Therapeutic Interventions in the Management of Severe Asthma

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. 2 Issues -receptor mediated bronchoconstriction Complex inflammatory/allergic response 2 Goals Acute (quick) relief Healing/reverse of inflammatory/allergic response Basic Approach 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. Systematic Reviews Gold Standard of systematic reviews Rigorous methodology Weighted, pooled estimates Updated q 2yrs Multidisciplinary Cochrane Collaboration

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 VT? • 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% O2 • 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”