1. Therapeutic Interventions in the Management of Severe Asthma Mark A. Hostetler, MD, MPH Emergency Medicine & Pediatrics The University of Chicago Pritzker School of Medicine

2. Outline Pathophysiology Basic Approach & Aims of Treatment Therapeutic Options Theory, Evidence, and Limitations Summary

4. Pathophysiology Adrenoceptor mediated bronchospasm 2 Types: alpha & beta Direct Indirect Airway Injury & Inflammation Injury Mediators Immune dysregulation

5. Adrenoceptors  2 receptors cause bronchodilation much more prevalent, supersede  number increases the smaller the airway  receptors cause bronchoconstriction relatively few

6.  2 Adrenoceptor

9. Inflamm marker table 1

11. Basic Approach 2 Issues  -receptor mediated bronchoconstriction Complex inflammatory/allergic response 2 Goals Acute (quick) relief Healing/reverse of inflammatory/allergic response Requires a comprehensive approach from multiple directions

12. Therapeutic Options Epinephrine Inhaled  -agonists, multidose ipratropium Steroids (systemic vs. inhaled) Mg ++ Parenteral infusions (terb, theoph/aminoph) Ketamine Heliox NIPPV (CPAP/BiPAP) Leukotriene inhibitors

13. Format Theory Evidence Pros/Cons Dosing & Administration

14. Evidence & Limitations Well, at “the Mecca”….I was always taught…. I’ve reviewed the literature… Where’s the data? Evidence-based? Problem: Outcome-based, single intervention, Megatrials often lacking for severe asthma

15. Cochrane Collaboration Systematic Reviews Gold Standard of systematic reviews Rigorous methodology Weighted, pooled estimates Updated q 2yrs Multidisciplinary

16. Epinephrine Theory:  +  agonist Evidence: ? pending SQ: historical Inhaled: no better than pure beta Pros/Cons: cheap, effective….CAD Dosing & Administration 0.01mg/kg sq (max 0.3mg)

17.  -agonist effects Sm muscle relaxation  bronchodilation Additional effects: inhibition of inflammatory mediator release inhibition of smooth muscle proliferation stimulation of mucociliary transport cytoprotection of respiratory mucosa attenuation of neutrophil activation

18. Albuterol Theory:  agonist Evidence: plethora of studies Pros/Cons: cheap, effective….tachy Dosing & Administration: Extreme paucity of data Dosed per kg? vs. Autodosing by V T ? Is more better? Is more worse?

19. Ipratropium (multidose) Theory: inhibits parasympathetic mediated bronchochonstriction may inhibit the cholinergic effects of S-albuterol ? Evidence: Pros/Cons: cheap, effective…none Dosing & Administration 0.5mg/dose x 3 in first hour

20. Ipratropium, multidose (Admission)

21. Systemic Corticosteroids Theory: decreased inflammation Evidence: Pros/Cons: cheap…immunosupression Dosing & Administration 2mg/kg

22. Systemic CS (Admission)

23. Magnesium Theory: inhibits Ca-mediated smooth muscle constriction inhibits release of acetylcholine potentiates effects of  -agonists inhibits degranulation of mast cells Evidence: Pros/Cons: cheap…painful, separate IV Dosing & Administration: 50-75mg/kg (2g-4g max) [+15mg/kg/hr infusion ?]

24. Magnesium (Admission)

25. Inhaled Budesonide Theory: steroid + vasoconstrictor? Evidence: ? Pros/Cons: easy … insuff data Dosing & Administration: 0.5mg/2cc (Pulmocort  ) ampules Insufficient evidence to recommend dosage

26. Inhaled CS (Admission)

27. Terbutaline Theory:  -agonist Evidence: ? Pros/Cons: cheap, but... Dosing & Administration: 10 mcg/kg load over 5min (max 0.3mg) 1 mcg/kg/min infusion (titrated 0.4-6mcg/kg/min)

28. IV Beta-agonists (PEFR)

29. IV Beta-agonists (Clinical Failure)

30. Methylxanthines Theory: phosphodiesterase inhibitors enhances mucociliary & diaphragm fxn inhibits release of inflamm mediators Evidence: ? Pros/Cons: cheap...toxicity/maintenance Newer agents more effective? Aminophylline Dosing & Administration: 6mg/kg load 1mg/kg/hr infusion

31. IV Aminophylline (Adults-Admissions)

32. IV Aminophylline (Adults-Arrythmia/Palps)

33. IV Aminophylline (Children-ICU)

34. IV Aminophylline (Children-Severity Scores)

35. Ketamine Theory: decr intracellular Ca ++ VOCC/ROCC (Voltage vs. Receptor operated Ca ++ channel) Neurally-mediated (vagolytic vs. sympathomimetic) Evidence: not much Pros/Cons: cheap…inexperience, behavior Dosing & Administration: 0.5-1mg/kg load (50mg max) over 2 min 1.5mg/kg/hr infusion

36. Heliox Theory: laminar/less turbulent flow Evidence: ? Pros/Cons: effective ? difficult, 30-40% O 2 Dosing & Administration: Bulky set-up 70:30 Helium:Oxygen mix

37. Heliox (Admissions)

38. Heliox (Dyspnea scores)

39. Heliox (All Studies)

40. NIPPV: BiPAP Theory: Improved air exchange Evidence: Meta-analysis Pros/Cons: Noninvasive … bulky Application: “Test” for suitability with CPAP bag Labor intensive patient preparation Consider early

41. BiPAP * Opens bronchioles to decrease alveolar air-trapping

42. BiPAP Equipment

43. Leukotriene Inhibitors Theory: decreased inflammatory mediators Evidence: effective, but IV use in ED ? Pros/Cons: alternate … new, expensive Dosing & Administration: insufficient data

44. Leukotriene inhibitors (Asthma Symptom Score)

45. Summary of Evidence * Still missing: Levalbuterol, Formoterol, Inhaled Mg, Lidocaine, Ketamine, IV LT inhibitors

46. Summary Best Practice: Standardized assessment and treatment – continuous vs intermittent treatments 1) Consider Epi for very severe 2) Albuterol, multidose IB, Steroids 3) Magnesium 4) Consider Terbutaline, (Aminoph), Heliox, Ketamine 5) Tincture of time … NIPPV … intubate as “last resort”