Management of asthma exacerbation - Alternative and future pharmacologic therapy

1. Management of asthma exacerbation- Alternative and future pharmacologic therapy Ri 吳廷郁/ VS郭順文

2. Standard/Initail management • Assessment of severity

3. Oxygen • Inhaled rapid actingβ2-agonist • Inhaled anticholinergic • Glucocorticosteroids

4. Alternative treatment • Magnesium Sulfate • Theophylline • Severe and potentially fatal side effects • Benefit as add-on treatment has not been demonstrated • Epinephrine • May be indicated for anaphylaxis and angioedema • Leukotriene modifiers • Little data to suggest a role in acute asthma

5. MgSO4 - Possible Mechanism • Not clear; can potentially effect on many pathways • Relaxation of bronchial smooth muscle • Modulation of calcium ion movement both within the cell and through transmembrane calcium channels • Decrease the amount of neurotransmitter released at motor nerve terminals • Prostaglandin-mediated vascular smooth-muscle relaxation is magnesium dependent • Decreases superoxide production in neutrophils obtained from adult asthmatics

6. Intravenous Magnesium Sulfate

7. Materials • Design: All randomized controlled trials • Population: Either children or adult presenting to an ED for treatment of acute asthma • Intervention: Randomly assigned to receive magnesium sulfate compared with placebo early • Outcomes: Admission to hospital, Pulmonary function tests, Vital signs, Side effects

9. All patients received inhaled β-agonists • Corticosteroids were routinely administered to all patients in 6 studies, and to those with the most severe asthma in the other

10. Results

11. Hospital admission • No statistically significant difference was identified • For patients within the severe asthma subgroup, lower in those treated with magnesium sulfate • No difference in mild-moderate subgroup • Both children and adults with severe asthma improved similarly

12. PEFR and % predicted FEV1 • Nonsignificant improvements in PEFR (29 L/min,) and % predicted FEV1 (4%) • Severe acute asthma, PEFR WMD improved by 52 L/min; % predicted FEV1 also improved by 10%

14. Vital signs • Heart rate and respiratory rates did not change (6 beats/min / 0 breaths/min) • Systolic BP was slightly decreased (–5 mm Hg) • Side effects • No major side effects • Minor side effects (burning at intravenous site, flushing, fatigue…) 58% of patients in one trial

15. Discussion • The pooled results failed to demonstrate statistically significant evidence of a beneficial effect of magnesium sulfate in terms of admission rates or pulmonary functions • Patients who presented with severe asthma appeared to benefit from the use of intravenous magnesium sulfate

16. Questions unanswered • Optimal dose and duration of therapy. • Needed to confirm: no effect of magnesium sulfate in mild and moderate asthma • Severity must be clearly defined • Very young children • Examine the effect of magnesium sulfate based on the prior inhaled steroid use

17. Inhaled magnesium sulfate

18. Materials • Randomized controlled trials • Either children or adult with acute asthma • MgSO4 +β2-agonist V.S.β2-agonist alone Inhaled MgSO4 V.S. β2-agonist • Outcomes: Change in pulmonary function tests, Admission to hospital, Vital signs, Side effects

19. Results • MgSO4 +β2-agonist V.S.β2-agonist alone Pulmonary function test • Overall: improved • No significant difference between the results from adults and those in children. • When compared to the mild-moderate group this difference was not significant • Significant difference in the results from the severe asthma trials

20. Admission to hospital • Overall: failed to demonstrate a clear reduction • No significant difference when formal sub-group testing was carried out between adults and children, or between severe and less severe asthma

21. MgSO4 V.S.β2-agonist Pulmonary function test • No evidence of an significant advantage • One study demonstrated a significant advantage for β2-agonist Admission to hospital • No significant difference

22. Discussion • Nebulised MgSO4 with or without β2-agonist can be safely administered to patients with acute moderate-severe asthma • Clear additive benefit with respect to pulmonary functions, particularly in patients presenting to the ED with severe asthma, when MgSO4 is administered in combination with β2-agonists

23. Heterogeneous nature of the patient populations studied, magnesium regimens, cointerventions,and outcome measurements preclude a clear recommendation on the use of inhaled MgSO4 • A trial where systemic corticosteroids,β2-agonists and anticholinergics are administered to both groups and inhaled MgSO4 or placebo is added to the treatment regimen in a double-blind manner is needed

25. GINA - Magnesium • Intravenous magnesium sulphate (Usually a single 2 g infusion over 20 minutes) • Adults with FEV1 25-30% predicted at presentation • Adults and children who fail to respond to initial treatment • Children whose FEV1 fails to improve above 60% predicted after 1 hour of care • Nebulized salbutamol administered in isotonic magnesium sulfate provides greater benefit

26. Future therapeutic targets • Target inflammatory cells such as eosinophils, mast cells, and Th2 T lymphocytes • Modulators of the actions or generation of Th2 cytokines (e.g., IL-4 and IL-5 antagonists) • Chemokine receptor (e.g., CCR3) antagonists • Inhibitors of leukocyte adhesion molecules such as very late antigen-4, or signaling pathways (c-Jun N terminal kinase and Syk kinase inhibitors)

27. References • “Global Strategy for Asthma Management and Prevention 2006” Global Initiative for Asthma • “Intravenous Magnesium Sulfate Treatment for Acute Asthma in the Emergency Department: A Systematic Review of the Literature”Ann Emerg Med. 2000 Sep;36(3):181-90. • “IV Magnesium Sulfate in the Treatment of Acute Severe Asthma* : A Multicenter Randomized Controlled Trial”Chest 2002;122;489-497 • “Inhaled magnesium sulfate in the treatment of acute asthma (Review)”Cochrane Database of Systematic Reviews 2005, Issue 4. • “Nebulized magnesium sulfate in the management of acute exacerbations of asthma”Ann Pharmacother 2006;40:1118-24. • “Current and Future Pharmacologic Therapy of Exacerbations in Chronic Obstructive Pulmonary Disease and Asthma” Proc Am Thorac Soc Vol 1. pp 136–142, 2004