A 19-year old female college student with a history of persistent asthma and allergic rhinitis was admitted to the student health service overnight for increased shortness of breath, wheezing, poor exercise tolerance, and nasal stuffiness. She improved after receiving oxygen, bronchodilators, and corticosteroids. The document discusses asthma pathogenesis, diagnosis, treatment including pharmacotherapy and environmental control, and goals of chronic asthma management.
2. A19-year-old female, college student with a history of persistent asthma
and perennial allergic rhinitis presents to the student health service with
complaints of increased shortness of breath, wheezing, poor exercise
tolerance, and nasal stuffiness. She is admitted for treatment overnight
and improves substantially after receiving oxygen, bronchodilators, &
corticosteroids.
– Possible factors that may have precipitated asthma?
– Information indicating presence of uncontrolled chronic asthma?
– Non-pharmacologic therapies to be considered?
– Pharmacotherapeutic regimen?
– Other concern/treatment plan?
2
3. Chronic inflammatory disorder of airways/ lung disease
– Reversible airflow obstruction
– Increase in bronchial hyperresponsiveness (BHR)
Recurrent symptoms
– Wheezing
– Breathlessness
– Chest tightness
– Coughing especially at night or early morning
3
4. Around 300 million people are affected across the world
Affects about 23 million Americans (~8.4% of population)
– Most common childhood chronic disease ( 7 million)
– Prevalence rate high 0-17 yrs old (9.5%)
– By early adulthood (30 to 70% will markedly improve/be symptom-
free)
Higher prevalence in minorities
– Urbanization
– Poor access to care
4
American Lung Association. Lung Disease Data: 2008. http://www.lungusa.org.
5. Significant burden on healthcare system
– leading cause of preventable hospitalization
– > $19 billion direct & indirect costs
Can be life-threatening if not properly managed
– Nearly 4,000 asthma deaths per year
– 80 to 90% preventable
– Education is key to prevention of death from asthma
5
NIH, National Heart, Lung, and Blood Institute. NAEPP. Full Report of the Expert Panel: Guidelines for the diagnosis and management of
asthma (EPR-3) 2007. http://www.nhlbi.nih.gov/guidelines/asthma
6. Genetic predisposition (60% to 80% of the susceptibility) +
– Atopy*
– Linked with metalloproteinase genes
– Remodeling process (e.g, ADAM33) vs asthma dev’t & disease deterioration (CHI3L1)
Environmental exposure
– Risk factors
– Socioeconomic status
– Family size
– Tobacco smoke **
– Hygiene hypothesis
6
–Allergen exposure, viral infection RSV, rhino
–Urbanization/air pollution
–Exposure to common childhood infectious agents
*significant risk factor** in utero/infancy/second hand
16. Signs & Symptoms
– Chronic asthma: dyspnea/SOB, chest tightness,
– Dry hacking cough/Coughing esp at night, wheezing/whistling sound/rhonchi
– Signs of atopy (allergic rhinitis and/or atopic dermatitis)
– FEV1/FVC > 0.75 to 0.80 in adults; >0.90 in children
– Severe acute asthma: acute respiratory distress
“Not all that wheezes is asthma ?.. “all of asthma does not wheeze’’?
16
17. Signs & Symptoms… Severe acute asthma
– Acute respiratory distress/anxious
– Severe dyspnea/SOB, chest tightness, or burning
– Only able to say a few words with each breath
– Symptoms are unresponsive to usual measures (SABA)
– Expiratory and inspiratory wheezing
17
18. – Dry hacking cough, tachypnea, tachycardia, Pale or cyanotic skin,
– Hyper-inflated chest with intercostal & supraclavicular retractions
– Hypoxic seizures ……if very severe
Laboratory
– FEV1 <40% of normal predicted values
– Decreased arterial O2 (PaO2)
– O2 saturation: <90%
– Metabolic acidosis (lactic acidosis)…. in severe obstruction
– Electrolytes, CxR
18
19. Clinical pictures
No single test can diagnose asthma
– Careful patient history
– Spirometry …….demonstrates reversible airway obstruction
Primarily…. history
– Family hx of allergy or asthma or
– Symptoms of allergic rhinitis, or atopic dermatitis
19
24. Must determine which device is best for each patient
Metered-dose inhaler (MDI)…solution/suspension
– Spacers
– Valved holding chamber (VHC)
Dry-powder inhaler (DPI)
Nebulizers
– Jet.. Small volume
– Ultrasonic
24
25. Factors Determining Lung Deposition of Aerosols
25
Device Device Factors Patient Factors
Metered-dose
inhaler (MDI)
Canister held inverted
Formulation (HFA, solution, suspension)
Actuator cleanliness
Addition of a spacer device
Inspiratory flow (slow, deep)
Breath-holding
Coordinating actuation with inhalation
Priming and shaking the device
Dry-powder
inhaler (DPI)
Device cleanliness
Resistance to inhalation
Humidity
Inspiratory flow (deep, forceful)
Tilting head back
Maintaining parallel to ground once activated
Jet nebulizer
(small
volume)
Volume fill (3–6 mL)
Gas flow (6–12 L/min)
Dead-space volume
Open versus closed system
Thumb-activating valve
Mouthpiece versus face mask
Inspiratory flow (slow, deep)
Breath-holding
Tapping nebulizer
Ultrasonic
nebulizer
Volume fill
Not effective for suspensions
Mouthpiece versus face mask
Inspiratory flow (slow, deep)
Breath-holding
Tapping nebulizer
Spacer
device
Volume (650 mL)
One-way valves
Holding chamber versus open-ended
Static vs nonstatic
Mouthpiece versus face mask
Inspiratory flow (slow, deep)
Time between actuation and inhalation (< 5 s)
Cleaning with detergent to reduce static
Multiple actuations decrease delivery
Coordination of actuation and inhalation for the
simple open-tube spacers
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 10th ed.
27. Appropriate inhalation technique is vital for optimal drug delivery and
therapeutic effect
– Up to 30% cannot master MDI technique
Rinse mouth after inhaled corticosteroids (ICS)
< 4 years old usually need to attach a face mask to the inhalation
device
27
28. 1. Remove the cap and hold inhaler upright
2. Shake the inhaler
3. Tilt your head back slightly and breathe out slowly
4. Position the inhaler
– A or B is optimal
– C is acceptable for those who have difficulty with A or B; required for
breath-activated inhalers
28
29. 5. Press down on the inhaler to release medication as you start to breath
in slowly
6. Breathe in slowly (3 to 5 seconds)
7. Hold your breath for 10 seconds to allow the medicine to reach
deeply into your lungs
8. Repeat puff as directed. Waiting 1 minute between puffs may permit
second puff to penetrate your lungs better
9. Spacers/holding chambers are useful for all patients. Recommended
for young children and older adults and for use with corticosteroids.
29DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 1th ed.
30. Avoid common inhaler mistakes
– breathe out before pressing your inhaler
– inhale slowly
– breathe in through your mouth, not your nose
– press down on your inhaler at the start of inhalation (or within the
first second of inhalation)
– keep inhaling as you press down on inhaler
– press your inhaler only once while you are inhaling (one breath for
each puff)
– make sure you breathe in evenly & deeply
Different type of inhalers require different techniques
30
34. Correct significant hypoxemia
Rapid reversal of airflow obstruction
Reduce likelihood of relapse or future recurrence of severe obstruction
Develop written action plan
34
35. Early recognition of deterioration & aggressive treatment are vital
– Patient/family education
Primary therapy
– Short-acting β2-agonist (SABA)
Additional therapy depending on severity
– Systemic corticosteroids
– Inhaled anticholinergic
– O2
35
39. Children < 4 years old may have higher risk for respiratory failure
Require use of a face mask for aerosolized medication
– Appropriate size/fit
– Reduces drug delivery to lung by 50%
• Minimal dose is recommended vs weight based dose
39
41. Treatment of choice
– most effective bronchodilator for severe acute asthma
Frequent administration
– Inhalations every 20 minutes
– Continuous nebulization
• Young children
• Unsatisfactory response to initial 3 doses of inhaled SABA
• PEF or FEV1 < 30% predicted or personal best
41
42. Mechanism: antiinflammatory
– Reduce number of mast cells & eosinophils
– Increase number of β-adrenergic receptors, improve receptor
responsiveness
– Reduce mucus production, hypersecretion
– Reduce BHR
– Reduce airway edema/exudation
42
44. Use
– Incomplete response to initial inhaled SABA doses
Continue full dose until peak flow 70% of predicted or personal best
Adverse effects dependent on dose & duration
– Short “bursts” do not cause serious toxicities
– Adrenal suppression less common with shorter-acting corticosteroids
(e.g. prednisone)
44
45. Mechanism: bronchodilator
– Competitively inhibit muscarinic receptors
– No effect on BHR
Less effective bronchodilator than β2-agonists
Not FDA approved for asthma
Available inhaled anticholinergics
– Ipratropium
– Tiotropium: studies inconclusive for use in asthma
45
46. Use
– Adjunct when incomplete response to SABA alone
Duration of action
– 4 to 8 hours
– Duration/intensity of action dose dependent
Negligible systemic effects
46
47. Emergency department
– unresponsive to standard doses of inhaled β2-agonists
– treat with IV magnesium sulfate?
Magnesium sulfate
– moderately potent bronchodilator
– adverse effects include hypotension
– some require dopamine to treat hypotension
47
48. Severe obstruction
– Response improves with ipratropium & continuous SABA nebulization
Subset analyses of 2 studies
– less hospitalizations for magnesium versus placebo in patients with severe
obstruction
– Large randomized study did not find less hospitalizations even in severe
subset
48
49. Guideline recommendations
– May consider IV magnesium sulfate in patients with severe exacerbations
& poor response to initial inhaled β2-agonists
49
50. Inhaled β2-agonists administration
– MDI plus VHC versus jet nebulization
– treatment outcomes similar
– is MDI plus VHC more cost effective?
– no studies
Thus, current practice should be based on comfort level of clinic staff
50Dolovich MB, Ahrens RC, Hess DR, et al. Device selection & outcomes of aerosol therapy: Evidence-based guidelines. Chest 2005;127:335–371.
51. Frequency dependent on exacerbation severity
– Lung function
• spirometry
• peak flow
– O2 saturation
51
52. Self management plan
– Written action plan
– Peak flow monitoring
Asthma education
– Signs, symptoms of exacerbation
– Removal, avoidance of triggers
52
54. Reduce impairment
– Prevent chronic, troublesome symptoms
– Require infrequent use (≤ 2 days a week) of inhaled SABA for quick
relief of symptoms
– Maintain (near-) normal pulmonary function
– Maintain normal activity levels
– Meet patients’ & families’ expectations of and satisfaction with care
54
55. Reduce risk
– Prevent recurrent exacerbations
– Minimize need for visits/hospitalizations
– Prevent loss of lung function
– Prevent reduced lung growth in children
– Minimal adverse effects of therapy
55
56. Environmental control
Manage comorbid conditions
Self-management skills
– Written action plans
– Recognize early signs of deterioration
Education
– Asthma, role of medications, inhalation technique, environmental
control, how to use action plan
– Reinforce every visit
56
57. National Asthma Education Prevention Program (NAEPP) recommendations
categorized by age
– 0 to 4 years
– 5 to 11 years
– ≥12 years
Stepwise approach
– Initial therapy based on asthma severity
– Therapy adjusted based on asthma control
57National Institutes of Health, National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Full Report of
the Expert Panel: Guidelines for the diagnosis and management of asthma (EPR-3) 2007. http://www.nhlbi.nih.gov/guidelines/asthma
58. Quick relief: SABA for all patients
Long-term control
– Preferred
• ICS for persistent asthma
• increased ICS dose or/and LABA for further control
– Alternatives
• No to minimal difference in efficacy between alternatives
• Cromolyn, nedocromil, leukotriene modifiers, theophylline
– Omalizumab: severe uncontrolled asthma & atopy
58
59. Classifying Asthma Severity for Patients Not Currently Taking Long-Term
Control Medications (Children 0-4 and 5-11 years)
Components Intermittent
Persistent
Mild Moderate Severe
Impairment
Symptoms ≤2 days/week >2 days/week but
not daily
Daily Throughout the
day
Nighttime awakenings
(0-4 yr)
None 1-2 times/month 2-3 times/month > Once a week
Nighttime awakenings
(5-11 yr)
≤twice/month 3-4 times/month > Once per week
but not nightly
Often 7
times/week
SABA use for
symptom control
≤2 days/week >2 days/week but
not daily
Daily Several times per
day
Interference with
normal activity
None Minor limitation Some limitation Extremely limited
Lung function (5-11 yr) FEV1 >80%
FEV1/FVC >85%
FEV1 >80%
FEV1/FVC >80%
FEV1 60-80%
FEV1/FVC 75-80%
FEV1 <60%
FEV1/FVC <75%
Risk
Exacerbations Intermittent Persistent
(0-4 yr) 0-1/year ≥2 in 6 months or ≥4 wheezing episodes/1 yr lasting >1 day
(5-11 yr) 0-2/year >2 in 1 year
Recommended step for
initiating treatment
Step 1 Step 2 Step 3 and consider short course of
systemic oral corticosteroids
59DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 10h Edition:
60. Components Intermittent
Persistent
Mild Moderate Severe
Impairment
Symptoms ≤2 days/week >2 days/week
but not daily
Daily Throughout the
day
Nighttime awakenings ≤twice/month 3-4 times/month > Once per week
but not nightly
Often 7
times/week
SABA use for symptom
control
≤2 days/week >2 days/week
but not > once
per day
Daily Several times per
day
Interference with normal
activity
None Minor limitation Some limitation Extremely limited
Lung function (Normal
FEV1/FVC: age 8-19 y
85%; 20-39 y 80%; 40-
59 y 75%; 60-80 y 70%)
FEV1 >80%
FEV1/FVC
normal
FEV1 >80%
FEV1/FVC
normal
FEV1 60-80%
FEV1/FVC reduced
5%
FEV1 <60%
FEV1/FVC
reduced > 5%
Risk
Intermittent Persistent
Exacerbations 0-2/year >2 in 1 year
Recommended step for
initiating treatment
Step 1 Step 2 Step 3 and
consider short
course of systemic
oral corticosteroids
Step 4 or 5
Classifying Asthma Severity for Patients Not Currently Taking Long-Term
Control Medications (≥12 years old)
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 10th Edition: 60
67. Young children, especially 0-4 years
– Many recommendations based on extrapolated data
– Studies of ICS show improvement
– Combination therapy inadequately studied
Elderly
– Osteoporosis risk increased with high dose ICS
Pregnancy
– Budesonide preferred ICS
– Albuterol preferred for quick relief
67
68. Use: cornerstone of chronic asthma therapy
– Improve lung function
– Reduce severe exacerbations
– Only therapy shown to reduce risk of asthma death
Low systemic activity
Response delayed for several weeks
68
70. Adverse effects dose dependent
– Systemic effects can occur at high doses
– Oropharyngeal candidiasis
– Dysphonia
Growth retardation may occur
– Dose-dependent
– Transient
– Susceptible populations
– Studies suggest reaching predicted adult height not affected
70
National Institutes of Health, National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Full Report of the
Expert Panel: Guidelines for the diagnosis and management of asthma (EPR-3) 2007
Kelly HW. Potential adverse effects of the inhaled corticosteroids. J Allergy Clin Immunol 2003;112:469–478.
71. Use: preferred adjunct/ICS combination
– Adults & most children
– Better control than increasing ICS dose alone
Not for quick relief
Provide long lasting bronchodilation (≥ 12 hrs)
Products
– Formoterol
– Salmeterol
71
72. Systemic side effects dose dependent
Not to be used as monotherapy
– Increased risk of severe, life threatening exacerbation & asthma
related death
– Preliminary data suggest concomitant ICS may prevent/decrease risk
72
Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: A comparison of usual
pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15–26.
Kelly HW. Risk versus benefit considerations for the 2-agonists. Pharmacotherapy 2006;26:164S–174S.
73. Mechanism: bronchodilation
– Non-selective phosphodiesterase inhibitor
• Isoenzyme III: airway smooth muscle
• Isoenzyme IV: inflammatory cell regulation
– Competitively inhibit adenosine
– Stimulate catecholamine release
Use declined due to risk for toxicity
– alternative/adjunct therapy
73
74. Routine serum concentration monitoring
– Significant bronchodilation by 5 mcg/mL
– Most will not have toxic symptoms when <15 mcg/mL
Much potential for interactions
– CYP-450 1A2, 3A3 metabolism
– Age dependent clearance
74
78. Mechanism
– No bronchodilatory effect
– Inhibit neurally mediated bronchoconstriction
Improvement in 1 to 2 weeks
Alternative to initial ICS therapy but not as effective
Cromolyn
– MDI or nebulizer
78
80. Mechanism: recombinant anti-IgE antibody
– Prevents binding of IgE to mast cells & basophils
• Decreases release of mediators following allergen exposure
Use
– Allergic asthma not well controlled by corticosteroids
– ≥ 12 years old
– Severe persistent asthma
80
81. Dosage/administration
– Subcutaneous every 2 to 4 weeks
– Dosage based on serum IgE level & weight
Adverse effect
– Anaphylaxis
• 70% occur within 2 hours
• May occur up to 24 hours after injection
81
82. Inhaled β2-agonists worsen asthma?
A. SABAs
– Regular administration did not worsen asthma
– Patients with β-receptor genotyped as homozygous Arg-16
– ~16% of population
– Predisposed to worsening (lower PEFs)
– Does not occur with as needed SABA use
82
Kelly HW. Risk versus benefit considerations for the β2-agonists. Pharmacotherapy 2006;26:164S–174S
83. B. Do LABAs produce the same effect?
– Unknown
– Retrospective data has not shown worsening or whether concurrent ICS is
protective
– Patients do respond to acute use of β2-agonists
– Only use SABA as needed
83
Kelly HW. Risk versus benefit considerations for the β2-agonists. Pharmacotherapy 2006;26:164S–174S
84. Regular follow up
– 1 to 6 month intervals depending on control
– 3 month interval if step down anticipated
Evaluate asthma control
– Symptoms
– Lung function
– Validated questionnaires
– Medication adverse effects
– Adherence, environmental control, comorbid condition
84
85. Asthma is a disease of increasing prevalence
– caused by genetic & environmental factors
– chronic inflammatory pulmonary disorder
No known cure or 1˚ prevention
Immuno-histopathologic features include:
– Cell infiltration by eosinophils, neutrophils, T-helper type 2
lymphocytes, mast cells, epithelial cells
85
86. Intermittent or persistent airflow obstruction
– Inflammation & bronchial smooth muscle constriction
– Persistent changes in airway structure may occur
ICs have the greatest efficacy/safety profile for long-term management
across all age groups
Bronchial smooth muscle constriction prevented/treated most effectively
with inhaled β2-adrenergic receptor agonists
86
87. Variability in response to medications requires individualization of
therapy
– use lowest dose to maintain control
Ongoing patient education for a partnership in asthma care essential for
optimal outcomes
87