Therapeutic Interventions in the Management of Severe Asthma

Mark A. Hostetler, MD, MPHEmergency Medicine & Pediatrics

The University of Chicago Pritzker School of Medicine

Outline

• Pathophysiology• Basic Approach & Aims of Treatment• Therapeutic Options• Theory, Evidence, and Limitations• Summary

Pathophysiology

• Adrenoceptor mediated bronchospasm2 Types: alpha & betaDirect Indirect

• Airway Injury & Inflammation InjuryMediators Immune dysregulation

Adrenoceptors

2 receptorscause bronchodilationmuch more prevalent, supersede number increases the smaller the airway

receptorscause bronchoconstriction relatively few

2 Adrenoceptor

Inflamm marker table 1

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

Therapeutic Options• Epinephrine

• Inhaled -agonists, multidose ipratropium• Steroids (systemic vs. inhaled)• Mg++

• Parenteral infusions (terb, theoph/aminoph)• Ketamine• Heliox• NIPPV (CPAP/BiPAP) • Leukotriene inhibitors

Format

• Theory• Evidence• Pros/Cons• Dosing & Administration

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

Cochrane Collaboration

• Systematic Reviews Gold Standard of

systematic reviews Rigorous

methodology Weighted, pooled

estimates Updated q 2yrs Multidisciplinary

Epinephrine

• Theory: + agonist

• Evidence: ? pendingSQ: historical Inhaled: no better than pure beta

• Pros/Cons: cheap, effective….CAD• Dosing & Administration

0.01mg/kg sq (max 0.3mg)

-agonist effects

• Sm muscle relaxation bronchodilation• Additional effects:

inhibition of inflammatory mediator release inhibition of smooth muscle proliferationstimulation of mucociliary transportcytoprotection of respiratory mucosaattenuation of neutrophil activation

Albuterol

• Theory: agonist• Evidence: plethora of studies• Pros/Cons: cheap, effective….tachy• Dosing & Administration:

Extreme paucity of dataDosed per kg? vs. Autodosing by VT? Is more better? Is more worse?

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

Ipratropium, multidose(Admission)

Systemic Corticosteroids

• Theory: decreased inflammation• Evidence:• Pros/Cons: cheap…immunosupression• Dosing & Administration

2mg/kg

Systemic CS(Admission)

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 ?]

Magnesium(Admission)

Inhaled Budesonide

• Theory: steroid + vasoconstrictor?

• Evidence: ?• Pros/Cons: easy … insuff data• Dosing & Administration:

0.5mg/2cc (Pulmocort) ampules Insufficient evidence to recommend

dosage

Inhaled CS(Admission)

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)

IV Beta-agonists(PEFR)

IV Beta-agonists(Clinical Failure)

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 load1mg/kg/hr infusion

IV Aminophylline(Adults-Admissions)

IV Aminophylline(Adults-Arrythmia/Palps)

IV Aminophylline(Children-ICU)

IV Aminophylline(Children-Severity Scores)

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 min1.5mg/kg/hr infusion

Heliox

• Theory: laminar/less turbulent flow• Evidence: ? • Pros/Cons: effective ? difficult, 30-40% O2

• Dosing & Administration:Bulky set-up70:30 Helium:Oxygen mix

Heliox(Admissions)

Heliox(Dyspnea scores)

Heliox (All Studies)

NIPPV: BiPAP

• Theory: Improved air exchange• Evidence: Meta-analysis • Pros/Cons: Noninvasive … bulky• Application:

“Test” for suitability with CPAP bagLabor intensive patient preparationConsider early

BiPAP

* Opens bronchioles todecrease alveolar air-trapping

BiPAP Equipment

Leukotriene Inhibitors

• Theory:decreased inflammatory mediators

• Evidence: effective, but IV use in ED ?• Pros/Cons: alternate … new, expensive• Dosing & Administration:

insufficient data

Leukotriene inhibitors(Asthma Symptom Score)

Summary of Evidence OR

(Adm) % PEFR

Notes

Steroids 0.50 (0.31-0.81)

NNT 5

Multi IB 0.75 (0.62-0.89)

9.7% (5.7-13.7)

NNT 7-11

Magnesium 0.10 (0.04-0.27)

9.8% (3.8-15.8)

Inhaled CS 0.45 (0.18-1.14)

8% (3-13%)

IV Aminoph (Adults)

0.58 (0.3-1.1)

2.3% @ 12hrs 6.4% @ 24hrs

Adverse Rxns OR 2.9-4.2

IV Aminoph (Children)

8.4% FEV1 SevScore –0.7

Adverse Rxns OR 2.2-6.3

IV Terb - 24.7% (2.9- -52.3)

Clin Failure OR 1.3

* Still missing: Levalbuterol, Formoterol, Inhaled Mg, Lidocaine, Ketamine, IV LT inhibitors

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”