Treatment of Acute Asthma: Beyond B-Agonists and Steroids

1. Treatment of Acute Asthma: Beyond B-Agonists and Steroids by Nicholas Kallay

2. ED Management of Asthma Exacerbation * Adapted from Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Fig 3-11

3. B-agonists Corticosteroids Oxygen Intubation & Mechanical Ventilation Methylxanthines Ipratropium Bromide BiPAP Heliox MgSO4 Infusion Mucolytics Chest Physical Therapy Aggressive Hydration Antibiotics Inhalational Anesthetics ECMO Inhalational Furosemide Inhalational MgSO4 Potential Treatments for Acute Asthma

4. Methylxanthines (Theophylline) • Used for over 50 years to treat asthma • Poorly understood mechanism of action • Physiologic effects thought to include bronchodilation, stimulation of diaphragmatic contractility, mucocilliary clearance, and possibly some anti-inflammatory effect. • Dose related toxicities include nausea, vomiting, headache, CNS stimulation, seizure, hematemasis, hyperglycemia, and hypokalemia

5. Rossing and Associates Effect on FEV1 • 48 patients randomized to 60 min of epinephrine SQ, isoproterenol neb, or aminophylline • All groups showed improvement, but aminophylline significantly less • strengths: randomized, treatment groups similar • weakness: not blinded FEV1 (l) Time (min) * Adapted from Amer Rev Respir Dis 1980. 122: 365-371. Fig 2

6. Carlos and Gustavo Rodrigo Side Effects Reported at End of Trial • 94 patients treated 2 hours with salbutamol MDI, hydrocortisone, and aminophylline or placebo • No significant difference in PFT’s, ED treatment times or rate of admission • Increased incidence of side effects in aminophylline group • Strengths: randomized, double-blind, placebo controlled, adequate sample size % ofPatients * Adapted form Chest 1994. 106: 1071-1076. Fig 2

7. Corroborating Studies and a Caveat • Several other studies, including those by Fanta, Murphy, and Siegel have shown similar results • Of note: these studies were done at presentation in the ED • Some studies, such as by Huang, suggest benefits of theophylline after admission

8. Bottom Line on Methylxanthines • Guidelines published by the NIH report that in the ED, "theophylline/aminophylline is not recommended because it appears to provide no additional benefit to optimal inhaled B2-agonist therapy and may increase adverse effects.” • Use after admission remains controversial

9. Ipratropium Bromide • A synthetic anticholinergic compound • Anticholinergic compounds are known to cause bronchodilation • Atropine has been used, but often limited due to side effects such as tachycardia, dry mouth, disturbances of visual accommodation, etc. • Ipratropium thought to be relatively free of side effects, but with preservation of bronchodilatory properties

10. Bryant Fenoterol vs. Ipratropium • 28 patients with mild/mod asthma exacerbations • Given two drugs: at 0 and 90 minutes • 1st treatment favored B-agonist only, but 2nd treatment and final result favored combination • Strengths: randomized, controlled, double-blind • Weakness: small study FEV1 (liters) Time (minutes) * Adapted from Chest 1985. 88: 24-29

11. Ward Salbutamol vs. Ipratropium • 24 patients given hydrocortisone and salbutamol followed by salbutamol or ipratropium two hours later • Combo group with significant improvement • Strengths: randomized, controlled, double-blind • Weaknesses: small study PEFR (l/min) Time (hour) *Adapted from Br J Dis Chest 1985. 79: 374-378. Fig 1

12. 384 patients Randomized, double-blind Albuterol or albuterol / ipratropium at 0 and 45 minutes Significantly more responders in combo group at 45 min, but no significant difference after, or in other categories 342 patients Randomized, double-blind Salbutamol or salbutamol / ipratropium at 0 and 45 minutes All patients given O2 and methylprednisolone No significant differences found between groups Karpel FitzGerald

13. Ipratropium Bromide Bottom Line • Small, early studies tend to favor its use • More recent, larger studies fail to find benefit • NIH Guidelines state ipratropium “may be considered” • Given ipratropium’s relative lack of toxicity, I will probably generally use it by “shouldn’t hurt, might help” reasoning

14. Noninvasive Positive-Pressure Ventilation (BiPAP) • Literature is extensive in treatment of COPD, but sparse in treatment of acute asthma • Studies using CPAP in asthma have shown it to improve symptoms, but not gas exchange

15. BiPAP • BiPAP theoretical benefits: • Decreased work of breathing (and CO2 production) • Ameliorating large negative intrapleural pressures and accompanying potential for hemodynamic compromise • Bronchodilation with decreased airway resistance (due to “splinting” airways open with air pressure) • Improved delivery of inhalational medication • Problems include: • Discomfort with facemask and pressure apparatus • Requires very close observation by trained personnel

16. Meduri and Colleagues Results on BiPAP • 17 patients with severe asthma & hypercarbia started on BiPAP (with corticosteroids and B-agonist by nebulizer • Significant improvement in less than 2 hours • Reported well tolerated • Weakness: uncontrolled case series Time (hrs) * Adapted from Chest. 1996. 110: 767-774. Figs 1 &2

17. Pollack and Associates Modes of B-agonist Application • 100 asthmatics given 2 albuterol treatments by nebulizer or BiPAP 20 minutes apart • Significantly improved PEFR in BiPAP group • Strengths: moderate sized trial, randomized, controlled • Weaknesses: not blinded, only followed patients for brief time Mean PEFR (l/min) * Adapted from Ann Emerg Med 1995. 26: 552-557. Fig 1

18. BiPAP Bottom Line • Little evidence to guide us • Existing evidence seems to support its use • Given few known risks with an attempt, would consider BiPAP in patients refractory to conventional therapy (B-agonists and corticosteroids), or facing impending intubation

19. Magnesium Sulfate (Infused) • Mechanism of action not well understood but may inhibit bronchial smooth muscle contraction by inhibiting intracellular influx of calcium • Side effects are dose and rate related: • facial warmth, flushing, decrease in BP, sweating, nausea, emesis, CNS effects (including coma)

20. Green and Rothrock • 120 patients received steroids, albuterol inhalation and + MgSO4 2g iv over 20 minutes • No difference in ED treatment time, admissions, PEFR, or relapse rates • Strengths: prospective, randomized, relatively large sample size • Weaknesses: not blinded, ? inclusion COPD, ? adequate levels serum Mg achieved

21. Skobeloff and Colleagues Change In PEFR • 38 patients with moderate/severe asthma who failed to improve significantly in 90 min following treatment with steroids, aminophylline, and metaproterenol neb (x2) were given MgSO4 1.2g iv over 20 min • Modest but significant improvement in PEFR • Strengths: randomized, placebo controlled, double-blind • Weaknesses: small study, minimally aggressive with B-agonist PEFR, L/min Time, min * Adapted from JAMA 1989. 262:1210-1213. Fig 1

22. Bloch and Associates FEV1 Change in Severe Asthma • 135 patients treated with albuterol, steroids, + MgSO4 2g iv over 20 min • MgSO4 only benefited severe subgroup • Strength: randomized, double-blind, placebo controlled • Weakness: subgroup needed for significance Mg FEV1 (% pred) Time (minutes) * Adapted from Chest 1995. 107: 1576-1581. Fig 1

23. Is bronchodilation dose dependent? • Okayama found benefit with 2.5g MgSO4 over 20 minutes in smaller Asian patients • At least 2 case series reporting benefit with higher doses MgSO4 • MgSO4 2g iv over 2 minutes • some nausea/vomiting • MgSO4 10-20g iv over 1 hour followed by 0.4 g/hr • some patients did have mild/mod hypotention

24. Bottom Line on MgSO4 • Lower doses (2g in 20 min) well tolerated but probably only helpful in severe asthma if at all • Weak evidence that higher doses (2g in 2 min or 10-20 g in 1 hour) more effective, but side effects may be more of a problem • Doses on the order of 2g in 2 min shown to be safe in obstetrical literature

25. Heliox • As described by Gluck: “Helium-oxygen mixtures improve ventilation by reducing the Reynolds number and reducing density dependent resistance. Helium’s beneficial effects are due to its high kinematic viscosity, high binary diffusion coefficient for CO2, and high diffusivity.” • In English: Helium flows through airways more “easily” that nitrogen, decreasing work of breathing • Not thought to directly promote bronchodilation

26. Heliox: an Ethereal Treatment • Few clinical trials mostly consisting of case series, uncontrolled studies, and some pediatric literature • No “definitive” study, but seems to be a consensus in the literature supporting its use in some cases - particularly severe asthma

27. Manthous and Associates • 27 patients who presented to ED with acute asthma and did not significantly improve with 30 minutes treatment using B-agonists and steroids • Patients randomized to heliox or room air • PP, HR, RR, PEFR, and visual analog dyspnea scores measured at 30 min, 15 min into study gas, and 15 min after returning to room air • Strengths: controlled • Weaknesses: not randomized or blinded, small study, heliox group significantly greater baseline PP

28. Manthous and Associates Asthmatic PP on Air & Heliox Asthmatic PEFR on Air & Heliox Pulsus Paradoxus (mmHg) Peak Flow (lpm) Time After B-agonist (min) Time After B-agonist (min) * Adapted from Am J Respir Crit Care Med 1995. 151: 310-314. Figs1 & 3

29. Heliox Bottom Line • Little available evidence • May be helpful (at least in very severe asthma) in “buying time” until other treatments become effective • Use unlikely to cause harm unless it delays other necessary treatment such as B-agonists or necessary intubation

30. The Bottom, Bottom Line • B-agonists and corticosteroids remain the mainstay treatments for asthma exacerbation • Methylxanthines not helpful acutely, but may play a role subacutely and/or in chronic management • Ipratropium Bromide not harmful, may help • BiPAP and Heliox may spare a patient from more morbid treatments such as intubation • MgSO4 is without good evidence of benefit, but high doses may be helpful in severe asthma