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ASTHMA MANAGEMENT

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EVIDENCE BASE MEDICINE
By : Parhusip RS, Sadarita S
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Evidence Medicine
Definition : Phylosophical Study of Clinical Thinking

Problem-Based Problem-Based Learning Learning

Evidence-Based Evidence-Based Medicine Medicine

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Caracteristic :
1. 2. 3. Conscientious Explicit Judicious

E B M

P B L

DECISION IN CLINICAL PRACTISE

OUTCOMES: 1. Diagnosis test 2. Treatment strategies 3. Quality of care 4. Medical economic

 Origins : Integrating of :

Individual Clinical Expertise

The Best External Evidence

Outcomes

Types : Evidence-based (research Design)

1. Bibliography data base 2. CD-Room Recent article

I. Research design II. Clinical trials III. Randomized controlled trials IV. Met analysis V. Cohort studies VI. Case-control studies

1. By Estimating Probabilities 2. Applying statistical tools

Level of Evidence
Level 1 : Trial Multi Control Study Single Level 2 : Variety quash-experimental studies Level 3 : Correlative descriptive study
Evaluation Synthesis Analysis Application Understanding Knowledge-review
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Definition of Asthma
Episodic attacks of wheezing, breathlessness, chest tightness, and cough Chronic airway inflammation Hyper responsive airways react to various stimuli or triggers Obstructed airways and limited airflow (bronchoconstriction, mucus plugs)
NIH/NHLBI. Global Initiative for Asthma. Bethesda, Md: 1998, NIH Publication No. 96-3659B; NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997, NIH Publication No. 97-4051; NIH/NHLBI. International Consensus Report on Diagnosis and Treatment of Asthma. Bethesda, Md: 1992, NIH Publication No. 92-3091 9

Definition of Asthma
Many cells and cellular elements play role, including mast cells, eosinophils, neutrophils, T-lymphocytes, and epithelial cells Airflow obstruction reversible Requires long-term management

NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997, NIH Publication No. 974051; NIH/NHLBI. International Consensus Report on Diagnosis and Treatment of Asthma. Bethesda, Md: 1992, NIH Publication No. 92-3091

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Asthma in USA: Morbidity and Mortality

15 million asthmatic patients 6% prevalence

75% increase in last 15 yr

466,000 hospitalizations 2 million emergency department visits

5000 deaths
$11.3 billion healthcare costs

Mannino DM et al. Mor Mortal Wkly Rep. 1998;47(suppl 1):1; US Department of Health and Human Services/HHS Fact Sheet. Available at: http://www.os.dhhs.gov/news/press/2001pres/01fsasthma.html. Accessed February 21, 2001

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Impact of Asthma on Quality of Life

Unscheduled ED visits in past yr Limited sports/recreation Missed school in past yr Missed work in past yr Sleep disruption once/wk

23 48 49 25 30

0
N=2509

10

20

30

40

50

60

Patients (%)
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Rickard KA, Stempel DA. J Allergy Clin Immunol. 1999;103(1 pt 2):S171

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Acute Exacerbation of Asthma

Initial Assessment Initial Treatment Assess Response

Good Response

Moderate Exacerbation

Severe Exacerbation

2-agonist Double inhaled steroid dose 10 days or begin medium to high dose inhaled steroid Consider oral steroid taper Consider home PF meter Physician follow-up

Repeat Assessment in 13 hr

Good Response

Incomplete Response

Poor Response Admit to Intensive Care Unit Consider intubation and mechanical ventilation for Continued deterioration Clinical signs of fatigue Rising PCO2 despite therapy pH <7.25; respirations >35

Admit to Hospital

Reassessment: PF, clinical exam Continue 2-agonist, Glucocorticoids until improved Patient education Good Response Poor Response

NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997, NIH Publication No. 97-4051; NIH/NHLBI. International Consensus Report on Diagnosis and Treatment of Asthma. Bethesda, Md: 1992, NIH Publication No. 92-3091; Manthous CA. Am J Med. 1995;99:298

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Asthma Inflammatory Process

Allergen Exposure
Inflammatory mediators released

Glucocorticoids
Block activation of this pathway

Arachidonic acid Cyclooxygenase Lipoxygenase Chemotactic factors Platelet-activating factor (PAF) Histamine Prostaglandins Leukotrienes

Bronchoconstriction

Increased mucus secretion

Decreased mucus clearance

Chemotaxis

Increased vascular permeability

Symptoms of Asthma
Schleimer RP. American Review of Respiratory Disease. 1990;141(2 pt 2):S59

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Asthma Pathophysiology
Smooth Muscle Dysfunction Airway Inflammation

Bronchoconstriction Bronchial hyperreactivity Hypertrophy/hyperplasia Inflammatory mediator release

Inflammatory cell infiltration/ activation

Mucosal edema
Cellular proliferation Epithelial damage
Basement membrane thickening

Symptoms/Exacerbations
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CLASSIFICATION :

Stepwise Approach to Asthma Management

Classify Severity of Clinical Features Before Treatment

Daytime
Symptoms
ARF / RF SA / LTA

Nighttime Symptoms

Step 4
Severe persistent

Continuous; limited physical activity Daily; use 2-agonist daily, attacks affect activity once/wk but once/d < once/wk; asymptomatic and normal PEF between attacks

Frequent > once/wk > twice/mo twice/mo

Step 3
Moderate persistent

Step 2
Mild persistent

Step 1
Intermittent

NIH/NHLBI. Global Initiative for Asthma. Bethesda, Md: 1998, NIH Publication No. 96-3659B

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Diagnosis
Anamnesis
FD Laboratories

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Diffrential Diagnosis
I. Upper & Lower airway disorders 1. Vocal cord paralysis 2. Vocal cord dysfunction syndrome 3. Foreign body aspiration 4. Laryngo tracheal masses 5. Tracheal narrowing 6. Tracheomalacia 7. Airway edema : - angio edema - inhalation injury
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II.

Lower airway disorders, non asthmatic

1. 2. 3. 4. 5. 6. COPD (chronic bronchitis or emphysema) Bronchiectasis Allergic bronchopulmonary-mycosis Cystic fibrosis Eosinophilic pneumonia Bronchiolitis obliterans

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III. Systematic vasculitides

Chrurg-strauss syndrome & other systemic vasculitides.

IV. Psychiatric causes

1. 2. Conversion disorders Emotional laryngeal wheezing

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Complication :
1. 2. 3. 4. 5. 6. 7. Exhaustion Dehydration Airway infection Cor pulmonale Tussive syncope Pneuomothorax Respiratory failure (acute hypercapnia & hypoxic)

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Management
Phylosophies : GOAL

Why : - Consensus - Control - Result - The AIRE study (n-2803)

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 Non Medicament : Education Medicament Corticosteroid / non corticosteroid Adrenegic agents Anti cholinergic agents Mucoactive agents Anti infective agents Exogenous surfactants

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Progression of Pharmacologic Therapy in Asthma

Mild Intermittent PRN 2-agonists

Mild Persistent Moderate Persistent Severe

Antiinflammatory therapy Inhaled glucocorticoids Cromolyn/nedocromil (for patients <12 yr)

High-dose inhaled glucocorticoids Long-acting bronchodilator

Oral glucocorticoids Other experimental therapies

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NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997, NIH Publication No. 97-4051

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Acute Care
Why do we still have a problem?
Morbidity and mortality Lack of compliance Underaccess to care

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Effectiveness of Systemic Steroids for Acute Treatment of Asthma

How soon?
How soon do they work? Are they useful in ED setting? How much? How long?

Which route?
Which steroids?

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Methylprednisolone in Emergency Treatment of Asthma

97 asthmatics Mean age 3233 yr Methylprednisolone (125 mg IV) vs placebo Followed through ED discharge (112.5 hr) Conclusions
Decreased hospitalizations Improved symptom scores (0.68 steroid vs 1.02 control on 03 scale)
Adapted with permission from Littenberg B, Gluck EH. N Engl J Med. 1986;314:150

70 60 50 40 30 20 10 0

P=0.07

Control Steroid
P<0.003

FEV1 Hospital (Mean Predicted) Admission Rate

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Meta-analysis: Methylprednisolone Dosing in Acute Asthma

9 trials with 344 patients Low dose: equivalent of <80 mg/d methylprednisolone Medium dose: equivalent of 80160 mg/d methylprednisolone High dose: equivalent of >360 mg/d methylprednisolone

Manser R et al. In: The Cochrane Database of Systematic Reviews. Oxford: Update Software; 2001 (4):1

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How Long Should Systemic Steroids Be Given After Acute Exacerbation?

Studies limited in number and power
Meta-analysis shows significantly fewer patients relapse after 710 days of systemic steroids

Patients given IV glucocorticoids should continue oral systemic glucocorticoids for 310 days
Taper not needed with inhaled steroids

NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997, NIH Publication No. 97-4051

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Short-Term Glucocorticoid Therapy in Patients With Acute Bronchial Asthma

76 asthmatics (1545 yr) discharged from emergency department

Methylprednisolone (4 mg/kg IV bolus), followed by 8-day taper starting at 32 mg bid vs placebo

Outcome variables Relapse Symptoms
Fiel SB et al. Am J Med. 1983;75:259

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Which Route?
Inhalation Oral Intravenous Intramuscular After acute exacerbation

Chronic steroid-dependent asthma

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Methylprednisolone vs Prednisolone: Lung Penetration

BALF Concentration (ng Glucocorticoid/g Urea)

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Methylprednisolone r=0.95 (P<0.001)

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Prednisolone r=0.54 (P<0.05)

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Plasma Concentration (ng Glucocorticoid/gUrea)

Adapted with permission from Vichyanond P et al. J Allergy Clin Immunol. 1989;84;867

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Methylprednisolone vs Prednisolone: Pharmacokinetics

Single and multiple oral doses for 3 days in 24 men
Methylprednisolone 180 mg Prednisolone 1.25100 mg

Methylprednisolone (pharmacokinetics more predictable)

Linear pharmacokinetics No apparent dose or time dependency Concentrations proportional to dose Plasma protein determination not necessary

Prednisolone
No linear pharmacokinetics Dose and time dependency
Rohatagi S et al. J Clin Pharmacol. 1997;37:916

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Acute Exacerbation of Asthma

Glucocorticoids: Recommended minimum dose of methylprednisolone 120180 mg/d divided q68hr 48 hr, then 6080 mg/d until PF 70% of predicted personal best Epinephrine: 0.3 mg of 1:1000 dilution SC q20min 3 doses

NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997, NIH Publication No. 97-4051; NIH/NHLBI. International Consensus Report on Diagnosis and Treatment of Asthma. Bethesda, Md: 1992, NIH Publication No. 92-3091; Manthous CA. Am J Med. 1995;99:298

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