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N230B: Advanced Pathophysiology.

The
CF
Foundations
Mission
Advanced Nurse Practice Program.
UCLA School of Nursing. October 21, 2015.

Mechanisms of
Pulmonary Disease
Thomas G. Keens, M.D.
Professor of Pediatrics, Physiology and Biophysics,
Keck School of Medicine of the University of Southern California.
Division of Pediatric Pulmonology and Sleep Medicine,
Childrens Hospital Los Angeles.
E-mail:

No Conflicts of Interest to Disclose

N230B: Advanced Pathophysiology.


Advanced Nurse Practice Program.
UCLA School of Nursing. October 21, 2015.

Respiratory
Physiology and
Pathophysiology

Normal Lung
Function
The maintenance
of normal arterial
oxygen tension
(Po2), carbon
dioxide tension
(Pco2), and pH,
without excessive
cardiac or
pulmonary work.

Adequate Gas Exchange

Adequate

Ventilation.

Adequate

Perfusion.

Distribution of
Ventilation.

Diffusion of O
Comroe, J.H., et al. The Lung. Year Book
Medical Publishers, Chicago, 1962.

and

CO2 across the


alveolar-capillary
membrane.

Adequate Gas Exchange

Non-uniform

Comroe, J.H., et al. The Lung. Year Book


Medical Publishers, Chicago, 1962.

distribution of
ventilation is
the most
important
cause of gas
exchange
abnormalities
in human lung
disease.

Structure of
the Lungs

Airways:

23 generations.
0-16: conducting

airways.
17-23: respiratory
bronchioles.

Alveoli:

300-500 million

Netter, F.H. Respiratory System. Volume 7, CIBA


Collection of Medical Illustrations. 1979.

alveoli.
Gas exchange
surface.

Berne, R.M., and M.N. Levy. Principles of Physiology. Mosby, St. Louis, 2000.

Berne, R.M., and M.N. Levy. Principles of Physiology. Mosby, St. Louis, 2000.

Alveoli

Site of most gas exchange.


Adults have 300-500 million
alveoli.

and CO2 exchange is by


diffusion across the alveolar
capillary membrane.
2

Thin membrane 0.5-1.0 m thick.


Berne, R.M., and M.N. Levy. Principles of Physiology. Mosby, St. Louis, 2000.

Berne, R.M., and M.N. Levy. Principles of Physiology. Mosby, St. Louis, 2000.

Tisi, G.M. Pulmonary Physiology in Clinical Medicine. Williams and Wilkins, Baltimore, 1980.

USC

UCLA

Alveolar Surface Area


of Adult Lungs

Alveolar surface area of adult lungs = 75 M2 = 90 square


yards. (1.7% [1/60th] the area of a college football field).

Comroe, J.H., et al. The Lung. Year Book Medical Publishers, Chicago, 1962.

Compensation for
Regional Hypoxia

One can not correct regional


Po2 by V/Q in another
lung region.

Thus, Po

is the most
sensitive index of the
presence of lung disease.

One can Po2 by O2


entering the hypoxic region,
by FIo2.

Tisi, G.M. Pulmonary Physiology in Clinical Medicine. Williams and Wilkins, Baltimore, 1980.

Tisi, G.M. Pulmonary Physiology in Clinical Medicine. Williams and Wilkins, Baltimore, 1980.

Typesof
of Respiratory
Respiratory Dead
Types
DeadSpace
Space

Conducting
Airways

Alveoli with
No Bloodflow

Comroe, J.H., et al. The Lung. Year Book Medical Publishers, Chicago, 1962.

Causes of Hypoxemia

Diffusion defect.
Hypoventilation.
Decreased V/Q.
Right-to-Left shunt.

Causes of Hypercapnia

Hypoventilation.
Decreased V/Q.

Distribution of Ventilation

Decreased
Compliance

Airway
Obstruction

Pulmonary Mechanics

Compliance.

Volume
Compliance =
Pressure
Resistance.
Pressure
Resistance =
Flow

Pulmonary
Compliance (CL)
of the line is
Slope
compliance.

Volume
CL =
Pressure

pressure The
volume curve of the

Tisi, G.M. Pulmonary Physiology in Clinical Medicine.


Williams and Wilkins, Baltimore, 1980.

lung is not a line,


but a loop.
Referred to as
hysteresis.

Volume
CL =
Pressure

Tisi, G.M. Pulmonary Physiology in Clinical Medicine. Williams and Wilkins, Baltimore, 1980.

Pressure
Resistance =
Flow

Comroe, J.H., et al. The Lung. Year Book Medical Publishers, Chicago, 1962.

Extrathoracic Upper Airway Obstruction

Intra Pulmonary Airway Obstruction

Tisi, G.M. Pulmonary Physiology in Clinical Medicine. Williams and Wilkins, Baltimore, 1980.

Pressure Acting
on Airways

Sasaki, H., et al. J. Appl. Physiol., 45: 858-869, 1978.

Airway Obstruction

Cherniack, R.M., et al. Respiration in Health and Disease. W.B. Saunders, Philadelphia, 1972.

Hyperinflation

Cherniack, R.M., et al. Respiration in Health and Disease. W.B. Saunders, Philadelphia, 1972.

Atelectasis

Cherniack, R.M., et al. Respiration in Health and Disease. W.B. Saunders, Philadelphia, 1972.

Airway Obstruction

Increased airway resistance.

Bronchospasm.
Airway Inflammation.
Mucous plugging.
Extrinsic compression of the airway.
Foreign body in the airway.

Decreased Elastic Recoil.

Emphysema.

Airway Inflammation
Causes airway
obstruction by:

Mucous plugging.
Increased mucous
Mucosal edema.

secretions.

Bronchospasm.

Common in:

Asthma.
Chronic

bronchitis.

Cystic

Fibrosis.

Airway Obstruction

Cherniack, R.M., et al. Respiration in Health and Disease. W.B. Saunders, Philadelphia, 1972.

Emphysema

Tisi, G.M. Pulmonary Physiology in Clinical Medicine. Williams and Wilkins, Baltimore, 1980.

Netter, F.H. Respiratory System. Volume 7, CIBA Collection of Medical Illustrations. 1979.

Lung
Apex

Lung
Base

Rest

Exercise

N230B: Advanced Pathophysiology.


Advanced Nurse Practice Program.
UCLA School of Nursing. October 21, 2015.

Pulmonary
Disorders

Pulmonary Disorders
Pneumonia.
Aspiration

pneumonia.
Influenza pneumonia.
Tuberculosis.
Pulmonary fibrosis.
Bronchiolitis.
Asthma.

Chronic bronchitis.
Emphysema.
Bronchiectasis.
Cystic fibrosis.
Pneumothorax.
Pulmonary edema.
Pulmonary
embolus.

Pneumonia

Infection of the lung.

Requires treatment
of the infection with
antibiotics.

Alveoli are filled with


infected material.

Systemic
antibiotics are
usually required.

Pneumonia

Infection may also


cause:

Bronchospasm
requiring
bronchodilators.

pulmonary
capillary
permeability
causing edema.

Normal Chest X-ray

Pneumonia

Pneumonia

Radiographic Patterns
of Lobar Infiltrates
RUL

LUL
RML

LLL
RLL

Pneumonia Caveats
Recurrent pneumonias are not normal.
Consider underlying disorders which might
predispose the patient to >2 pneumonias:
Chronic Lung Disease.
Recurrent aspiration.
Untreated asthma.
Cystic Fibrosis.
Abnormal mucociliary clearance, host
defenses, or immune deficiency,
Congenital malformations.

Aspiration
Pneumonia

Aspiration occurs

most commonly in
patients with
swallowing
dysfunction.
Elderly.

Neurologically
impaired.

Seizures.
GERD.

Aspiration Pneumonia

RML is the most common site.

1918 Influenza pandemic killed as


many as 50,000,000 people world-

Influenza Virus

Influenza Pneumonia

Influenza
Pneumonia

Annual outbreaks
in winter.

High fever, muscle


aches.

Pneumonia is the
usual cause of
death.

Antiviral agents
only partly
effective.

Tuberculosis
2,000,000 deaths per
year worldwide.

One-third of worlds

population infected.

>8,000,000 new

cases diagnosed
each year.

Multiple drug

resistant TB
emerging as a
worldwide public
health threat.

Tuberculosis (Gohn complex)

Tuberculosis (Gohn complex)

Tuberculosis

Miliary Tuberculosis

Tuberculosis: Caseating Granuloma

Tuberculosis Cavitary Lung Disease

Tuberculosis Cavitary Lung Disease

Tuberculin
Test
Tuberculin Skin
Skin Test

Diagnoses TB infection.
Positive 2-12 weeks after
infection.

Criteria for positive TST.


Induration Population (Risk)

American Academy of Pediatrics.


The Red Book. 2006.

5 mm

Immunocompromised
Contact with TB
patient.

10 mm

Risk of dissemination.
Increased exposure to
TB disease.

15 mm

No risk factors.

Tuberculin Skin Test

Diagnoses TB infection.
Positive 2-12 weeks after
infection.

Criteria for positive TST.


Induration Population (Risk)

American Academy of Pediatrics.


The Red Book. 2006.

5 mm

Immunocompromised
Contact with TB
patient.

10 mm

Risk of dissemination.
Increased exposure to
TB disease.

15 mm

No risk factors.

Interstitial Pneumonitis
and Fibrosis

If untreated, interstitial

pneumonitis progresses to
fibrosis, destroying alveolar
tissue and blood vessels
lung volumes and CL.

Patients have shortness of


breath, tachypnea, and
exercise tolerance.

May result from many types


of lung injury.

Digital Clubbing

Commonly seen in chronic lung diseases


associated with hypoxia and/or inflammation.

Pulmonary Fibrosis

Pulmonary Fibrosis

Normal Chest CT Scan

Pulmonary Fibrosis

Pulmonary Fibrosis

Interstitial Pneumonitis
and Fibrosis

Restrictive lung disease.


Treatment is that of the
underlying cause.
High dose systemic
corticosteroids suppress
active inflammation.
Other chronic medications:
Azathioprine.
Cyclophosphamide.
Hydroxychloraquine.

Bronchiolitis
Acute, life-threatening
disorder in infants.

Infectious

inflammation of
bronchioles 75-300 in
diameter.

Respiratory syncytial
virus (RSV).

Hypoxia, airway

obstruction, and
hyperinflation.

Bronchiolitis

Asthma

Most common chronic lung


disease.

15% of U.S. children.

Inhalation is the route of choice


for the administration of
medications, as it is associated
with the least side effects.

Characterized by episodes of
airway narrowing resulting from
bronchospasm and
inflammation.

Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, 2007.

Inflammation
Airway mucosal inflammation
causes swelling of the airway
lining and mucous secretion.

Release of inflammatory
mediators.

Cytokines.
Leukotrienes.
Primary target to control asthma
symptoms.

Nebulizers

Metered Dose Inhalers

Chronic Bronchitis
Chronic infection and

inflammation of the
bronchi and bronchioles.

Narrowing of airways due


to bronchospasm,
inflammation, and
infection.

Bronchiectasis: airways

lose cartilaginous
support; collect infectious
materials.
Netter, F.H. Respiratory System. Volume 7, CIBA Collection of Medical Illustrations. 1979.

Netter, F.H.
Respiratory
System. Volume
7, CIBA Collection
of Medical
Illustrations.
1979.

Chronic Bronchitis
(Blue Bloater)

Chronic Bronchitis
Treatment.

Bronchodilators to treat
bronchospasm.

Inhaled corticosteroids to
treat inflammation.

Antibiotics to treat
infection.

Supplemental O2 to treat
hypoxia.

Emphysema

Destruction of alveolar
walls.

Decreased surface area


available for gas
exchange.

Decreased elastic
support of airways.

Airway obstruction.
Severe hyperinflation
often present.

Netter, F.H. Respiratory System. Volume 7, CIBA Collection of Medical Illustrations. 1979.

Tisi, G.M. Pulmonary Physiology in Clinical Medicine. Williams and Wilkins, Baltimore, 1980.

Chest x-ray of Emphysema (Pink Puffer)

Netter, F.H. Respiratory System. Volume 7, CIBA Collection of Medical Illustrations. 1979.

Airway Obstruction in
Emphysema (Pel)

Tisi, G.M. Pulmonary Physiology in Clinical Medicine. Williams and Wilkins, Baltimore, 1980.

Emphysema
Treatment.

Bronchodilators to reverse
bronchospasm.
Corticosteroids for
inflammation.
Antibiotics to treat infection.
Diuretics and digitalis to
treat right heart failure (cor
pulmonale).

A 12-year old boy


was chewing on his
pencil eraser tip.
He accidentally
swallowed it.
He coughed for
2-months.
Did he really
swallow the eraser
tip?

Retained Foreign Body


Aspiration

Foreign body puts pressure on airway mucosa;


compromises bloodflow, and destroys airways.

Chronic infection sets in, causing further airway


destruction.

Bronchiectasis
Abnormal dilatation of
bronchi.

Involves destruction of
cartilaginous walls.

Most commonly due to


chronic infection.

Can be focal or diffuse.


Always due to an

underlying lung disease.

Bronchiectasis

Bronchiectasis

Common in chronic lung


diseases.

Cystic Fibrosis.
Primary ciliary dyskinesia.
Immune deficiencies.
Tuberculosis.

Chronic infection destroys


cartilaginous airways.

Obstructive lung disease.


Risk of massive
hemoptysis.

Woe the child who


tastes salty from
a kiss on the brow,
for he is hexed,
and soon must die.
--- Medieval German Folk Saying

Cystic Fibrosis

Most common inherited


serious exocrine
disorder in Caucasians.

Autosomal recessive.

Most serious clinical


problem and most
common cause of death
is CF lung disease.

Multiple systems
involved.

Discovery of the
Cystic Fibrosis
gene in 1989.

Cystic Fibrosis

Transmembrane
Conductance
Regulator
(CFTR) Protein.

Chloride

channel in
exocrine cells.

Rommens, J.M., et al.


Science, 245: 1059-1080, 1989.

Normal

CF

Na+
Cl-

ASL

H2O

ASL

Na+

H2O
H2O

H2O
H2O

Matsui, H., et al. Cell, 95: 1005-1015, 1998.

CF Bronchiectasis

CF Bronchiectasis

CF Bronchiectasis

CF

Cystic Fibrosis

Cystic Fibrosis
Home Pulmonary Therapy

Median Survival for CF Improves


50
40
Age (years)
30
20
10
0
1940 1950 1960 1970 1980 1990 2000 2010 2020

Pneumothorax

Pneumothorax can arise from


ruptured bullae or blebs.

Pneumothorax

Pneumothorax

Pneumothorax in an Infant

Tension Pneumothorax

Fluid Exchange in
Pulmonary Capillaries

The alveolar-capillary
membrane is porous.

Fluid exchange can


occur across the
membrane.

In the lung, fluid

should remain in the


capillary, not in the
alveolus.

What forces keep fluid


in pulmonary
capillaries?

Tisi, G.M. Pulmonary Physiology in Clinical


Medicine. Williams and Wilkins, Baltimore, 1980.

Fluid Exchange in
Pulmonary Capillaries

Capillary
Colloid
osmotic
pressure.

Alveolar
pressure.

Alveolus
Capillary

hydrostatic
pressure.

Alveolar
surface
tension.

Tisi, G.M. Pulmonary Physiology in Clinical Medicine. Williams and Wilkins, Baltimore, 1980.

Fluid Exchange in
Pulmonary Capillaries

capillary

hydrostatic
pressure pushes
fluid into alveoli,
causing pulmonary
edema.

capillary

Tisi, G.M. Pulmonary Physiology in Clinical


Medicine. Williams and Wilkins, Baltimore, 1980.

hydrostatic
pressure pushes
fluid into interstitial
space, causing stiff
lungs.

Pulmonary Lymphatics

Fluid is cleared

from the interstitial


space by
lymphatics.

Pulmonary

lymphatics drain
through the hilum
to the thoracic duct
in the superior
vena cava.

Netter, F.H. Respiratory System. Volume 7, CIBA


Collection of Medical Illustrations. 1979.

Heart Failure and


Pulmonary Edema
Left Heart Failure.

Blood backs up from the


left ventricle into the
lungs.

Increases capillary
pressure.

Right Heart Failure.

Tisi, G.M. Pulmonary Physiology in Clinical


Medicine. Williams and Wilkins, Baltimore, 1980.

Blood backs up from


the right ventricle into
systemic veins.
Thoracic duct flow.
Pulmonary fluid
clearance.

Pulmonary Embolism

Clot travels from venous


system to the lungs.

Can cause infarction of a


portion of lung.

Massive PE can occlude

most or all of pulmonary


outflow tract.

Can cause Right Heart


Failure.

Can cause sudden death.

Requires prompt diagnosis


and treatment.

Pulmonary Embolism

Deep venous thrombosis in

femoral veins is a common cause.

Other risk factors are

immobilization of legs for


prolonged periods.

Signs and Symptoms:


Cough.
Chest pain.
Dyspnea.
Hypoxia.
Treatment is anticoagulation.

Lung Response to Injury


Although we have reviewed a
number of specific lung
diseases, the lung has only a
few ways to respond to
injury.

Inflammation.
Airway obstruction,
remodeling, and
bronchiectasis.

Fibrosis.
Loss of alveoli.
Repair (return to normal

Why the Respiratory System is


the most important organ system

To know even
one life has
breathed easier
because you
have lived - that
is to have
succeeded.
Ralph Waldo Emerson
1803-1882