children.

Alternative endpoints

Objective measurements of asthma control are at the center of clinical trials testing the efficacy of asthma medications. Spirometry plays an important part in this, and is recommended as a core asthma outcome for children across all aspects of prospective clinical trials. However, the limitations of traditional spirometrical measurements (eg, FEV ₁) in children highlight a need for alternatives. One such alternative, FEF ₂₅₋₇₅, is a sensitive measure of small airway obstruction that quantifies the maximum mid-expiratory flow rate. FEF ₂₅₋₇₅ has been purported as more reflective of small airways function than FEV ₁ and in a large cohort of patients it was significantly associated with asthma control. Unlike FEV ₁, FEF ₂₅₋₇₅ has been linked with acute wheezing, response to bronchodilators and ventilation defects, and is predictive of asthma severity in children. However, some investigators have questioned its contribution to clinical decision making; one database study found that although abnormally low FEF ₂₅₋₇₅ values were more prevalent in children than in adults, only in a very small number of patients did FEF ₂₅₋₇₅ detect an impairment that FEV ₁ and FVC measures did not.

There is a keen interest in the use of alternative acceptable measures of lung function in children who cannot perform spirometry, such as impulse oscillometry (IOS). IOS is a type of airway mechanic measurement performed by non-invasively superimposing pressure fluctuations on the airway during spontaneous breathing of the subject. A comparison of IOS and spirometry as measures of pediatric asthma control found that IOS complemented information gained by FEV ₁. Furthermore, IOS offered some additional insights into alterations in airway mechanics in response to therapy. However, there are cost considerations associated with IOS due to the high cost of the machines.

Biomarkers are another non-invasive objective measurement of asthma control, but are lacking in children, and utility as a broad measure of asthma control across ages and phenotypes seems unlikely.

Patient considerations when choosing an anticholinergic for pediatric asthma

In children with asthma, poor adherence to medication has been shown to lead to increased morbidity. When selecting a treatment for pediatric asthma, patient preferences must be considered to help maintain therapeutic adherence. In children, a particularly relevant aspect of this is drug delivery, which poses significant challenges in young patients. Inhalers are the main device used in asthma treatment, and the GINA Report recommends they should reproducibly deliver a predetermined dose to the lungs with minimal deposition elsewhere in the body. Administration of ICS is most commonly performed using a pressured metered-dose inhaler (pMDI) device connected to a spacer, yet only a small fraction of the dose from these devices reach the distal airways. Anticholinergics can also be administered by inhalation, using pMDIs, nebulizers and DPIs.

Patient satisfaction was a priority in the development of the inhaler used to administer tiotropium in pediatric clinical trials (Respimat ® Soft Mist™ Inhaler, Boehringer Ingelheim Pharma). This pocket-sized inhaler has been shown to reproducibly deliver a single-breath, metered dose of inhalable aerosol from an aqueous drug solution in an environmentally friendly manner. Optimization of delivery to the lungs and minimal inspiratory effort were key in the design of this device, and likely explain why patients favored this inhaler over the commonly used Turbuhaler ® (AstraZeneca UK Ltd, Luton, UK) DPI in a clinical trial. The two devices were compared in a randomized, placebo-controlled study, which found that 74% of patients preferred Respimat ® compared with 17% who preferred Turbuhaler ® and 9% who had no preference. Among pediatric patients with asthma, the benefits and ease of use of this innovative tiotropium inhaler could help to maximize patient adherence.

Conclusion

Pediatric asthma is a chronic disease leading to significant morbidity and health care utilization. As many as 50% of patients remain uncontrolled despite national and international guidelines designed to improve control. As this review reveals, new add-on therapy options to ICS/LABA are required, particularly for children and adolescents. However, developing such treatments is challenging. There are limitations to the conclusions that we can draw from the data sources used in this review, for example to the paucity of pediatric trials, the smaller sample sizes than in adult trials and the lack of information on LAMAs other than tiotropium in pediatric populations. It is also clearly essential that clinical trial design continues to consider alternative clinical endpoints, such as FEF ₂₅₋₇₅ and IOS, that are likely to be more suitable for use in clinical trials of pediatric asthma.

Tiotropium Respimat ® is approved in asthma for adult patients (aged ≥18 years) in Singapore, patients aged ≥15 years in Japan and, most recently, approved for patients aged ≥6 years in the US and EU. The clinical trials of tiotropium in pediatric asthma summarized in this review support the safety and efficacy of tiotropium in children and adolescents, irrespective of disease severity and phenotype. At present, tiotropium is considered as an option for add-on to ICS/LABA combination. However, data suggest that it could be considered as an alternative to adding a LABA to ICS, and this may prove an attractive option for future therapeutic strategies.

Acknowledgments

Editorial support (writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Wemimo Omotosho, PhD (MediTech Media, London, UK) and was funded by Boehringer Ingelheim. The author would like to thank Kjeld Hansen, a member of the Patient Ambassador Group for the European Lung Foundation, for his input to the video summary for this manuscript.

Disclosure

The author reports no conflicts of interest in this work.

References

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Clinical efficacy and safety of anticholinergic therapies in pediatric | TCRM

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Stanley Goldstein Allergy and Asthma Care of Long Island, Rockville Centre, New York, NY, USA Abstract: The burden of uncontrolled asthma in children and adolescents is high. Treatment options for pediatric patients (aged under 18 years) with asthma are largely influenced by the Global Initiative for Asthma recommendations.

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Resultados:

Los datos obtenidos de 696 pacientes asmáticos se extrajeron de 4 ensayos controlados aleatorios publicados entre 2015 y 2018. La doxofilina fue significativamente ( P <0,05) más eficaz que la teofilina para reducir los episodios de asma diarios (diferencia media - 0,14, IC del 95%: -0,27 - 0,00 ) y riesgo de EA (riesgo relativo 0,76; IC del 95%: 0,59-0,99). La doxofilina fue tan eficaz como la teofilina para mejorar el FEV ₁ , y  se detectó una tendencia de superioridad ( P = 0,058) para la doxofilina sobre la teofilina con respecto a la reducción en el uso de salbutamol como medicación de rescate. El rango de efectividad fue doxofilina> teofilina>> placebo, y el rango de seguridad fue placebo> doxofilina>> teofilina.

Conclusión:

La doxofilina es una metilxantina eficaz y segura para el tratamiento del asma, con un perfil de eficacia / seguridad superior al de la teofilina.

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Search strategy

This meta-analysis has been submitted to the international database of prospectively registered systematic reviews (PROSPERO, registration number: CRD42019119849), and performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) [ 15]. The PRISMA flow diagram is reported in Fig. 1a. This quantitative synthesis satisfied all the recommended items reported by the PRISMA-P checklist [ 15].

PRISMA flow diagram for the identification of studies included in the meta-analysis ( a) and diagram displaying the network across the treatments; the links between nodes indicate the direct comparisons between pairs of treatments; the numbers shown along the link lines indicate the number of patients comparing pairs of treatments head-to-head ( b)

Two reviewers performed a comprehensive literature search for randomized controlled trials (RCTs) evaluating the influence of doxofylline and theophylline in adolescent and adult asthmatic patients. The PICO (Patient problem, Intervention, Comparison, and Outcome) framework was used to develop the literature search strategy, as previously described [ 16]. Namely, the "Patient problem" included subject affected by asthma; the "Intervention" regarded the administration of doxofylline and theophylline; the "Comparison" was performed with regard to placebo and across each active treatment; the "Outcomes" were the asthma events, adverse events (AEs), lung function expressed as forced expiratory volume in 1 s (FEV ₁), and use of salbutamol as rescue medication.

The terms "doxofylline" AND "theophylline" AND "asthma" were searched in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Scopus, Web of Science, ClinicalTrials.gov and EU Clinical Trials Register databases in order to provide for relevant studies available up to December 7, 2018. No language restriction was applied. The following Query Translation was used: ("asthma" [MeSH Terms] OR "asthma"[All Fields]) AND ("theophylline" [MeSH Terms] OR "theophylline" [All Fields]) AND ("doxofylline" [Supplementary Concept] OR "doxofylline"[All Fields]).

Citations of previously published analyses and relevant reviews were examined to identify further pertinent studies, if any [ 6, 8, 17, 18, 19].

Study selection

Published RCTs involving asthmatic patients treated with oral formulations of doxofylline and theophylline were included in this meta-analysis.

Two reviewers independently checked the relevant studies identified from literature searches obtained from the already mentioned databases. The studies were selected in agreement with the above-mentioned criteria, and any difference in opinion about eligibility was resolved by general consensus.

Endpoints

The primary endpoints of this meta-analysis were the impact of doxofylline on the change in asthma events and the risk of AEs, compared to theophylline and placebo. Asthma events were defined as episodes of increased symptoms or increased airflow limitation responsive to as needed short-acting β ₂ agonists or resulting in either unscheduled medical attention, unscheduled use of oral corticosteroids, hospital admission [ 20]. The secondary endpoints were the impact of doxofylline on the change in FEV ₁ and salbutamol use, compared to theophylline.

Quality score, risk of bias and evidence profile

The Jadad score, with a scale of 1 to 5 (score of 5 being the best quality), was used to assess the quality of the RCTs concerning the likelihood of biases related to randomization, double blinding, withdrawals and dropouts [ 21]. A Jadad score ≥ 3 was defined to identify high quality studies. Two reviewers independently assessed the quality of individual studies, and any difference in opinion about the quality score was resolved by consensus.

In the pairwise meta-analysis moderate to high levels of heterogeneity between-studies were considered for I ² > 50%; the risk of publication bias was assessed by applying the funnel plot and Egger's test, as previously described [ 21]. Evidence of asymmetry from Egger's test was considered to be significant at P < 0.1, and the graphical representation of 90% confidence bands have been presented [ 21]. The risk of bias in the network meta-analysis was checked via the consistency/inconsistency analysis to assess whether the outcomes resulting from the consistency and inconsistency models fit adequately with the line of equality, as previously described [ 22].

The quality of the evidence was assessed for the primary endpoint in agreement with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, indicating ++++ for high quality of evidence, +++ for moderate quality of evidence, ++ for low quality of evidence, and + for very low quality of evidence [ 23].

Data extraction

Data from included RCTs were extracted and checked for study characteristics and duration, enrolled patients, treatments and doses, disease characteristics, age, gender, asthma events, previous hospitalizations, lung function, and Jadad score. Data have been extracted in agreement with DECiMAL recommendations [ 24].

Data analysis

A pairwise meta-analysis was performed to quantify the impact of doxofylline compared to theophylline on primary and secondary endpoints.

Results of the pairwise meta-analysis are expressed as mean difference (MD) or relative risk (RR), and 95% confidence interval (95%CI). Since data were selected from a series of studies performed by researchers operating independently, and a common effect size cannot be assumed, binary random-effects model was used in order to balance the study weights and adequately estimate the 95%CI of the mean distribution of drugs effect on the investigated variables [ 21].

A network meta-analysis was also carried out to perform a comparison across doxofylline, theophylline, and placebo with respect to the primary endpoints, and to rank their efficacy in reducing asthma events and the risk of AEs.

The network meta-analysis was carried out by including RCTs that introduced no significant heterogeneity and bias in the effect estimates of primary endpoint. Since heterogeneity and bias may propagate through a network of RCTs, and thus affect the estimates differentially across regions of the network, this approach permitted to identify those studies that might alter the correct results of the network meta-analysis [ 25].

Full Bayesian evidence network was used in the network meta-analysis (chains: 4; initial values scaling: 2.5; tuning iterations: 20.000; simulation iterations: 50.000; tuning interval: 10). The convergence diagnostics for consistency and inconsistency was assessed via the Brooks-Gelman-Rubin method, as previously described [ 26]. Results of the network meta-analysis are expressed as relative effect (RE) and 95% credible interval (95%CrI). The probability that each intervention arm was the most effective was calculated by counting the proportion of iterations of the chain in which each intervention arm had the highest mean difference, and the surface under the cumulative ranking curve (SUCRA), representing the summary of these probabilities, was also calculated. The SUCRA is 1 when a treatment is certain to be the best, and 0 when a treatment is certain to be the worst [ 27].

Sensitivity analysis was performed to identify the studies that introduced heterogeneity and bias in the effect estimate of primary endpoints, if any. Meta-regression analysis was performed to identify the factors that might modulate the efficacy and safety profile of the investigated agents with regard to primary endpoints.

The specisafety profile of the investigated treatments was investigated through a pooled analysis of the frequency of specific AEs.

OpenMetaAnalyst [ 28] and GeMTC [ 29] software were used for performing the meta-analysis, GraphPad Prism (CA, US) software to graph the data, and GRADEpro GDT to assess the quality of evidence [ 23]. The statistical significance for the effect estimates resulting from the pairwise and network meta-analyses was assessed for P  < 0.05.

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Efficacy and safety profile of doxofylline compared to theophylline in asthma: a meta-analysis - Multidisciplinary Respiratory Medicine

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Background Oral methylxanthines are effective drugs for the treatment of chronic obstructive respiratory disorders. The novel methylxanthine doxofylline, that has bronchodilator and anti-inflammatory activities, is not affected by the major drawback of theophylline. Nowadays large-scale quantitative synthesis comparing the efficacy and safety profile of doxofylline vs.

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Título: Anticolinérgico versus β-agonista de acción prolongada en combinación con corticosteroides inhalados en adultos de raza negra con asma
Tipo de estudio: Ensayo Clínico Aleatorizado
Año: 2015
Resultados: El resultado primario fue el tiempo transcurrido hasta la exacerbación del asma, definida como un empeoramiento del evento de asma que requirió corticosteroides orales o parenterales
Conclusiones:  Entre los adultos de raza negra con asma tratados con corticosteroides inhalados, la adición de un agonista beta2 adrenérgicos de acción larga no mejoró el tiempo de recuperación si no provocó una exacerbación del asma en comparación con la adición de tiotropio

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Titulo: Eficacia de dos métodos de administración de bromuro de salbutamol-ipratropio en crisis de asma
Tipo de Estudio: ECA
Año: 2009
Resultado: Los pacientes pediátricos con crisis de asma no severa tuvieron una mejor evolución con la combinación de salbutamol y bromuro de ipratropio administrada por dispositivo de dosis medidas y cámara espacial que con los mismos fármacos nebulizados con oxígeno suplementario, y se redujo el porcentaje de hospitalizaciones de niños con crisis de asma. (p = 0,037).
Conclusión: La administración de salbutamol y bromuro de ipratropio con dispositivo de dosis medidas fue más eficiente que su administración nebulizada con oxígeno suplementario para el tratamiento de crisis asmáticas en niños.

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[Efficacy of two methods of administration of salbutamol-ipratropium bromide in asthma crises] - PubMed

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Administration of salbutamol and ipratropium bromide with device of measured doses was more efficient that their administration nebulized with supplementary oxygen for treating asthmatic crises in children.

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https://pubmed.ncbi.nlm.nih.gov/22592685/
Titulo:

Agentes antileucotrienos comparados con corticosteroides inhalados en el tratamiento del asma recurrente y / o crónica en adultos y niños

Autor y año: Bhupendrasinh F Chauhan - 2012
Tipo de estudio:  ECA
Resultado: Un total de Sesenta y cinco ensayos cumplieron los criterios de inclusión para esta revisión. Los pacientes tratados con antileucotrienos tenían más probabilidades de sufrir una exacerbación que requiriera corticosteroides sistémicos (N = 6077 participantes; cociente de riesgos (RR) 1,51; intervalo de confianza (IC) del 95%: 1,17; 1,96). Por cada 28 (IC del 95%: 15 a 82) pacientes tratados con antileucotrienos en lugar de corticosteroides inhalados, hubo un paciente adicional con una exacerbación que requirió corticosteroides sistémicos de rescate.  La duración de los ensayos varió de cuatro a 52 semanas en conclusión los corticosteroides inhalados muestran una eficacia superior a los antileucotrienos en adultos y niños con asma persistente; la superioridad es particularmente marcada en pacientes con obstrucción moderada de las vías respiratorias. Sobre la base de la eficacia, los resultados apoyan la recomendación de las guías actuales de que los corticosteroides inhalados siguen siendo la monoterapia preferida.

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Abstract

Background: Anti-leukotrienes (5-lipoxygenase inhibitors and leukotriene receptors antagonists) serve as alternative monotherapy to inhaled corticosteroids (ICS) in the management of recurrent and/or chronic asthma in adults and children.

Objectives: To determine the safety and efficacy of anti-leukotrienes compared to inhaled corticosteroids as monotherapy in adults and children with asthma and to provide better insight into the influence of patient and treatment characteristics on the magnitude of effects.

Search methods: We searched MEDLINE (1966 to Dec 2010), EMBASE (1980 to Dec 2010), CINAHL (1982 to Dec 2010), the Cochrane Airways Group trials register, and the Cochrane Central Register of Controlled Trials (Dec 2010), abstract books, and reference lists of review articles and trials. We contacted colleagues and the international headquarters of anti-leukotrienes producers.

Selection criteria: We included randomised trials that compared anti-leukotrienes with inhaled corticosteroids as monotherapy for a minimum period of four weeks in patients with asthma aged two years and older.

Data collection and analysis: Two review authors independently assessed the methodological quality of trials and extracted data. The primary outcome was the number of patients with at least one exacerbation requiring systemic corticosteroids. Secondary outcomes included patients with at least one exacerbation requiring hospital admission, lung function tests, indices of chronic asthma control, adverse effects, withdrawal rates and biological inflammatory markers.

Main results: Sixty-five trials met the inclusion criteria for this review. Fifty-six trials (19 paediatric trials) contributed data (representing total of 10,005 adults and 3,333 children); 21 trials were of high methodological quality; 44 were published in full-text. All trials pertained to patients with mild or moderate persistent asthma. Trial durations varied from four to 52 weeks. The median dose of inhaled corticosteroids was quite homogeneous at 200 µg/day of microfine hydrofluoroalkane-propelled beclomethasone or equivalent (HFA-BDP eq). Patients treated with anti-leukotrienes were more likely to suffer an exacerbation requiring systemic corticosteroids (N = 6077 participants; risk ratio (RR) 1.51, 95% confidence interval (CI) 1.17, 1.96). For every 28 (95% CI 15 to 82) patients treated with anti-leukotrienes instead of inhaled corticosteroids, there was one additional patient with an exacerbation requiring rescue systemic corticosteroids. The magnitude of effect was significantly greater in patients with moderate compared with those with mild airway obstruction (RR 2.03, 95% CI 1.41, 2.91 versus RR 1.25, 95% CI 0.97, 1.61), but was not significantly influenced by age group (children representing 23% of the weight versus adults), anti-leukotriene used, duration of intervention, methodological quality, and funding source. Significant group differences favouring inhaled corticosteroids were noted in most secondary outcomes including patients with at least one exacerbation requiring hospital admission (N = 2715 participants; RR 3.33; 95% CI 1.02 to 10.94), the change from baseline FEV(1) (N = 7128 participants; mean group difference (MD) 110 mL, 95% CI 140 to 80) as well as other lung function parameters, asthma symptoms, nocturnal awakenings, rescue medication use, symptom-free days, the quality of life, parents' and physicians' satisfaction. Anti-leukotriene therapy was associated with increased risk of withdrawals due to poor asthma control (N = 7669 participants; RR 2.56; 95% CI 2.01 to 3.27). For every thirty one (95% CI 22 to 47) patients treated with anti-leukotrienes instead of inhaled corticosteroids, there was one additional withdrawal due to poor control. Risk of side effects was not significantly different between both groups.

Authors' conclusions: As monotherapy, inhaled corticosteroids display superior efficacy to anti-leukotrienes in adults and children with persistent asthma; the superiority is particularly marked in patients with moderate airway obstruction. On the basis of efficacy, the results support the current guidelines' recommendation that inhaled corticosteroids remain the preferred monotherapy.

Conflict of interest statement

Bhupendrasinh Chauhan ‐ none known.

Prof. Francine Ducharme has received travel support, research funds and fees for speaking from Glaxo SmithKline, Novartis, Nycomed, and Merck Frosst Inc.

Controller Medication Use and Exacerbations for Children and Adults With Asthma in High-Deductible Health Plans.

Galbraith AA, Ross-Degnan D, Zhang F, Wu AC, Sinaiko A, Peltz A, Xu X, Wallace J, Wharam JF. Galbraith AA, et al. JAMA Pediatr. 2021 Aug 1;175(8):807-816. doi: 10.1001/jamapediatrics.2021.0747. JAMA Pediatr. 2021. PMID: 33970186

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anti-asthmatic agents / therapeutic use*

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anti-inflammatory agents / administration & dosage

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anti-inflammatory agents / therapeutic use*

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leukotriene antagonists / therapeutic use*

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national center for biotechnology information

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Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children - PubMed

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As monotherapy, inhaled corticosteroids display superior efficacy to anti-leukotrienes in adults and children with persistent asthma; the superiority is particularly marked in patients with moderate airway obstruction. On the basis of efficacy, the results support the current guidelines' recommendat ...

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Perfil de eficacia y seguridad de las xantinas en la EPOC: un metanálisis en red | Sociedad Respiratoria Europea (ersjournals.com)
TITULO: Efficacy and safety profile of xanthines in COPD: a network meta-analysis
AÑO DE ESTUDIO: 2018 - METAANALASIS
RESULTADOS: en el presente articulo podemos extraer que la doxoxilina parece ser la mejor xantina para el tratamiento de la EPOC.
debemos tomar en cuenta que aunque es un metanalisis este estudio tiene altas probabilidades de sesgo debido a los conflicto de intereses.

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Mario Cazzola , Luigino Calzetta , Peter J. Barnes , Gerard J. Criner , Fernando J. Martinez , Alberto Papi , Maria Gabriella Matera

Abstract

Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.

The primary end-point of this meta-analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.

The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).

Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD.

Introduction

Theophylline is one of the most widely prescribed drugs worldwide for the treatment of chronic obstructive pulmonary disease (COPD), not only because it is inexpensive and widely available, but also because it may benefit patients with COPD [ 1]. In fact, it improves both trough and peak forced expiratory volume in 1 s (FEV ₁) and forced vital capacity in clinically stable COPD patients [ 2]. Furthermore, it is able to increase exercise tolerance [ 3, 4], probably because it reduces air trapping, suggesting an effect on peripheral airways [ 5], and this may explain why some patients with COPD may obtain considerable symptomatic improvement without any increase in spirometric values [ 6]. In patients with severe COPD, withdrawal of theophylline causes significant clinical deterioration despite therapy with other bronchodilators, indicating its added value [ 7]. Besides, compared with placebo, theophylline seems more effective over 12 months at reducing the frequency and duration of acute COPD exacerbations [ 8]. In addition, the use of theophylline leads to effects such as anti-inflammatory activity and improved diaphragm contractility, but their clinical relevance has not been firmly established [ 1].

Therefore, theophylline can have a role in the management of stable COPD [ 1]. However, recommendations for treating COPD with theophylline vary across national guidelines [ 9], probably because there are many controversies about its use [ 10], as it is less effective and well tolerated than inhaled long-acting bronchodilators and inhaled corticosteroids have a greater anti-inflammatory effect [ 1]. In most treatment guidelines, theophylline is relegated to second- or third-line therapy because of its narrow therapeutic window and propensity for pharmacological interactions [ 10], which makes its use challenging, especially in elderly patients with comorbidities receiving multiple classes of drug. Moreover, a recent meta-analysis of seven observational studies has suggested that theophylline slightly increases all-cause death in COPD patients [ 11].

Several other xanthines, such as aminophylline, bamiphylline and doxofylline, have been synthesised to be used clinically in various parts of the world for the treatment of respiratory disease, with the anticipation that such drugs would have greater efficacy than theophylline, but with improved side-effect profiles because of their different pharmacological profiles ( table 1).

There is evidence that doxofylline, at least, is an effective bronchodilator for relieving airway obstruction and displays a better safety profile than theophylline, having a favourable risk-to-benefit ratio [ 12- 14]. These findings suggest that it could be an attractive alternative to theophylline in the treatment of patients with COPD. However, doxofylline is not included in any guideline for management of COPD, probably also because most trials of doxofylline in people with COPD have used small numbers of participants. Undoubtedly, there is an evident dichotomy between the safety and efficacy profile of doxofylline that arises from clinical trials and positioning of this oral xanthine in the treatment of COPD.

Given the number of xanthines available for COPD and the absence of clinical trials that have directly compared all relevant agents, we performed a systematic review and network meta-analysis of randomised and nonrandomised clinical trials with the aim of evaluating their comparative efficacy and safety in patients with stable COPD.

Materials and methods

Search strategy

This network meta-analysis has been registered at PROSPERO ( www.crd.york.ac.uk/PROSPERO identifier number CRD42017077901), and performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement ( figure S1A) [ 15]. This quantitative synthesis satisfied all the recommended items reported by the PRISMA-P 2015 checklist [ 16].

Two reviewers (MC and LC) performed a comprehensive literature search for clinical studies evaluating the influence of xanthines in COPD patients. The PICO (patient problem, intervention, comparison and outcome) framework was used to develop the literature search strategy, as previously described [ 17]. Namely, the "patient problem" included subject affected by stable COPD; the "intervention" regarded the administration of different xanthines; the effect of placebo and/or the values at baseline in clinical trials were used as "control"; and the assessed "outcomes" were the lung function, risk of adverse events, the therapeutic efficacy and dyspnoea. Thus, the terms aminophylline, bamiphylline, doxofylline, enprophylline and theophylline were searched for the drugs, and the terms chronic obstructive pulmonary disease or COPD were searched for the disease. The main pharmacological characteristics of the xanthines investigated in this quantitative synthesis are reported in table 1.

The search was performed in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Scopus, Google Scholar, Web of Science and ClinicalTrials.gov databases through February 2018, in order to provide for relevant studies available up to February 27, 2018. No language restriction was applied.

The clinical trials reporting the efficacy and/or safety profile of xanthines in COPD patients were searched in agreement with the following query translation: ["pulmonary disease, chronic obstructive"[medical subject heading (MeSH) terms] OR ("pulmonary"[All Fields] AND "disease"[All Fields] AND "chronic"[All Fields] AND "obstructive"[All Fields]) OR "chronic obstructive pulmonary disease"[All Fields] OR "copd"[All Fields]) AND (("bamiphylline"[Supplementary Concept] OR "bamiphylline"[All Fields]) OR ("enprophylline"[Supplementary Concept] OR "enprophylline"[All Fields]) OR ("doxofylline"[Supplementary Concept] OR "doxofylline"[All Fields]) OR ("theophylline"[MeSH Terms] OR "theophylline"[All Fields]) OR ("aminophylline"[MeSH Terms] OR "aminophylline"[All Fields]))].

Study selection

Published and unpublished clinical trials (both randomised and non-randomised) involving COPD patients and reporting the direct comparison between at least two different xanthines with regard to the efficacy and/or safety profile were included in this network meta-analysis.

Clinical trials reporting no direct comparison across xanthines, those not reporting data on efficacy and/or safety profile, and those available exclusively as abstracts were excluded by this network meta-analysis synthesis. Furthermore, nonclinical trials were excluded by this quantitative synthesis.

Two reviewers (MC and LC) independently checked the relevant studies identified from literature searches obtained from the abovementioned databases. The studies were selected in agreement with the abovementioned criteria, and any difference in opinion about eligibility was resolved by general consensus.

Quality score, risk of bias and evidence profile

The Jadad score, with a scale of 1-5 (score of 5 being the best quality), was used to assess the quality of the clinical trials concerning the likelihood of biases related to randomisation, double blinding, withdrawals and dropouts [ 18]. A Jadad score ≥3 was defined to identify high-quality studies. Two reviewers independently assessed the quality of individual studies, and any difference in opinion about the quality score was resolved by consensus.

The risk of bias for the impact of xanthines on lung function and their safety profile in stable COPD patients was assessed via the consistency/inconsistency analysis to check whether the outcomes resulting from the consistency and inconsistency models fit adequately with the line of equality, as previously described [ 19]. Furthermore, the inconsistency of evidence was also assessed by quantifying the inconsistency factor, indicating whether one of the treatment had a different effect when it was compared with the others [ 20].

Meta-regression analysis was performed to examine the source of heterogeneity between studies and identify potential confounder covariates specifically for the impact of xanthines on lung function and the risk of adverse events [ 19].

The quality of the evidence concerning the impact of xanthines on lung function and the risk of adverse events was assessed in agreement with the grading of recommendations assessment, development and evaluation (GRADE) system [ 21].

Data extraction

Data from included studies were extracted and checked for study characteristics and duration, doses of xanthines, concomitant medications, disease characteristics, ethnicity, age, sex, lung function, safety, therapeutic efficacy, dyspnoea and Jadad score. Due to the complexity of this meta-analysis, data have been extracted in agreement with data extraction for complex meta-analysis (DECiMAL) recommendations [ 22].

End-points

The primary end-point of this meta-analysis was the impact of different xanthines on the change from baselines in FEV ₁.

The secondary end-point were the risk of adverse events, via normalising the data on safety as a function of person-weeks, therapeutic efficacy (the rate of patients that achieved the 3rd or 4th rank in a four-point nonvalidated scale, or that achieved the 2nd or 3rd rank in a three-point nonvalidated scale, where the higher values represented greater therapeutic efficacy [ 23- 27]) and the change from baseline in dyspnoea via the Medical Research Council scale [ 28] or a nonvalidated dyspnoea score that assessed dyspnoea using a four-point scale [ 29, 30]. More details concerning the scales used to assess the therapeutic efficacy and dyspnoea are reported in table S1.

Data analysis

This network meta-analysis was performed to compare the impact of specific xanthines in COPD patients by analysing the data extracted from studies that directly compared at least two different xanthines. Results are expressed as relative effect and 95% credible interval (95% CrI).

A full Bayesian evidence network was used (chains: 4; initial values scaling: 2.5; tuning iterations: 20 000; simulation iterations: 50 000; tuning interval: 10), and the convergence diagnostics for consistency and inconsistency was assessed via the Brooks-Gelman-Rubin method, as previously reported [ 31].

Due to the characteristics of parameters besides the available data, the noninformative distributions specified the prior densities, in agreement with the Bayesian approaches to clinical trials and healthcare evaluation [ 32, 33]. Since the distributions were sufficiently vague, the reference treatment, study baseline effects and heterogeneity variance were unlikely to have a noticeable impact on model results. In this condition, GeMTC software automatically generates and runs the required Bayesian hierarchical model and selects the prior distributions and starting values as well, via heuristically determining a value for the outcome scale parameter ( i.e. outcome scale S) [ 34, 35]. The posterior mean deviance of data points in the unrelated mean effects model were plotted against their posterior mean deviance in the consistency model in order to provide information for identifying the loops in the treatment network where evidence was inconsistent [ 36].

The efficacy/safety profile was assessed by plotting the summary findings regarding the relative efficacy and safety of specific xanthines comparisons, as previously described [ 37]. Furthermore, the probability that each intervention arm was the most effective than the others was calculated by counting the proportion of iterations of the chain in which each intervention arm had the highest mean difference, and the surface under the cumulative ranking curve (SUCRA), representing the summary of these probabilities, was also calculated. The SUCRA is 100% when a treatment is certain to be the best, and 0% when a treatment is certain to be the worst [ 31, 38].

A pooled analysis was performed to calculate the frequency of adverse events, ranked in agreement with the European Medicine Agency undesirable effects (section 4.8), as follows. Very common: ≥1/10; common ≥1/100 to <1/10; uncommon ≥1/1000 to <1/100; frequency not known if not calculable from the available data ( www.ema.europa.eu/docs/en_GB/document_library/Presentation/2013/01/WC500137021.pdf). The overall adverse events frequency and the frequency of specific adverse events were compared across the investigated drugs.

OpenMetaAnalyst [ 39] and GeMTC [ 34] software were used for performing the network meta-analysis and meta-regression, OpenEpi [ 40] software for the pooled analysis, GraphPad Prism (La Jolla, CA, USA) software to graph the data, and GRADEpro software to assess the quality of evidence [ 21]. Statistical significance was considered to be p<0.05.

Results

Study characteristics

Data obtained from 998 COPD patients (47.94% treated with doxofylline, 24.82% treated with theophylline, 21.71% treated with aminophylline and 5.53% treated with bamiphylline) were selected from 14 studies [ 23- 27, 29, 30, 41- 47] published between 1987 and 2016. The relevant studies and patients' characteristics are described in table S2, and figure S1B shows the network across the xanthines involved in the Bayesian analysis.

All the meta-analysed clinical trials were published as full-text papers [ 23- 27, 29, 30, 41- 47]. Four studies had a Jadad score ≥3 [ 23, 24, 42, 45, 47], and 10 studies had a Jadad score ≥1 and <3 [ 25- 27, 29, 30, 41, 43, 44, 46, 47]. The length of treatment ranged from 1 day to 12 weeks.

Network meta-analysis

Primary end-point

No significant differences were detected with regard to the change from baseline in FEV ₁ across aminophylline, doxofylline, and theophylline. The subset analysis of the studies that expressed the change from baseline in FEV ₁ as volume (mL or L) indicated that theophylline increased FEV ₁ by 12.0 (95% CrI −142.5-173.7) mL versus doxofylline and 69.6 (95% CrI −211.6-348.2) mL versus aminophylline, and that doxofylline increased FEV ₁ by 55.4 (95% CrI −212.5-310.5) mL versus aminophylline. In contrast, aminophylline, doxofylline and theophylline were both significantly (p<0.001) more effective than bamiphylline ( figure 1a). Specifically, aminophylline, doxofylline and theophylline increased FEV ₁ by 538.1 (95% CrI 122.6 -850.7) mL, 593.5 (95% CrI 271.1-791.6) mL and 604.3 (95% CrI 246.2-846.1) mL, respectively, versus bamiphylline (p<0.001).

Secondary end-points

Doxofylline was significantly (p<0.001) safer than both aminophylline and theophylline, whereas no difference resulted versus bamiphylline. No significant differences were detected with regard to the risk of adverse events across aminophylline, bamiphylline and theophylline ( figure 1b).

When coupling relative effects for efficacy and safety, doxofylline appeared to be superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety) and theophylline (comparable efficacy and significantly better safety), as shown by the efficacy/safety analysis reported in figure 2a. The superiority of doxofylline over aminophylline, bamiphylline and theophylline was further confirmed by the combined efficacy/safety SUCRA analysis ( figure 2b).

The SUCRA analysis also indicated that doxofylline was the most effective xanthine with regard to the impact on therapeutic efficacy (SUCRA value 0.71), followed by aminophylline (SUCRA value 0.49) and theophylline (SUCRA value 0.31). Doxofylline and aminophylline both elicited a greater beneficial impact on the improvement of dyspnoea score (SUCRA values 0.75 and 0.71, respectively), compared with theophylline (SUCRA value 0.04).

Pooled analysis of safety profile

The overall pooled analysis of the safety profile showed that the frequency of adverse events detected in COPD patients treated with doxofylline (22.0%) was significantly (p<0.001) lower than that found for both theophylline (61.7%) and aminophylline (54.55%).

The analysis of specific adverse events is reported in table 2, and showed that the most frequent adverse events were correlated with the administration of aminophylline (palpitations 12.73%, gastrointestinal discomfort 11.82% and insomnia 9.09%) and theophylline (nausea 10.8%, epigastralgia 9.1%, headache 8.6% and dyspepsia 7.3%). Generally, the frequency of specific adverse events induced by doxofylline was significantly (p<0.05) lower than that detected for both theophylline and aminophylline. The pooled analysis was not performed on bamiphylline since no data were available concerning the specific adverse events.

The percentage of patients that withdrew from the clinical trials due to adverse events was significantly (p<0.001) higher in the subjects treated with theophylline (10.0%) compared with those treated with doxofylline (2.6%). Overall, the reported adverse events that led to study discontinuation were dyspepsia, epigastralgia, nausea and palpitations. No data are available concerning the withdrawal due to adverse events for the other investigated xanthines.

Bias and quality of evidence

The analysis of inconsistency showed that no significant discrepancy exists between direct and indirect evidences for both efficacy (inconsistency factor −0.05, 95% CrI −0.64-0.69; p≥0.05) and safety profile (inconsistency factor −1.39, 95% CrI −4.69-0.73; p≥0.05). The consistency/inconsistency analysis indicated that all points fit adequately with the line of equality (efficacy R ² 0.99, slope 0.99, 95% CI 0.92-1.07; safety: R ² 0.95, slope 1.26, 95% CI 0.86-1.66) ( figure S2).

The meta-regression model of the effect estimates resulting for FEV ₁ indicated that neither the total dose (study duration × daily dose) of xanthines administered to COPD patients during the studies, nor the route of administration, lung function, ethnicity and Jadad score were significant (p>0.05) confounder variables that may have altered the results of this meta-analysis. The meta-regression model of the effect estimates resulting for adverse events indicated that neither lung function, nor ethnicity and Jadad score represented effect modifiers. Conversely, the total dose of xanthines administered during the studies (coefficient −0.08, p<0.001) and the route of administration (oral versus i.v. coefficient 1.41, p<0.001) were significant confounding factors for the frequency of adverse events ( figure S3).

The GRADE analysis of the change from baseline in FEV ₁ indicated moderate quality of evidence (+++) for the use of doxofylline versus theophylline/aminophylline, low quality of evidence (++) for the use of doxofylline versus bamiphylline and very low quality of evidence (+) for the use of theophylline versus aminophylline/bamiphylline and aminophylline versus bamiphylline.

The GRADE analysis of the risk of adverse events indicated high quality of evidence (++++) for the use of doxofylline versus theophylline/aminophylline and very low quality of evidence (+) for the use of doxofylline versus bamiphylline, theophylline versus aminophylline/bamiphylline and aminophylline versus bamiphylline ( table 3).

Discussion

The results of our network meta-analysis demonstrate that doxofylline seems to be the best xanthine in the treatment of COPD. The SUCRA analysis has shown that doxofylline was the most effective xanthine with regard to the impact on therapeutic efficacy, followed by aminophylline and theophylline. Although no significant differences have been detected with regard to the change from baseline in FEV ₁ across aminophylline, doxofylline and theophylline, doxofylline and aminophylline elicited a greater beneficial impact on the improvement of dyspnoea score compared to theophylline. Moreover, doxofylline was significantly safer than both aminophylline and theophylline. The superiority of doxofylline over aminophylline, bamiphylline and theophylline has further been confirmed by the combined efficacy/safety SUCRA analysis. It is noteworthy that the meta-regression has shown that both the lung function and the total dose of xanthines administered during the studies, which can be translated as the expression of the severity of COPD, did not influence the results.

Although improving lung function is not an objective of COPD management [ 10], it is the primary end-point most frequently used by regulatory authorities in interpreting drug efficacy in COPD trials. A minimal clinically important difference (MCID) of 100 mL for pre-dose or trough FEV ₁ has been proposed, based on clinical anchoring to end-points such as exacerbations, perception of dyspnoea and decline in lung function [ 48]. This MCID was largely achieved with aminophylline, doxofylline and theophylline when compared with bamiphylline, but not across them. The diversity of the tools used to evaluate the impact of treatments on dyspnoea makes the evaluation of the real clinical impact of the different xanthines on this symptom much more problematic. However, to rank the treatments for an outcome, we used SUCRA probabilities, which express as a percentage the efficacy of every intervention relative to an imaginary intervention that is always the best without uncertainty. Thus, large SUCRA scores might indicate a more effective intervention [ 32, 39]. The high SUCRA ranking of doxofylline suggests that it is more effective than theophylline in reducing dyspnoea. Interestingly, the combined efficacy/safety SUCRA analysis documented the superiority of doxofylline over aminophylline, bamiphylline and theophylline.

The results of the present meta-analysis are not surprising considering that doxofylline should not be assumed just as another theophylline [ 14]. It is now well established that doxofylline possesses a distinct pharmacological profile from theophylline ( table 1 and figure S4). In fact, it does not elicit any significant effect on any of the known phosphodiesterase isoforms, lacks significant adenosine receptor antagonism, does not cause a direct effect on any of the known histone deacetylase enzymes, and interacts favourably with β ₂-adrenoceptors [ 49, 50].

Theophylline is inexpensive and widely available, and it might improve the action of another bronchodilator or even be a sufficient bronchodilator by itself in certain patients [ 51]. Furthermore, a potent anti-inflammatory effect at lower doses, which suggests the drug may be useful as a steroid-sparing therapy in patients with severe COPD, has been identified [ 1]. Nevertheless, because of its toxicity at levels close to the therapeutic range [ 9], theophylline is rarely used as a first-line COPD medication [ 1]. However, in low doses theophylline can still be considered to be an add-on therapy in those patients with severe or very severe COPD. In fact, the Spanish COPD guidelines (GesEPOC) 2017 [ 52] relegate it to third-line treatment, mainly in high-risk patients who continue to be dyspnoeic following dual bronchodilator therapy. In addition, the French-Language Respiratory Society (Société de Pneumologie de Langue Française) proposes its use for patients with dyspnoea on long-acting bronchodilators [ 53].

Given the pharmacological profile of doxofylline [ 49, 50]; its significant anti-inflammatory activity that can result in significant steroid sparing activity, as documented at least in both an allergic and a nonallergic murine model of lung inflammation [ 54]; its documented clinical activity [ 12- 14]; and, above all, the results of the present meta-analysis, there is a clear need to understand what is the room in the treatment of COPD for a xanthine that induces the same, if not even better, therapeutic effects of theophylline but with a totally different safety profile. Specifically, the rate of study withdrawal due to adverse events such as dyspepsia, epigastralgia, nausea and palpitation was approximately four-fold higher in COPD patients treated with theophylline than in those treated with doxofylline.

Meta-analysis is an analytical technique designed to summarise the results of multiple studies in order to effectively increase sample size and provide valid pooled effect estimates [ 55]. It can be considered a systematic study of the currently available studies undertaken to answer specific questions or hypotheses [ 56]. In this regard, meta-analyses are mainly focused on questions ideally intended to solve clinical problems in agreement with the PICO strategy [ 17, 57]. Actually, the network meta-analytical approach is an extension of traditional pairwise meta-analysis. It represents a novel and effective statistical method that permits to incorporate clinical evidence from both direct and indirect treatment comparisons in a complete network of trials in order to assess the efficacy and risk of adverse events of multiple interventions [ 58]. Furthermore, the network meta-analytical approach permits to report the treatment rankings via the SUCRA method, a simple numerical summary to supplement the graphical display [ 59]. As already mentioned, this method facilitates the interpretation of the effect estimates resulting from indirect/mixed comparisons, and it can be important for clinicians who wish to know what is the best treatment for certain clinical conditions [ 58].

Despite the several advantages that a network meta-analysis can provide with respect to the real impact of different xanthines in the treatment of stable COPD patients, this quantitative synthesis has also some limitations, which mainly stem from the quality of reported data.

First of all, we must point out that xanthines have mostly been compared to placebo rather than active agents; trials were relatively small; and most studies are old, i.e. performed at a time when none of the current reference inhaled treatments were available. Clearly, this means that the results of our meta-analysis do not allow the placement of xanthines within the global COPD therapeutic framework. However, theophylline, being cheap and widely available, remains one of the most widely prescribed drugs for COPD treatment in developing countries [ 60]. Doxofylline, which presently is used in some regions of the world, can offer an alternative safer treatment, because of the lower risk of adverse events when compared with conventional "high-dose" theophylline, making blood monitoring unnecessary.

Another important limitation of the present meta-analysis relates to the lack of information on important outcomes such as exacerbations. Xanthines are considered to have no role in the acute exacerbation of COPD because a lack of solid information and, in effect, the last European Respiratory Society/American Thoracic Society document on prevention of COPD exacerbations did not mention xanthines [ 61]. Only two studies have compared oral theophylline with placebo to explore its capacity in reducing the frequency of COPD exacerbations, with contrasting results [ 62, 63]. No study has evaluated the impact of aminophylline, bamiphylline and doxofylline in reducing the frequency of COPD exacerbations.

Furthermore, it was impossible to establish whether there is any difference between slow- and rapid-release preparations of aminophylline or theophylline when compared with doxofylline. In addition, data in the literature did not allow us to evaluate the impact of duration of exposure to medications and that of comorbid conditions on our results. The adverse events relative to the concomitant medications remain unknown, but we must point out that the total dose of xanthines administered during the studies and the route of administration have influenced our scores.

Despite these limitations, we believe that this network meta-analysis provides valuable information on the efficacy and safety of doxofylline in people with stable COPD. It is our opinion that the use of an orally active drug that is safe, effective and relatively inexpensive, as doxofylline is, must be encouraged, particularly for those COPD patients who find inhalers difficult to use or who do not get adequate control from other pharmacological classes. In any case, we would encourage further randomised clinical trials of doxofylline to investigate the use of this drug to reduce acute exacerbations and hospitalisations due to COPD as an alternative to more expensive combined therapies, and certainly as an alternative to theophylline.

Footnotes

This article has supplementary material available from err.ersjournals.com

Provenance: Submitted article, peer reviewed.

Conflict of interest: M. Cazzola reports personal fees from ABC Farmaceutici, outside the submitted work, and received personal fees to perform the meta-analysis and write the article.

Conflict of interest: L. Calzetta reports personal fees from ABC Farmaceutici, during the conduct of the study, and received personal fees to perform the meta-analysis and write the article.

Conflict of interest: M.G. Matera reports personal fees from ABC Farmaceutici, outside the submitted work. She is also a consultant at ABC Farmaceutici and was supported to write the article.

Support statement: ABC Farmaceutici that manufactures and sells medicinal products containing doxofylline provided the funds to perform the meta-analysis and write the article. Funding information for this article has been deposited with the Crossref Funder Registry.

Received February 1, 2018.

Accepted March 11, 2018.

ERR articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

# data[].attributes.attachment_link.title
Efficacy and safety profile of xanthines in COPD: a network meta-analysis

# data[].attributes.attachment_link.description
Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline.

# data[].attributes.body
TITULO: Eficacia y efectos secundarios de la teofilina intravenosa en el asma aguda: revisión sistemática y metaanálisis.
TIPO DE ESTUDIO: Revisión sistemática y metaanálisis.
AÑO: 2018
OBJETIVO: comparar la efectividad de la teofilina intravenosa con todos los comparadores disponibles.
CONCLUSIÓN: Los datos muestran que la teofilina intravenosa es superior a otros tratamientos con respecto a la frecuencia cardíaca y la duración de la estancia hospitalaria, e igual a otros tratamientos para casi todos los demás resultados informados. Dado el bajo costo de la teofilina y su eficacia y tasa de efectos secundarios similares en comparación con otros medicamentos, sugerimos que la teofilina, cuando se administra con broncodilatadores con o sin esteroides, es una opción rentable y segura para las exacerbaciones agudas del asma.

# data[].attributes.attachment_link.readable_text
Abstract

Background and objective

Theophylline has been used for decades to treat both acute and chronic asthma. Despite its longevity in the practitioner's formulary, no detailed meta-analysis has been performed to determine the conditions, including concomitant medications, under which theophylline should be used for acute exacerbations of asthma. We aimed to quantify the usefulness and side effects of theophylline with or without ethylene diamine (aminophylline) in acute asthma, with particular emphasis on patient subgroups, such as children, adults, and concomitant medications.

Methods

We searched PubMed, EMBASE, The Cochrane Library, ClinicalTrials.gov, and the WHO Clinical Trials Registry for randomized, controlled clinical trials. We planned a priori subgroup analyses by time post-medication, concomitant medication, control type, and age.

Results

We included 52 study arms from 42 individual trials. Of these, 29 study arms included an active control, such as adrenaline, beta-2 agonists, or leukotriene receptor antagonists, and 23 study arms compared theophylline (with or without ethylene diamine) with placebo or no drug. Theophylline significantly reduced heart rate when compared with active control ( p=0.01) and overall duration of stay ( p=0.002), but beta-2 agonists were superior to theophylline at improving forced expiratory volume in one second (FEV1) ( p=0.002). Theophylline was not significantly different from other drugs in its effects on respiratory rate, forced vital capacity (FVC), peak expiratory flow rate, admission rate, use of rescue medication, oxygen saturation, or symptom score. Closer examination of the data revealed that the medications given in addition to theophylline or control significantly changed the effectiveness of theophylline (subgroup difference: p<0.00001).

Conclusion

Given the low cost of theophylline, and its similar efficacy and rate of side effects compared with other drugs, we suggest that theophylline, when given with bronchodilators with or without steroids, is a cost-effective and safe choice for acute asthma exacerbations.

Keywords: theophylline, theophylline with ethylene diamine, aminophylline, asthma, bronchodilators, beta-2 agonists, adrenaline, FEV, PEFR, affordable drugs

Introduction

Acute asthma exacerbations are a frequent and serious reason for presentation to hospital emergency departments. Asthma prevalence in adults globally is estimated at 4.3%, with Australia, the UK, Sweden, and the Netherlands all exceeding 15%. 1 In children, the prevalence is even higher, with many countries reporting asthma rates in children over 20%. 2 In many parts of the world, asthma prevalence in increasing, although in some countries with high rates of asthma, the prevalence may now be levelling off. 3

Severe asthma exacerbations in children or adults are very serious and can be life-threatening. According to the World Health Organization, asthma causes ~250,000 deaths worldwide each year. 4 Despite a range of drugs for the treatment of asthma, 5 systematic evidence for the efficacy of these drugs is not universal. Thus, especially in developing countries, it is essential that the comparative effectiveness of all asthma treatments, including older and more affordable drugs, be available to health practitioners.

Theophylline, a methylxanthine, is a bronchodilator. When combined with ethylene diamine as "aminophylline", it is more soluble and is thus the more common form of theophylline used for intravenous (IV) administration. 6, 7 Available in generic form, theophylline with or without ethylene diamine is certainly affordable. However, its efficacy, especially in children, and the effective doses are a matter of dispute. We therefore undertook this study to compare the effectiveness of IV theophylline with all available comparators.

Methods

The current systematic review and meta-analysis was performed on the principles of the Cochrane Collaboration. 8

Data sources and search strategy

We searched PubMed, EMBASE, the Cochrane Library, ClinicalTrials.gov, and the WHO international clinical trials registry for relevant articles. Our search strategy used the following keywords, as full-text and MESH terms (where appropriate): (Theophylline OR 1,3-dimethylxanthine OR Elixophyllin OR Norphyl OR Phyllocontin OR Quibron-TSR OR Theo-24 OR TheoCap OR Theochron OR Theo-Dur OR Theo-Time OR Truxophyllin OR Uniphyl OR aminophylline) AND ("Short-acting beta2 agonist" OR "short-acting beta agonist" OR "beta* adrenergic receptor agonist" OR SABA OR salbutamol OR formoterol OR eformoterol OR "long-acting beta agonist" OR LABA OR albuterol OR levalbuterol OR betamethasone OR hydro-cortisone OR methylprednisolone OR prednisolone OR Ventolin OR Proventil OR Atock OR Atimos OR Foradil OR Oxis OR Perforomist OR salmeterol OR bambuterol OR fluticasone OR budesonide OR glucocorticoid OR Flixotide OR Flixonase OR Pulmicort OR Rhinocort OR anticholinergic OR ipratropium OR epinephrine OR beclamethasone OR montelukast OR zafirlukast OR "5-LOX inhibitor" OR cromolyn OR placebo OR no drug) AND Asthma AND (Intravenous OR IV OR iv) AND (RCT OR random OR randomised OR randomized OR groups OR "randomised controlled trial" OR "randomized controlled trial" OR "controlled clinical trial"). No date or language restrictions were applied. All citations were uploaded into EPPI-Reviewer 4 9 and were independently coded by two investigators. The date of the last search was 9 July 2017.

Inclusion criteria

Citations were included if they matched the following PICOTS: the population was children or adults presenting to an emergency department with an acute asthma exacerbation; the intervention was theophylline with or without ethylene diamine, administered intravenously; the control was placebo, no drug or active comparator; the outcomes were forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), symptom scores, admission rates, duration of stay, rescue medication use, oxygen saturation, pulse rate, respiratory rate, or adverse events; the time was between 15 minutes and 48 hours after administration of theophylline; the setting was acute, inpatient treatment in a hospital.

Study selection and study quality

Two authors independently assessed all citations at the title/abstract level in EPPI-Reviewer 4. Disagreements between the authors were resolved by consensus. Two authors then examined the full texts of all included abstracts in EPPI-Reviewer 4. In addition to the previously mentioned PICOTS criteria, studies were only included if they were randomized, controlled trials.

The Cochrane tool for assessing the risk of bias in RCTs 10 was used to assess study quality. Two investigators assessed the risk of bias according to random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, attrition, selective reporting, and other bias. We did not exclude studies if they were not blinded, but planned a sensitivity analysis to test the importance of blinding in assessing the outcomes.

Data extraction

One investigator extracted data from all included studies. A second investigator confirmed the data extraction. Data that were not given in the text or in tables were extracted using WebPlotDigitizer. 11 We extracted the data as given in the text. For the meta-analysis, we converted standard errors to standard deviations. Where more than one control was present, we extracted all study arms. If more than one study arm was used in an analysis, we avoided a unit of analysis error by dividing the number in the study arm by the number of study arms used in the analysis.

Statistical analysis

Meta-analysis was done using Review Manager (RevMan 5.3). 12 Mean differences and standardized mean differences with 95% confidence intervals (CIs) were calculated using an inverse variance model. 12 Odds ratios with 95% CI were calculated using the Mantel-Haenszel statistical method. 13 Because of differences in study design and participants, we used a random effects model for all analyses.

Results

All study results refer to "theophylline" whether or not it contained ethylene diamine. For a breakdown of which studies used which drug, please refer to the study characteristics given in the following section, as well as Table 1 .

Table 1

Study ID

Intervention
(N)

Control
(N)

Study type

Study length

Population

Age range, years

Average age, years

Inclusion (severity)

Intervention

Bolus dose

Ongoing dose

Control

Bolus dose

Ongoing dose

Background medication

Gender

Country

Blinding

Funding

NCT00442338 (2007) 28

31

30

P

60 minutes

Adults

No data

56

All

A

None

250 mg

Montelukast

None

14 mg

Inhaled beta-agonist or oxygen

Mixed

Multicenter

Unclear

Industry

Study characteristics

A total of 52 study arms from 42 individual trials were included in the meta-analysis ( Figure 1 , Table 1 ). Adults were studied in 29 study arms, 14- 36 with children the focus of 17 study arms. 37- 53 One study did not restrict the age of participants, 54 and one study did not report the age of participants. 55 Twenty-five study arms compared theophylline with an active control such as adrenaline, beta-2 agonists, or leukotriene receptor antagonists, 21 compared theophylline with placebo, and two studies compared theophylline with no drug. Forty-eight study arms used theophylline with ethylene diamine; and four used theophylline without ethylene diamine. Only two studies were funded or partly funded by industry. All other studies were funded and carried out by university or hospital clinical teams. Blinding of some kind took place in 37 study arms, with blinding being unclear in 11 arms. All studies were carried out in both males and females.

Quality of included studies

The quality of included studies is given in Figure 2 . In general, the risk of bias was unclear or low. Reporting of the method of randomization, allocation concealment, and study protocols was frequently missing. The lack of blinding in some studies led to an increase in the risk of bias to some degree.

FEV1/FVC

The FEV1 and FVC (after a full breath) are commonly measured outcomes for asthma studies. FEV1 can be measured in liters (L), or alternatively as a percent of the predicted value. In our analysis, the majority of the studies used liters to measure FEV1. We carried out a subgroup meta-analysis of FEV1 (L) by control type ( Figure 3A ). Intravenous (IV) theophylline was not significantly different from adrenaline ( p=0.12), a leukotriene receptor antagonist ( p=0.81), or placebo ( p=0.07) in increasing FEV1, but was significantly worse than beta-2 agonists (mean difference [MD] =−0.20 L [95% CI: −0.34, −0.07], p=0.002). A pooled analysis of all active controls, however, also showed a small but significantly improved FEV1 in the control compared with theophylline (MD =−0.14L [95% CI: −0.25, −0.02], p=0.001; Figure 3B ). Pooling of the six studies measuring FEV1 as a percent of predicted showed no difference between theophylline and control (MD =3.78 [95% CI: −1.08, 8.63], p=0.13, data not shown). Seven studies (nine study arms) reported on FVC ( Figure 3C ). There was no difference in FVC between theophylline and control groups ( p=0.73).

PEFR

PEFR is another common measurement of lung function in asthmatics. As for FEV1, PEFR can be measured in L or as a percent of the predicted value. A subgroup meta-analysis of PEFR (L) was performed to determine if theophylline was effective at increasing PEFR in the short-term (30 minutes-2 hours) or the longer-term (5 hours-24 hours) ( Figure 4A ). There were no significant differences between theophylline and control at either time point. A sensitivity analysis removing the placebo-controlled trials from this analysis did not alter the results (data not shown). When measured as a percent of predicted PEFR value ( Figure 4B ), neither the short-term studies (30 minutes-2 hours; p=0.56) nor the longer-term studies (5 hours-48 hours; p=0.44) showed any significant differences between theophylline and control groups.

Heart rate

During an asthma exacerbation, the heart rate increases to compensate for a reduction in oxygenation in the blood. Therefore, a lower heart rate, both immediately after the administration of medication as well as over the longer term, indicates that the medication is relieving the bronchoconstriction. In order to compare the effect of IV theophylline on heart rate, we undertook a subgroup meta-analysis by time after infusion ( Figure 5A ). In the short-term (30 minutes-3 hours post-infusion), theophylline lowered the heart rate by 4.17 beats per minute (bpm) compared with control therapy, which was significant ( p=0.02). At longer-term time points (24-36 hours post-infusion), the difference in heart rate between IV theophylline and control treatments was similar (−3.59 bpm), but failed to reach statistical significance ( p=0.32). In order to determine if theophylline was superior to other active therapies, we undertook a subgroup meta-analysis by control type ( Figure 5B ). In the active control studies, theophylline lowered the heart rate by 5.17 bpm more than active controls, and this difference was significant ( p=0.01). In the placebo-controlled trials, no significant difference was noted ( p=0.79).

Respiratory rate

An increased respiratory rate is, like heart rate, a sign of an ongoing asthma exacerbation. 56 Thus, a reduction in the respiratory rate should indicate an improvement in the status of a patient with acute asthma. We undertook a meta-analysis of the seven study arms measuring this outcome ( Figure 6 ). Theophylline was slightly less effective at lower respiratory rate, although this was not significant ( p=0.08).

Other outcomes

Other outcomes extracted were symptom scores, admission rate, duration of stay, use of rescue medication, and oxygen saturation ( Figure 7 ). In almost every case, there were no significant differences between theophylline and control. The exception was the duration of hospital stay ( Figure 7C ), with theophylline reducing the duration of stay by 0.23 hours (14 minutes) (95% CI: −0.37, −0.08 hours, p=0.002).

Subgroup analysis: background medication

Theophylline was neither more nor less effective than control treatments for almost all outcomes. This was true whether the control was an active comparator like salbutamol, or a placebo. We questioned whether the regimen of medications given to patients before or during the studies ("background medication") was responsible for the perceived lack of additional efficacy of theophylline over placebo.

In order to investigate this question, we undertook a subgroup analysis of FEV1 by background medication ( Figure 8 ). In studies where the background medication was oxygen only or no additional medication other than the study drug, the control drugs performed better than theophylline ( p<0.00001). Conversely, where patients were given bronchodilators with or without steroids, there was no significant differences between theophylline and control. Removal of the two studies comparing theophylline with placebo did not change the outcome.

Subgroup analysis: age of participants

As mentioned earlier, approximately two-thirds of the studies were conducted in adults, with one-third in children. In order to determine whether children responded differently to theophylline compared with adults, we intended to undertake a subgroup meta-analysis of FEV1 and PEFR by the age of participants. Unfortunately, these outcomes were rarely reported in children, as younger people can have great difficulty performing the necessary tests. Instead, we did a subgroup meta-analysis of symptom scores by age ( Figure 9 ). We found that there was no significant difference between adults and children in terms of symptoms ( p=0.38).

Subgroup analysis: blinded vs unblinded studies

In order to determine if blinding had any effect on the primary outcome (FEV1), we conducted a subgroup analysis of blinded vs unblinded studies. Studies that did not mention blinding were regarded as "unblinded". We found a slightly decreased efficacy for theophylline compared with controls in unblinded studies ( Figure 10 ), although the difference between blinded and unblinded studies was not significant ( p=0.18). Removal of placebo-controlled trials from the analysis did not change the results (data not shown).

Adverse events

Fortunately, many studies reported on adverse events ( Figure 11 ). Compared with placebo, IV theophylline caused more nausea, vomiting, and cardiovascular adverse events (such as palpitations and arrhythmias) ( Figure 11A ). There were no differences in abdominal pain, psychological side effects, headaches, seizures, or tremor. Compared with active comparators ( Figure 11B ), theophylline again caused more nausea and vomiting, but was not different from the active controls in terms of the frequency of psychological side effects, headaches, cardiovascular adverse events, tremor, CPK/CK elevation, or glucosuria/hyperglycemia.

Publication bias

In order to test for publication bias, we created funnel plots ( Figure 12 ). The funnel plot for FEV1 ( Figure 12A ) did not show significant asymmetry. This was true also for PEFR ( Figure 12B ), symptom scores ( Figure 12C ), or heart rate ( Figure 12D ).

Discussion

Our study has comprehensively reviewed the combined evidence for the efficacy and safety of IV theophylline in acute asthma. We found that theophylline somewhat reduced the heart rate and duration of stay, and was not significantly worse than adrenaline, beta-2 agonists, and leukotriene receptor antagonists. Furthermore, apart from an increase in nausea and vomiting, side effects from theophylline were not significantly different from other treatment regimes. That is, although theophylline was not clinically superior to other treatments, it was not significantly worse either.

However, of great importance was our subgroup analysis of FEV1 by the background medication given to patients ( Figure 8 ). Where the patients were given no medication, or oxygen alone, theophylline was inferior to subcutaneous epinephrine 15, 19, 30 and nebulized isoproterenol. 19, 30 However, in almost all circumstances, patients admitted to an emergency department for an acute asthma exacerbation are given nebulized beta-2 agonists and IV corticosteroids. 57- 59 If these treatments fail, additional treatments are then considered. Our data show that in the context of usual emergency department treatment, IV theophylline is at least as effective as montelukast 28 and IV salbutamol. 23, 34

Existing studies on theophylline point to inconsistencies. For example, Neame et al attempted to determine if salbutamol or theophylline should be used for acute severe asthma in children. 60 Despite a systematic search for articles, their qualitative analysis failed to draw any conclusions, due to "minimal and inconsistent" evidence.

A retrospective case-control study suggested that administration of theophylline increased hospital stay, compared with inhaled beta-2 agonists and corticosteroids. 61 A meta-analysis by Mitra et al found that, in children, addition of theophylline to nebulized short-acting beta-2 agonists and systemic steroids resulted in better lung function in the first 6 hours of treatment. 62 However, Mitra et al did not investigate the addition of other drugs to the same background therapy.

In contrast, a more recent meta-analysis analyzed trials directly comparing IV beta-2 agonists with IV theophylline in the treatment of acute asthma. 63 In this meta-analysis, Travers et al found no significant differences between IV beta-2 agonists and IV theophylline added to normal treatment in terms of hospital stay, PEFR, FEV1, heart rate, or clinical failure. In addition, Nair et al found that adding IV theophylline to inhaled beta-2 agonists did not provide additional benefit in adults with acute asthma. 64 None of these meta-analyses specifically investigated the role of background medication in the efficacy of theophylline, compared with other additional medications.

Recent data from the UK suggest that, at least in children, theophylline was the third most commonly administered drug in an acute setting, after salbutamol and magnesium sulfate. 65 However, different drugs, especially new, branded formulations of drugs, may differ in cost by a large degree. Indeed, a 2005 study included hospital cost in their analysis. 52 They found that treating their patients with theophylline was as effective as terbutaline, and the total treatment costs were less than a tenth of those with terbutaline.

Limitations of this analysis

We were fortunate to find a significant body of evidence testing the efficacy of theophylline. However, because asthma outcomes can be measured in a large number of different ways, we were limited in the investigations we could carry out. For example, we had planned to do meta-regression, but we felt there were insufficient studies in any one outcome to create a meaningful interpretation of the data. 8

Conclusion

Our data show that IV theophylline is superior to other treatments with regard to heart rate and duration of hospital stay, and equal to other treatments for almost all our other reported outcomes. Given the very low cost and similar safety profile of theophylline, it must surely be considered a cost-effective treatment for acute asthma exacerbations, especially for developing countries with restricted health budgets.

Acknowledgments

This study was supported by The Xinjiang Uygur Autonomous Region Natural Science Foundation Funded Projects (number: 2017D01C251).

Footnotes

Author contributions
GM developed and designed the concept for the systematic review and meta-analysis; she wrote the initial draft, did interpretation of the analyzed results, and finalized the manuscript. HZ, JL, NT, and LR did literature search, data collection, extraction, and analysis. GM, HZ, JL, NT, and LR wrote different sections of the manuscript. GM did the critical revision of the intellectual content of the article. All authors read and approved the final version of the manuscript.
Disclosure
The authors report no conflicts of interest in this work.

References

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Articles from Drug Design, Development and Therapy are provided here courtesy of Dove Press

# data[].attributes.attachment_link.title
Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis

# data[].attributes.attachment_link.description
Theophylline has been used for decades to treat both acute and chronic asthma. Despite its longevity in the practitioner's formulary, no detailed meta-analysis has been performed to determine the conditions, including concomitant medications, under which theophylline should be used for acute exacerbations of asthma.

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TITULO: Budesonida / Formoterol Antiinflamatorio y mantenimiento o propionato de fluticasona / salmeterol más agonista β 2 de acción corta según sea necesario: Estudio de eficacia en el mundo real en pacientes sin asma óptimamente controlada (REACT).
TIPO DE ESTUDIO Y AÑO: Ensayo clínico-2020

OBJETIVO: comparar la eficacia en el mundo real del mitigador y mantenimiento terapia antiinflamatoria con budesonida / formoterol (Symbicort ® Turbuhaler) y la terapia de mantenimiento con fijo de la dosis de fluticasona / salmeterol (Seretide ® ) más según sea necesario, de acción corta β ₂ agonistas (Sabas) en pacientes taiwaneses con el control del asma inadecuada.

RESULTADOS: Las puntuaciones de ACQ-5 mejoraron significativamente desde el inicio (es decir, disminuyeron) en ambos grupos en las semanas 4 y 16. Las puntuaciones de diferencia de ACQ-5 fueron significativamente más bajas en el grupo de budesonida / formoterol (−0,91 ± 1,11) que en el grupo de fluticasona / salmeterol (- 0,69 ± 1,27) al final del estudio (p = 0,027). La tasa de flujo espiratorio máximo mejoró significativamente desde el inicio en el grupo de budesonida / formoterol pero no en el grupo de fluticasona / salmeterol al final del estudio.

CONCLUSIÓN: En conjunto, los resultados indican la eficacia en el mundo real del analgésico antiinflamatorio budesonida / formoterol y la terapia de mantenimiento es mejor que la fluticasona / salmeterol en dosis fijas más SABA según sea necesario.
https://pubmed.ncbi.nlm.nih.gov/33324041/

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Affiliations

¹ Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.

² Department of Chemical Engineering and Materials Science, Yuan-Ze University, Taoyuan, Taiwan.

³ Division of Chest Medicine, Kuang Tien General Hospital, Taichung, Taiwan.

⁴ Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.

⁵ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

⁶ Division of Clinical Research, Taichung Veterans General Hospital, Taichung, Taiwan.

⁷ Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

⁸ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

⁹ Department of Internal Medicine, E-DA Cancer Hospital and Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

¹⁰ Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

¹¹ Division of Chest Medicine, Changhua Christian Hospital, Changhua, Taiwan.

¹² School of Nursing & Graduate Institute of Nursing, China Medical University, Taichung, Taiwan.

¹³ Sleep Medicine Center, China Medical University Hospital, Taichung, Taiwan.

¹⁴ Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.

¹⁵ Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

¹⁶ Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

¹⁷ Hyperbaric Oxygen Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan.

Free PMC article

Free PMC article

Affiliations

¹ Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.

² Department of Chemical Engineering and Materials Science, Yuan-Ze University, Taoyuan, Taiwan.

³ Division of Chest Medicine, Kuang Tien General Hospital, Taichung, Taiwan.

⁴ Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.

⁵ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

⁶ Division of Clinical Research, Taichung Veterans General Hospital, Taichung, Taiwan.

⁷ Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

⁸ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

⁹ Department of Internal Medicine, E-DA Cancer Hospital and Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

¹⁰ Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

¹¹ Division of Chest Medicine, Changhua Christian Hospital, Changhua, Taiwan.

¹² School of Nursing & Graduate Institute of Nursing, China Medical University, Taichung, Taiwan.

¹³ Sleep Medicine Center, China Medical University Hospital, Taichung, Taiwan.

¹⁴ Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.

¹⁵ Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

¹⁶ Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

¹⁷ Hyperbaric Oxygen Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan.

Abstract

Introduction: In the prospective, observational, 16-week REACT study conducted between October 21, 2008 and May 12, 2011, we compared the real-world effectiveness of anti-inflammatory reliever and maintenance therapy with budesonide/formoterol (Symbicort ® Turbuhaler) and maintenance therapy with fixed-dose fluticasone/salmeterol (Seretide ®) plus as-needed, short-acting β ₂ agonists (SABAs) in Taiwanese patients with inadequate asthma control.

Methods: Asthma control was assessed using the five-item Asthma Control Questionnaire (ACQ-5) and standardized pulmonary function testing. Assessments were performed at baseline and at weeks 4-5 and 12-16. Overall, we enrolled 842 patients at 11 clinics, 723 of whom were included in analyses (budesonide/formoterol, 563.3±1.3 μg/d, n=551; fluticasone/salmeterol, 1013.8±1.4 μg/d, n=172).

Results: At baseline, 72.5% and 27.5% of all patients had "partly" and "uncontrolled" asthma, respectively. Mean±SD ACQ-5 scores were 1.54±1.06 and 1.46±1.28 in the budesonide/formoterol and fluticasone/salmeterol groups, respectively. ACQ-5 scores significantly improved from baseline (ie, decreased) in both groups at weeks 4 and 16. ACQ-5 difference scores were significantly lower in the budesonide/formoterol group (-0.91±1.11) than the fluticasone/salmeterol group (-0.69±1.27) at the end of the study (p=0.027). Peak expiratory flow rate significantly improved from baseline in the budesonide/formoterol but not the fluticasone/salmeterol group at the end of the study. Severe exacerbation rates and medical resource utilization were comparable between the budesonide/formoterol and fluticasone/salmeterol groups.

Conclusion: Collectively, results indicate the real-world effectiveness of budesonide/formoterol anti-inflammatory reliever and maintenance therapy is better than fixed-dose fluticasone/salmeterol plus as-needed SABA.

Trial registration: ClinicalTrials.gov registration number: NCT00784953.

Keywords: anti-inflammatory reliever and maintenance; budesonide/formoterol; fluticasone propionate/salmeterol; real-world.

Conflict of interest statement

The REACT study was supported by AstraZeneca Taiwan. The authors declare that there are no additional conflicts of interest.

References

Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Resp J. 2008;31(1):143-178. doi:10.1183/09031936.00138707 - DOI - PubMed

Global strategy for asthma management and prevention; 2020. Available from: https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_-.... Accessed May15, 2020.

Partridge MR, van der Molen T, Myrseth SE, Busse WW. Attitudes and actions of asthma patients on regular maintenance therapy: the Inspire study. BMC Pulm Med. 2006;6(1):13. doi:10.1186/1471-2466-6-13 - DOI - PMC - PubMed

Su N, Lin J, Chen P, et al. Evaluation of asthma control and patient's perception of asthma: findings and analysis of a nationwide questionnaire-based survey in China. J Asthma. 2013;50(8):861-870. doi:10.3109/02770903.2013.808346 - DOI - PubMed

Price D, Fletcher M, van der Molen T. Asthma control and management in 8000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014;24(1):14009. doi:10.1038/npjpcrm.2014.9 - DOI - PMC - PubMed

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adrenergic beta-2 receptor agonists / therapeutic use*

# data[].attributes.attachment_link.keywords[]
anti-inflammatory agents / therapeutic use*

# data[].attributes.attachment_link.keywords[]
fluticasone-salmeterol drug combination / therapeutic use*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Budesonide/Formoterol Anti-Inflammatory Reliever and Maintenance or Fluticasone Propionate/Salmeterol Plus As-Needed, Short-Acting β 2 Agonist: Real-World Effectiveness in pAtients without Optimally Controlled asThma (REACT) Study - PubMed

# data[].attributes.attachment_link.description
1 Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan. 2 Department of Chemical Engineering and Materials Science, Yuan-Ze University, Taoyuan, Taiwan. 3 Division of Chest Medicine, Kuang Tien General Hospital, Taichung, Taiwan. 4 Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.

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TITULO:

El salbutamol y el ipratropio por inhalación es superior al nebulizador en niños con exacerbación aguda grave del asma: ensayo clínico aleatorizado

TIPO DE ESTUDIO: ECA
AÑO: 2019
RESULTADO:  Cincuenta y dos niños recibieron MDI-SIB y 51 NEB-SIB. Después de la cuarta hora, los niños con MDI-SIB tuvieron una tasa de ingreso hospitalario significativamente menor (P = 0,003) que con NEB-SIB (5,8% frente a 27,5%, RR: 0,21 [0,06-0,69], respectivamente). De manera similar, se observó una mejora significativa en la puntuación clínica después de 60 min y un aumento en la saturación de oxígeno después de 90 min de tratamiento en el grupo MDI-SIB versus NEB-SIB (4.46 ± 0.7 vs 5.76 ± 0.65, P <0.00001; y 90.5 ± 1.7 vs 88.43 1 ± 1, P <0,00001, respectivamente).
COCNCLUSION: Incluso en las exacerbaciones graves del asma, la administración de salbutamol e ipratropio por MDI con cámara de sujeción con válvula y mascarilla junto con oxígeno mediante una cánula por separado fue más eficaz que mediante un nebulizador.

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Affiliations

¹ Division of Pediatrics, Emergency Department, Clinical Hospital, National University of Asunción, Asunción, Paraguay.

² Emergency Department, Private Childreńs Institute Asunción, Asunción, Paraguay.

³ Division of Pediatrics, Department of Pediatric Respiratory and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Randomized Controlled Trial

Affiliations

¹ Division of Pediatrics, Emergency Department, Clinical Hospital, National University of Asunción, Asunción, Paraguay.

² Emergency Department, Private Childreńs Institute Asunción, Asunción, Paraguay.

³ Division of Pediatrics, Department of Pediatric Respiratory and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Abstract

Introduction: In moderate-severe asthma exacerbation, salbutamol by inhaler (MDI) is superior to salbutamol delivered by nebulizer (NEB); however, to our knowledge, no studies in children with exclusively severe exacerbations were performed.

Objective: To compare the efficacy of salbutamol and ipratropium bromide by MDI versus by NEB in severe asthma exacerbations.

Methods: We performed a clinical trial enrolling 103 children (2-14 years of age) with severe asthma exacerbations (defined by the Pulmonary Score ≥ 7) seen at the emergency room in Asuncion, Paraguay. One group received salbutamol and ipratropium (two puff every 10 min for 2 h and then every 30 min for 2 h more) by MDI with a valved-holding chamber and mask along with oxygen by a cannula separately (MDI-SIB); and the other received nebulization with oxygen (NEB-SIB) of salbutamol and ipratropium (1 every 20 min for 2 h and then every 30 min for 2 h more). Primary outcome was the rate of hospitalization (Pulmonary Score ≥ 7) after 4 h and secondary outcome was oxygen saturation.

Results: Fifty two children received MDI-SIB and 51 NEB-SIB. After the 4th hour, children on MDI-SIB had significantly (P = 0.003) lower rate of hospital admission than on NEB-SIB (5.8% vs 27.5%, RR: 0.21 [0.06-0.69], respectively). Similarly, a significant improved clinical score after 60 min and increase in oxygen saturation after 90 min of treatment was observed in MDI-SIB versus NEB-SIB group (4.46 ± 0.7 vs 5.76 ± 0.65, P < 0.00001; and 90.5 ± 1.7 vs 88.43 1 ± 1, P < 0.00001, respectively).

Conclusion: Even in severe asthma exacerbations administration of salbutamol and ipratropium by MDI with valved-holding chamber and mask along with oxygen by a cannula separately was more effective than by a nebulizer.

Keywords: MDI; children; ipratropium; nebulizer; salbutamol; severe acute asthma.

[Paediatric Life Support].

Van de Voorde P, Turner NM, Djakow J, de Lucas N, Martinez-Mejias A, Biarent D, Bingham R, Brissaud O, Hoffmann F, Johannesdottir GB, Lauritsen T, Maconochie I. Van de Voorde P, et al. Notf Rett Med. 2021 Jun 2:1-70. doi: 10.1007/s10049-021-00887-9. Online ahead of print. Notf Rett Med. 2021. PMID: 34093080 Free PMC article. Review. German.

Asthma and COVID-19 in children - a systematic review and call for data.

Castro-Rodriguez JA, Forno E. Castro-Rodriguez JA, et al. medRxiv. 2020 May 8:2020.05.04.20090845. doi: 10.1101/2020.05.04.20090845. Preprint. medRxiv. 2020. PMID: 32511474 Free PMC article. Updated.

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bronchodilator agents / administration & dosage*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Salbutamol and ipratropium by inhaler is superior to nebulizer in children with severe acute asthma exacerbation: Randomized clinical trial - PubMed

# data[].attributes.attachment_link.description
1 Division of Pediatrics, Emergency Department, Clinical Hospital, National University of Asunción, Asunción, Paraguay. 2 Emergency Department, Private Childreńs Institute Asunción, Asunción, Paraguay. 3 Division of Pediatrics, Department of Pediatric Respiratory and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

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TÍTULO:  Corticosteroides para prevenir la recaída después de las exacerbaciones agudas del asma

AÑO Y TIPO DE ESTUDIO: 2001- METAANÁLISIS
RESULTADOS: El grupo de pacientes que recibieron corticosteroides tuvieron una menor recaída significativa en la primera semana (OR: 0,35; (IC) del 95%: 0,17, 0,73), efecto que se mantuvo durante los primeros 21 días (OR 0,33; IC del 95%: 0,13, 0,82), por lo que tuvieron una menor de betaagonistas (inhaladores).
CONCLUSIONES: Un ciclo corto de corticosteroides para usar después del alta hospitalaria reduce las posibilidades de una recaída y disminuye la necesidad de usar inhaladores sin efectos adversos importantes. El beneficio dura unas tres semanas.

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TÍTULO:

Eficacia a corto plazo de la beclometasona nebulizada en episodios de sibilancias leves a moderadas en niños en edad preescolar

Tipo de estudio: ECA.

AÑO: 2011
RESULTADOS: El porcentaje de días sin síntomas  fue significativamente mayor en el grupo de Beclometasona (54,7%) que en el grupo de placebo (40,5%; p = 0,012), con una diferencia relativa del 35%.Así mismo, la puntuación de tos también se redujo en el grupo de Beclometasona (0,11) en comparación con el grupo de placebo.
CONCLUSIÓN:
Un tratamiento de 1 semana con Beclometasona nebulizado es eficaz para aumentar los porcentaje de días sin síntomas y mejorar la tos en los niños con sibilancias, lo que proporciona una justificación clínica para el uso a corto plazo de corticosteroides inhalados en las exacerbaciones episódicas de las sibilancias en niños en edad preescolar.

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Short term efficacy of nebulized beclomethasone in mild-to-moderate wheezing episodes in pre-school children

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Few data are available on the usefulness of short term treatment with low-medium dose of inhaled corticosteroids (ICS) in pre-school children with wheezing exacerbations.To compare the efficacy of one week treatment with 400 μg b.i.d. nebulized ...

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https://pubmed.ncbi.nlm.nih.gov/32006721/
TITULO: Corticosteroides inhalados nebulizados en el tratamiento del asma en niños de 5 años o menos: una revisión sistemática y un análisis global de expertos.
TIPO DE ESTUDIO: Revisión sistemática
AÑO: 2020
RESULTADOS: Las búsquedas bibliográficas arrojaron un total de 499 artículos sobre el uso de NebCSs en el asma. Después de examinar los resúmenes de los estudios, 135 se consideraron apropiados para la revisión de texto completo.
CONCLUSIÓN: Los NebCS son eficaces para el tratamiento del asma aguda y para

mantenimiento del asma en niños de 5 años o menos. Resultados de los estudios del mundo real sugieren que la terapia nebulizada es tanto eficaz y fácil de usar. En el asma aguda, la terapia nebulizada es

ya de rutina, y la adición de NebCS mejora los resultados mientras agrega poco o ningún riesgo. En la terapia de mantenimiento, continuada los NebCS han demostrado ser eficaces en estudios clínicos. Tomado en conjunto, la evidencia de doble ciego, controlado con placebo y

ensayos controlados aleatorios se indica que los NebCS son eficaces y bien tolerados para el manejo del asma en niños pequeños.

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Affiliations

¹ Boys Town National Research Hospital, Omaha, Neb. Electronic address: Kevin.Murphy@boystown.org.

² Department of Pediatrics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.

³ Division of Allergy and Clinical Immunology, Federal University of São Paulo, São Paulo, Brazil.

⁴ Hospital Médica Sur Clinical Foundation and Hospital, Mexico City, Mexico.

⁵ Cairo University, Cairo, Egypt.

⁶ Department of Pediatrics, Moscow State University of Medicine and Dentistry named after A.I. Evdokimov Moscow, Russia.

⁷ University of Southern Denmark, Odense, Denmark; Department of Pediatrics, Kolding Hospital, Kolding, Denmark.

Free article

Free article

Affiliations

¹ Boys Town National Research Hospital, Omaha, Neb. Electronic address: Kevin.Murphy@boystown.org.

² Department of Pediatrics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.

³ Division of Allergy and Clinical Immunology, Federal University of São Paulo, São Paulo, Brazil.

⁴ Hospital Médica Sur Clinical Foundation and Hospital, Mexico City, Mexico.

⁵ Cairo University, Cairo, Egypt.

⁶ Department of Pediatrics, Moscow State University of Medicine and Dentistry named after A.I. Evdokimov Moscow, Russia.

⁷ University of Southern Denmark, Odense, Denmark; Department of Pediatrics, Kolding Hospital, Kolding, Denmark.

Abstract

Although nebulized corticosteroids (NebCSs) are a key treatment option for young children with asthma or viral-induced wheezing (VIW), there are no uniform recommendations on their best use. This systematic review aimed to clarify the role of NebCSs in children 5 years or younger for the management of acute asthma exacerbations, asthma maintenance therapy, and the treatment of VIW. Electronic databases were used to identify relevant English language articles with no date restrictions. Studies reporting efficacy data in children 5 years or younger, with a double-blind, placebo- or open-controlled, randomized design, and inclusion of 40 or more participants (no lower patient limit for VIW) were included. Ten articles on asthma exacerbation, 9 on asthma maintenance, and 7 on VIW were identified. Results showed NebCSs to be at least as efficacious as oral corticosteroids in the emergency room for the management of mild to moderate asthma exacerbations. In asthma maintenance, nebulized budesonide, the agent of focus in all trials analyzed, significantly reduced the risk of further asthma exacerbations compared with placebo, cromolyn sodium, and montelukast. Intermittent NebCS treatment of VIW was as effective as continuous daily treatment. In summary, NebCSs are effective and well tolerated in patients 5 years or younger for the management of acute and chronic asthma.

Keywords: Asthma; Asthma exacerbation; Asthma maintenance; Beclomethasone; Budesonide; Fluticasone; Inhaled corticosteroids; Nebulization; Pediatric; Viral-induced wheezing.

International expert opinion on the use of nebulization for pediatric asthma therapy during the COVID-19 pandemic.

Shen K, Hong J, El Beleidy A, Furman E, Liu H, Yin Y, Cano-Salas MDC, AlJassim FM, Al-Shammari N, Lochindarat S, Dieu Thuy NT. Shen K, et al. J Thorac Dis. 2021 Jul;13(7):3934-3947. doi: 10.21037/jtd-21-841. J Thorac Dis. 2021. PMID: 34422324 Free PMC article. Review. No abstract available.

[Paediatric Life Support].

Van de Voorde P, Turner NM, Djakow J, de Lucas N, Martinez-Mejias A, Biarent D, Bingham R, Brissaud O, Hoffmann F, Johannesdottir GB, Lauritsen T, Maconochie I. Van de Voorde P, et al. Notf Rett Med. 2021 Jun 2:1-70. doi: 10.1007/s10049-021-00887-9. Online ahead of print. Notf Rett Med. 2021. PMID: 34093080 Free PMC article. Review. German.

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adrenal cortex hormones / therapeutic use

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anti-asthmatic agents* / therapeutic use

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national center for biotechnology information

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Nebulized Inhaled Corticosteroids in Asthma Treatment in Children 5 Years or Younger: A Systematic Review and Global Expert Analysis - PubMed

# data[].attributes.attachment_link.description
Although nebulized corticosteroids (NebCSs) are a key treatment option for young children with asthma or viral-induced wheezing (VIW), there are no uniform recommendations on their best use. This systematic review aimed to clarify the role of NebCSs in children 5 years or younger for the management ...

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Título de estudio:

Antagonistas de los receptores de leucotrienos versus placebo en el tratamiento del asma en adultos y adolescentes: revisión sistemática y metaanálisis.

Autor:  Miligkos, M., Bannuru, R. R., Alkofide, H., Kher, S. R., Schmid, C. H., & Balk, E. M. (2015).

Tipo de estudio: Metaanálisis
Resultados:   De los resúmenes de 2008 que se examinaron, 50 ensayos cumplieron con los criterios de elegibilidad. Los metanálisis de efectos aleatorios de seis ensayos de monoterapia con ARLT mostraron que los ARLT reducían el riesgo de exacerbación (cociente de riesgo resumido [RR], 0,60 [IC del 95%, 0,44 a 0,81]). En cuatro ensayos de ARLT como tratamiento adicional a los corticosteroides inhalados, el RR resumido para la exacerbación fue 0,80 (IC, 0,60 a 1,07). Los antagonistas de los receptores de leucotrienos, ya sea como monoterapia o como terapia complementaria a los corticosteroides inhalados, aumentaron el FEV1, mientras que el porcentaje de FEV1 de los valores predichos mejoró solo en los ensayos de monoterapia con LTRA. Las tasas de eventos adversos fueron similares en los grupos de intervención y de comparación.
Conclusión: Los antagonistas de los receptores de leucotrienos como monoterapia mejoraron el control del asma en comparación con el placebo, pero no está claro qué pacientes tienen más probabilidades de responder al tratamiento con ARLT.
https://pubmed.ncbi.nlm.nih.gov/26390230/

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Leukotriene-receptor antagonists versus placebo in the treatment of asthma in adults and adolescents: a systematic review and meta-analysis - PubMed

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TITULO: Efectos del uso de montelukast durante el ataque agudo de sibilancias en niños en edad preescolar hospitalizados sobre la tasa de alta y la puntuación clínica del asma

TIPO DE ESTUDIO Y AÑO: ECA -2021

OBJETIVO: Investigar la seguridad y eficacia del montelukast oral además del tratamiento estándar en niños hospitalizados de entre 6 y 72 meses con ataques agudos de sibilancias recurrentes.

RESULTADOS: La duración total de la estancia hospitalaria (LOS) no fue diferente entre los grupos de montelukast y placebo (p = 0,981). No hubo diferencias estadísticamente significativas entre los dos grupos de tratamiento en términos de tiempo de alta, CAS y saturación de oxígeno (p ≥ 0,05).

CONCLUSIÓN: La adición de montelukast al tratamiento estándar en pacientes hospitalizados por ataques de sibilancias de moderados a graves no afectó la LOS ni la CAS del hospital.
https://pubmed.ncbi.nlm.nih.gov/33844890/

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Affiliations

¹ Department of Pediatric Endocrinology, Dörtçelik Children's Hospital, Bursa, Turkey.

² Department of Pediatrics, Faculty of Medicine, Atilim University, Ankara, Turkey.

³ Department of Pediatric Endocrinology, Güven Hospital, Ankara, Turkey.

Randomized Controlled Trial

Affiliations

¹ Department of Pediatric Endocrinology, Dörtçelik Children's Hospital, Bursa, Turkey.

² Department of Pediatrics, Faculty of Medicine, Atilim University, Ankara, Turkey.

³ Department of Pediatric Endocrinology, Güven Hospital, Ankara, Turkey.

Abstract

Background: In chronic asthma treatment, leukotriene receptor antagonists have been recommended, but it is not clear whether montelukast can be used in acute recurrent wheezing attacks in children.

Objective: To investigate the safety and effectiveness of oral montelukast in addition to standard treatment in hospitalized children aged between 6 and 72 months with acute recurrent wheezing attacks.

Method: One hundred patients aged between 6 and 72 months who had wheezing attacks with clinical asthma scores (CAS) ≥3 and were hospitalized were included in this randomized, double-blind, placebo-controlled, parallel-group clinical trial. All the patients included in the study were given 0.15 mg/kg (maximum 5 mg) nebulized salbutamol (8 L/min and with 100% O ₂ ) with 4 h of intervals, 1 mg/kg prednisolone (maximum 5 days), nebulized ipratropium bromide (total eight doses) with 6 h of intervals. In addition to this treatment, one group received 4 mg montelukast, and the other group received a placebo. The CAS of the patients were evaluated with 4-h intervals.

Results: Total hospital length of stay (LOS) was not different between the montelukast and placebo groups (p = 0.981). There was no statistically significant difference between the two treatment groups in terms of discharge time, CAS, and oxygen saturation (p ≥ 0.05).

Conclusion: Adding montelukast to standard treatment in patients hospitalized for moderate-to-severe wheezing attacks did not affect hospital LOS and CAS.

Keywords: acute wheezing treatment; montelukast; wheezing childhood; wheezing treatment.

Similar articles

Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: A systematic review.

Castro-Rodriguez JA, Rodriguez-Martinez CE, Ducharme FM. Castro-Rodriguez JA, et al. Pediatr Pulmonol. 2018 Dec;53(12):1670-1677. doi: 10.1002/ppul.24176. Epub 2018 Nov 5. Pediatr Pulmonol. 2018. PMID: 30394700

References

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Bateman ED , Hurd SS , Barnes PJ , et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008;31(1):143-178.

Payne DNR . Airway inflammation in children with difficult asthma: relationships with airflow limitation and persistent symptoms. Thorax. 2004;59(10):862-869.

Arakawa H , Hamasaki Y , Kohno Y , et al. Japanese guidelines for childhood asthma 2017. Allergol Int. 2017;66(2):190-204.

Pike KC , Levy ML , Moreiras J , Fleming L . Managing problematic severe asthma: beyond the guidelines. Arch Dis Child. 2018;103(4):392-397.

Reddy AP , Gupta MR . Management of asthma: the current US and European guidelines. In: Brasier A, ed. Heterogeneity in Asthma, Advances in Experimental Medicine and Biology, Vol 795. Boston, MA: Humana Press; 2014:81-103.

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leukotriene antagonists / therapeutic use

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national center for biotechnology information

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Effects of using montelukast during acute wheezing attack in hospitalized preschool children on the discharge rate and the clinical asthma score - PubMed

# data[].attributes.attachment_link.description
1 Department of Pediatric Endocrinology, Dörtçelik Children's Hospital, Bursa, Turkey. 2 Department of Pediatrics, Faculty of Medicine, Atilim University, Ankara, Turkey. 3 Department of Pediatric Endocrinology, Güven Hospital, Ankara, Turkey. Randomized Controlled Trial 1 Department of Pediatric Endocrinology, Dörtçelik Children's Hospital, Bursa, Turkey. 2 Department of Pediatrics, Faculty of Medicine, Atilim University, Ankara, Turkey.

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TÍTULO:  Combinación de bromuro de ipratropio y salbutamol en niños y adolescentes con asma: un metanálisis

TIPO DE ESTUDIO: Metanálisis

AÑO: 2021

OBJETIVO: Evaluar la eficacia y la seguridad del IB (Bromuro de ipratropio) + salbutamol en el tratamiento del asma en niños y adolescentes.

CONCLUSIÓN: IB + salbutamol puede ser más eficaz que el salbutamol solo para el tratamiento del asma en niños y adolescentes, especialmente en aquellos con exacerbación del asma grave y de moderada a grave.

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Affiliations

¹ Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

² Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

Free PMC article

Free PMC article

Affiliations

¹ Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

² Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.

Abstract

Background: A combination of ipratropium bromide (IB) and salbutamol is commonly used to treat asthma in children and adolescents; however, there has been a lack of consistency in its usage in clinical practice.

Objective: To evaluate the efficacy and safety of IB + salbutamol in the treatment of asthma in children and adolescents.

Methods: The MEDLINE, Embase, and Cochrane Library as well as other Chinese biomedical databases (including China Biological Medicine Database, Chinese National Knowledge Infrastructure, Chongqing VIP, and Wanfang Chinese language bibliographic database) were systematically searched from the earliest record date to September 2020 for randomized controlled trials in children and adolescents (≤18 years) with asthma who received IB + salbutamol or salbutamol alone. The primary outcomes included hospital admission and adverse events. A random effects model with a 95% confidence interval (CI) was used. Subgroup analysis was performed according to age, severity of asthma, and co-interventions with other asthma controllers. This study was registered with PROSPERO.

Results: Of the 1061 studies that were identified, 55 met the inclusion criteria and involved 6396 participants. IB + salbutamol significantly reduced the risk of hospital admission compared with salbutamol alone (risk ratio [RR] 0.79; 95% CI 0.66-0.95; p = 0.01; I2 = 40%). Subgroup analysis only showed significant difference in the risk of hospital admission in participants with severe asthma exacerbation (RR 0.73; 95% CI 0.60-0.88; p = 0.0009; I2 = 4%) and moderate-to-severe exacerbation (RR 0.69; 95% CI 0.50-0.96; p = 0.03; I2 = 3%). There were no significant differences in the risk of adverse events between IB + salbutamol group and salbutamol alone group (RR 1.77; 95% CI 0.63-4.98).

Conclusion: IB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. The very low to high quality of evidence indicated that future well-designed double-blind RCTs with large sample are needed for research on evaluating the effectiveness of IB + salbutamol treatment for asthma in children and adolescents.

Conflict of interest statement

The authors have declared that no competing interests exist.

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Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma.

Kirkland SW, Vandenberghe C, Voaklander B, Nikel T, Campbell S, Rowe BH. Kirkland SW, et al. Cochrane Database Syst Rev. 2017 Jan 11;1(1):CD001284. doi: 10.1002/14651858.CD001284.pub2. Cochrane Database Syst Rev. 2017. PMID: 28076656 Free PMC article. Review.

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Grant support

The author(s) received no specific funding for this work.

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national center for biotechnology information

# data[].attributes.attachment_link.title
Combination of ipratropium bromide and salbutamol in children and adolescents with asthma: A meta-analysis - PubMed

# data[].attributes.attachment_link.description
IB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. The very low to high quality of evidence indicated that future well-designed double-blind RCTs with large s ...

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Título : Terapia anticolinérgica para el asma aguda en niños
Autor : Teoh L, et al
Año : (2012)
Tipo de estudio: Metaanálsis de
ECA Terapia anticolinérgica.
para el asma aguda en niños

Número de personas : 171
niños > 2 años Anticolinérgicos

Conclusiones de los autores: En niños mayores de dos años con exacerbaciones agudas del asma, los anticolinérgicos inhalados como agentes broncodilatadores únicos fueron menos eficaces que los agonistas beta .
Los niños que recibieron anticolinérgicos solos tuvieron una probabilidad significativamente mayor de tener un fracaso del tratamiento en comparación con los que recibieron agonistas beta (2)Los fármacos anticolinérgicos inhalados por sí solos no son apropiados para su uso como agente único en niños con exacerbaciones agudas del asma.cuatro ensayos de  171 niños , con un resultado de : (odds ratio (OR) 2,27; IC del 95%: 1,08 a 4,75)

Bibliografía https://pubmed.ncbi.nlm.nih.gov/22513916/