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Chapter 4Asthma

© 2007 McGraw-Hill Higher Education. All rights reserved.

Topics

• Pathology of asthma• Lung mechanics• Gas exchange• Airflow in the lung• Convection and diffusion• Airway resistance• Breathing cycle• Pathogenesis of asthma• Bronchoactive drugs

© 2007 McGraw-Hill Higher Education. All rights reserved.

Case Study #4: Debra• 30 yr old School teacher• Asthma for 20 yrs

– Shortness of breath• Particularly in

spring–Pollen

• During exercise• Exposure to cold

air

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Case Study #4: Debra

• Main complaint: SOB– Particularly in spring

• Frequent attacks of wheezing– Cold air and exercise

provoke her asthma– Stress also provokes

asthma• Otherwise healthy

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Pathology

• Hypertrophied smooth muscle– Enhanced bronchoconstriction

• Hypertrophied mucus glands• Bronchial inflammation and edema• Mucus plugs• Coughed up sputum (non-purulent)

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Pulmonary function tests• During an attack, all

indicesof expiratory flow are reduced significantly– FEV1.0

– FEV1.0/FVC– FEF25-75%

• FVC reduced; why?• Usually responds well

to bronchodilator; why?

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• Expiratory flow-volume loops also examined– Flow rates are reduced in asthma and EILV and

EELV are increased– Compare to restrictive lung disease, where EILV

and EELV are reduced

Pulmonary function in asthma

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Pathology• During asthma

– Lung volume is increased

– FRC, TLC and RV all increased

• Due to some loss of elastic recoil and premature closure of small airways

– Due to inflammation, edema and increased smooth muscle tone

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Gas exchange• Arterial hypoxemia common

– Caused by VA/Q mismatching– Caused by uneven ventilation and also uneven blood flow, which is caused by

hypoxic pulmonary vasoconstriction in regions of the lung where ventilation is greatly reduced

• Bronchodilators may improve lung function while worsening hypoxemia (relief of VC in poorly ventilated airways)

• However, the relief given (i.e. reduced perception of breathing effort) offset the drop in PaO2 at rest

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• Principle of airflow– Through tubes

• Laminar flow: low flow rates• Transitional: as flow rates increase, at branch points,

flow is no longer linear• High flow rates: turbulence; disorganized flow

Physiology & pathophysiology

Laminar flow:

Poiseuille’s law:

V=(pπr4)/(8nl)

P=ΔP; r=radius; n=viscosity and l=length

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• In laminar flow, the gas in the middle moves twice as fast as the average velocity; the friction of the sides of a tube slow down flow in those regions; flow rate is proportional to driving pressure: P=V; gas density has NO effect under these conditions. Greater ΔP, greater V

• Turbulent flow: P=V2 in addition, gas density becomes more important here; P1-P2 is greater for a given flow as gas density increases; or greater ΔP necessary to achieve a given V as gas density increases

Physiology & pathophysiology

Whether flow is laminar or not is dependent upon the Reynolds number:

Re=(2rvd)/n

R=radius, V=velocity and d=density, n=viscosity

Turbulence likely when # exceeds 2000

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Convection and diffusion in the airways•Convective flow and it’s attendent turbulence occurs in the conducting zone

•In terminal and respiratory bronchioles gas moves primarily by diffusion

•As the total cross sectional area increases flow rate is reduced

•Because volume flow is the same and the number of airways and their combined cross-sectional area are increased

•This is okay, because the distances are short and the diffusive resistance is small

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• Airway resistance:– R=(Pmouth-PA)/flow rate– R is the ration of ΔP to V

• A: Lung volume inc during inspiration and decreases during expiration

• B: Pleural pressure falls during insp. And rises during expiration– Always negative; why?– Asymmetrical profile due to the

elastic recoil (dashed line) and changing alveolar press. So solid line is actual

• C: Flow rate: increases during insp and exp; zero at transition

• D: Alveolar pressure: mirrors flow rate

Airway resistance and pressure cycles

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• As airways divide throughout lung, they become more numerous and narrow

• Where is the greatest resistance to flow?– As R=P/Q one might think the

small airways because of the small radius

• No, it’s the medium sized airways; why?

• Laminar flow in terminal airways– P=V

• Extremely large number of small airways– Each airway has high

resistance, but since flow is spread out over sooo many airways, total resistance is small

Sites of airway resistance

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Airway resistance• Bronchial smooth muscle

– Bronchoconstriction• Reflexive; controlled by

Vagus n.; Ach causes BC, sympathetic stim causes BD

• Lung volume– Bronchial diameter inc. as

lung vol inc.– Below a certain vol

(closing vol.); resistance is so high that no flow occurs (conductance is zero)

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• Gas density and viscosity effects

• Impact the Reynold’s number and the resistance– Flow resistance increases

during diving• Inc. gas density (inc.

Reynold’s #)• Helium reduces density

– Thus, these effects are mostly in medium sized bronchi where turbulence is most likely and resistance is highest and thus, can be changed the most

Airway resistance

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• Phases of expiration and the gas content after single breath of oxygen

• Phase one: rapid, pure O2 from upper airways

• Phase 2: N2 rises rapidly, washout of anatomic DS

• Phase 3: N2 plateaus, alveolar gas coming out– Slope is a measure of

ventilatory inequality• Phase 4: onset is closing

volume of lung; end is RV

Uneven Ventilation

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Airway closure and uneven ventilation• Uneven ventilation in the lung

– Partial obstruction of an airway– Series inequality

• Dilation of peripheral air sacs– Emphysema

– Collateral ventilation• Asthma

– S lows emptying of closed units

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Pathogenesis of Asthma

• Airway hyperresponsiveness and inflammation– They are related

• Triggers– Allergens– Cold, dry air– Pollution

• Chemical mediators– Mast cells, WBCs– Histamine, Leukotrienes (and

arachidonic acid), Bradykinin, cytokines (interleukins)

– Prostaglandins, reactive oxygen species, etc.

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Bronchoactive drugs• Β-adrenergic agonists

– Two types of β receptors• β1 in heart, β2 in lung

– Stimulation of β2 receptors» Relaxes smooth muscle in bronchi» Albuterol intermediate time course» Salmeterol long acting» Work through adenylate cyclase-cAMP pathway

• Corticosteroids– Inhibit inflammatory/immune response– Enhance β-receptor expression and/or function

• Methylxanthines (caffeine breakdown products)– Theophylline or aminophylline– Bronchodilatory and anti-inflammatory effects

• Anticholinergics– Block parasympathetic system; usu in sever COPD

• Cromolyn and nedocromil– Block inflammation, possibly through mast cell stabilizing effects

• New therapies– Leukotriene anatagonists (singulair) and 5-lipoxygenase inhibitors (perhaps more effective

with allergic asthma)