X-RAY INTERPRETATION  Lower cervical and thoracic spine Lung fields

 Destructive lesions - metastases  Normally, there are visible markings

Airway  Erosion by adjacent tumor, e.g. Pancoast throughout the lungs due to the pulmonary
Posterior-anterior (PA) Bones and soft tissue
Lateral  Rib fractures arteries and veins, continuing all the way to the
Cardia - Sensitivity of CXR is less than 20% chest wall
Anterior-posterior(AP) Diaphragm
Lateral decubitus - However, when you see one look carefully  Both lungs should be scanned, starting at the
Effusions for pneumothorax, hemothorax, lung apices and working downward, comparing the
Fields (lung fields) contusion left and right lung fields at the same level
Different parts of the Gastric bubble
body absorb the x-  Shoulder dislocation
Hila and mediastinum Pulmonary fissures
rays in Impression
varying Soft tissue  Formed with visceral pleura
degrees.  Supraclavicular fossae (enlarged nodes)  R lung = major/oblique fissure + minor/horizontal
 Lateral chest wall (surgical emphysema) fissure
 Under diaphragm (pneumoperitoneum)  L lung = major/oblique fissure
 Oblique fissure more clearly seen on Lateral view
Dense bone => white Cardia from T4-T5 vertebrae to reach the diaphragm and
Soft tissue => shades of grey  2/3 on the left side of the chest 5 cm behind the costophrenic angle on left and
Air => black  1/3 on the right side of the chest just behind the angle on R
Ribs and spine => white or light gray  Should be less than 1/2 of the thoracic cavity  Horizontal fissure more clearly seen on PA view
Lung tissue => dark  Right border = right atrium extending from right hilum to 6th rib in the
axillary line.
Absorbs more= whiter Aortopulmonary window  On a PA radiograph, the minor fissure can often
Overexposure -> with greater exposure of the chest  “space” located underneath the aortic be seen as a faint horizontal line dividing RML
radiograph, the heart becomes radiolucent, and the arch and above the left pulmonary artery. from RUL.
lungs become proportionately darker. Often gives  Contains fat  The major fissure are not usually seen on a PA
the appearance of lacking lung tissue, as would be  On the PA = concave shadow view because they are being viewed obliquely.
seen in a condition such as emphysema.  If adenopathy = convex shadow
ASSESSING FOR ROTATION - Spinous Hidden area
process should be equidistant from medial ends of Diaphragm  Apex – ribs often obscure the underlying lung
both clavicles.  R hemidiaphragm is higher than the L one  Hilar vessels – obscuring lung anteriorly and
 Both should form a sharp margin with the posteriorly
Airway -> check the position of trachea which can lateral chest wall  Cardiac shadow – hiding a considerable
be pulled/pushed  Both contours should be clearly visible amount of lung posteriorly
Carina = bifurcation of the trachea medially to the spine  Lung posterior to the diaphragm- and hidden
Bones and soft tissues by the liver, stomach and spleen.
 Look at each rib in turn Effusion - The pleura and pleural spaces
 Clavicles will be visible when there is an abnormality Hilum = made up of the main pulmonary arteries
 Scapulae and humeri if visible present (pleural thickening, fluid or air in the and major bronchi; L higher than R
pleural space). Lymph nodes are NOT normally seen on X-ray
SPIROMETRY GUIDE
1. VALIDITY

➔ Proper ( e.g. at least 6 seconds )

➔ Not proper ( e.g. cought)

2. PATTERN

a. Normal – if VC or FVC are below the predicted value

(see PredLL given in the spirometry), the result is
still considered normal, as both those values need to
be below the predicted value.
b. Restrictive – if both VC & FVC values in Act1 are
below the predicted value given in the PredLL
column in the spirometry.
c. Obstructive (FEV1%M < 70 in the Act1 column)
d. Mixed (restrictive + obstructive)

3. GRADE/SEVERITY

Check FEV1 in the %(A1/P) column and see if it is:

➔ < 50% (severe)

➔ 50-70% (moderate)
➔ > 70 % (mild/ normal)

4. Bronchodilator (BD) test

response (calculate it).

➔ If there are more than 10 minutes

between spirometries it means that it is a
bronchodilator test.
➔ It is POSITIVE if:
o 𝑭𝑬𝑽𝟏 (𝒑𝒐𝒔𝒕 𝑩𝑫) − 𝑭𝑬𝑽𝟏 (𝒑𝒓𝒆 𝑩𝑫) =
(𝑣𝑎𝑙𝑢𝑒 𝑖𝑛 𝐿𝑖𝑡𝑟𝑒𝑠) 𝑋 1000 =
𝑣𝑎𝑙𝑢𝑒 𝑖𝑛 𝑚𝑙 𝑡ℎ𝑎𝑡 𝑖𝑠 ℎ𝑖𝑔ℎ𝑒𝑟 𝑡ℎ𝑎𝑛 200𝑚𝑙
𝑭𝑬𝑽𝟏 (𝒑𝒐𝒔𝒕 𝑩𝑫)− 𝑭𝑬𝑽𝟏 (𝒑𝒓𝒆 𝑩𝑫)
o x100
𝑭𝑬𝑽 𝟏 (𝒑𝒓𝒆 𝑩𝑫)
is higher than 12%
CHEST X-RAYS
What do you see?
Basal lung consolidation

•This image shows subtle

consolidation at the left lung base,
partly obscured by the heart
What do you see?
• ‘Air bronchogram’ is a characteristic sign of
consolidation – here is an example in a
patient with pneumonia

• The black lines represent patent airways

within consolidated lung (highlighted area)
What do you see?
• Another example of consolidation
with air bronchogram due to
pneumonia
What do you see?
•Consolidation may be limited to a
particular lobe of the lung

•This image shows consolidation of

the right upper lobe which is
confined inferiorly by the horizontal
fissure

•If the consolidation is due to

infection, then the term ‘lobar
pneumonia’ is correctly used

•Lobar pneumonia is usually

caused by typical organisms –
such as Streptococcus
pneumoniae
What do you see?
•The right middle lobe is located
below the horizontal fissure which
confines the area of consolidation
in this image

•The right middle lobe is also next

to the right heart border which is
obscured in this image
What do you see?
•It is possible to determine that the
consolidation in this image is in the right
lower lobe rather than the middle lobe

•The right lower lobe is located adjacent

to the right hemidiaphragm which is not
clearly visible in this image

•The right heart border is still visible

which indicates that the consolidation is
not in the middle lobe
What do you see?
•The patchy consolidation in this
image is correctly described as being
located in the right lower zone

•It is possible to determine the

consolidation is not in the right upper
lobe as it is below the anatomical
level of the horizontal fissure
What do you see?
•This image shows a large area of dense
consolidation located in the right middle
zone – air bronchogram is visible

•No single well-defined lobe is affected

•Subtle consolidation of the left lower

zone with reduced definition of the left
hemidiaphragm indicates involvement of
a small area of the left lower lobe

•The left heart border remains well-

defined indicating the consolidation is
not in the lingula – part of the left upper
lobe
What do you see?
What do you see?
 ANATOMY AND PHYSIOLOGY OF THE RESPIRATORY SYSTEM

Respiratory function anatomy

A. Structurally
 Upper respiratory system
o Nose, pharynx and associated structures
 Lower respiratory system
o Larynx, trachea, bronchi and lungs
B. Functionally
 Conducting zone - conducts air to lungs
o Nose, pharynx, larynx, trachea, bronchi,
bronchioles and terminal bronchioles
 Respiratory zone - main site of gas exchange
o Respiratory bronchioles, alveolar ducts,
alveolar sacs, and alveoli

Trachea
 Windpipe, 12cm long
 Extends from larynx to superior border of T5 where it
divides into right and left primary bronchi
 4 layers - Mucosa , Submucosa, Hyaline cartilage,
Adventitia
 16-20 C-shaped rings of hyaline cartilage stacked one
above the other
 Open part faces esophagus

Lungs
 Separated from each other by the heart
and other structures in the mediastinum
 Each lung enclosed by double-layered
pleural membrane
o Parietal pleura - lines wall of thoracic
cavity
o Visceral pleura - covers lungs
themselves
 Pleural cavity is space between layers
o Pleural fluid reduces friction, produces surface tension (stick together)
 Cardiac notch - heart makes left lung 10% smaller than right
 Lobes - each lung divides by 1 or 2 fissures
o Each lobe receives it own secondary (lobar) bronchus that branch into tertiary (segmental) bronchi
 Lobules wrapped in elastic connective tissue and contains a lymphatic vessel, arteriole, venue and branch
from terminal bronchiole
 Terminal bronchioles branch into respiratory bronchioles which divide into alveolar ducts
ALVEOLI
 Respiratory membrane
o Alveolar wall - type I and type Il alveolar cells
o Epithelial basement membrane
o Capillary basement membrane
o Capillary endothelium
o Very thin - only 0.5 m thick to allow rapid diffusion of gases
 Lungs receive blood from
o Pulmonary artery - deoxygenated blood
o Bronchial arteries - oxygenated blood to perfuse muscular walls of bronchi and bronchioles.
 Cup-shaped pouch
 Alveolar sac - 2 or more alveoli sharing a common opening
 2 types of alveolar epithelial cells
o Type I alveolar cells - form nearly continuous lining, more numerous than type Il,F main site of gas exchange
o Type Il alveolar cells (septal cells) - free surfaces contain microvilli, secrete alveolar fluid (surfactant reduces
tendency to collapse)

Inhalation is active - Contraction of

 Diaphragm - most important muscle of inhalation
o Flattens, lowering dome when contracted
o Responsible for 75% of air entering lungs during normal quiet breathing
 External intercostals
o Contraction elevates ribs
o 25% of air entering lungs during normal quiet breathing
 Accessory muscles - For deep, forceful inhalation

Exhalation
 Breathing out is called as exhalation (Expiration)
 Pressure in lungs greater than atmospheric pressure
 Normally passive - muscle relax instead of contract
o Based on elastic recoil of chest wall and lungs from elastic fibers and surface tension of alveolar fluid
o Diaphragm relaxes and become dome shaped
o External intercostals relax and ribs drop down
 Exhalation only active during forceful breathing

Oxygen transport
 Only about 1.5% of O, is dissolved in plasma
 98.5% bound to hemoglobin in red blood cells
 Heme portion of hemoglobin contains 4 iron atoms - each can bind one O2 molecule
 Oxygen binds to hemoglobin to form Oxyhemoglobin
 Only dissolved portion can diffuse out of blood into cells
 Oxygen must be able to bind and dissociate from heme.
Acidity
 As acidity increases (pH decreases), affinity of Hb for O2 decreases.
 Increasing acidity enhances unloading
 When pH decreases, the entire oxygen- hemoglobin dissociation curve shifts to the right; at any given
PO2, Hb is less saturated with O2, a change termed the Bohr effect
The alveolar ventilation rate is the volume of air per minute that actually reache the respiratory zone. In the
example just given,
Alveolar ventilation rate = 350 mL/breath X 12 breaths/ min = 4200 mL/min.
By taking a very deep breath, you can inhale a good deal more than 500 mL. This additional inhaled air, called
the inspiratory reserve volume.
It is about 3100 mL in an average adult male and 1900 mL in an average adult female.

Pulmonary and Bronchial Circulation

 Pulmonary circulation has a lower pressure than systemic circulation (mean = 18 mmHg)
o Only one third of vessels filled with blood at any given time
o Increased pressure can increase recruitment
o Automatic distribution of blood to area of increased ventilation.
o Gas Exchange
o delivers nutrients to lung tissues, acts as a reservoir for the left side of the heart, and filters out clots,
air, and other debris from the circulation.
 Bronchial circulation is part of systemic circulation
o Supplies nutrients to conducting airways, nerves, lymph nodes, large pulmonary vessels, and pleurae.

Anatomy and mechanics

The respiratory system carries out several homeostatic functions, including:
1. gas exchange between the atmosphere and the blood to provide an adequate supply of
oxygen to tissues and to remove carbon dioxide (CO2) generated in oxidative metabolism.
02 + Food = CO2 + H2O + ATP
2. regulation of body pH by either retaining or eliminating CO2.
3. conversion of angiotensin I to angiotensin II which acts to control blood pressure
4. protection from inhaled particles.

The respiratory system consists of structures involved in moving air into and out of the lungs (bulk flow) and in
gas exchange (diffusion).

LUNGS AND CHEST WALL act as a unit. Each lung is surrounded by a membranous sac (pleura) filled with a
thin film of fluid (Fig. 1). This intrapleural fluid serves as a lubricant so the lungs can move freely within the
chest wall and functionally connects the lungs to the chest wall such that expansion of the chest expands the
lungs

CONDUCTING ZONE leads from the external environment to the gas exchange surfaces of the
lungs (Fig. 1). This zone includes a series of tubes (nasal cavity, pharynx, trachea, bronchus,
and bronchioles) with small radii and small surface areas. Their total volume is about 150 ml. Since no gas
exchange occurs in the conducting zone, it is often called the anatomical dead space.
Dichotomous division starting with trachea and ending in alveolar sac.

 Main=primary bronchi divide into secondary=lobar bronchi, each

supplies one lobe: 3 on the right and 2 on the left
 Lobar bronchi branch into tertiary = segmental bronchi
 Segmental bronchi further divide and redivide till terminal
bronchiole.
 Tubes smaller than 1 mm called bronchioles
 Smallest, terminal bronchioles, are less the 0.5 mm diameter
 Terminal bronchioles loose their cartilage to form respiratory
bronchiole.
 Lining-pseudostratified ciliated columnar epithelium up to terminal
bronchioles after which non ciliated epithelium.
 Terminal bronchiole lined by nonciliated columnar epithelium
 Respiratory bronchiole lined by cuboidal cells
 Alveoli are lined by squamous cells.

Lung Volumes and Capacities Based on Age, Gender, Height

• Dead space: oropharynx to division 16 of bronchioles
- volume about equal to ideal body weight
• Tidal volume V+ (per breath) 400-800 ml
• IRV 3000 ml additional air that could be inhaled

Segmental bronchi:

RESPIRATORY ZONE is the region of the lung

where gas exchange occurs (Fig. 2). The
respiratory zone is much larger than the
conducting zone and has a volume of about 3 L.
It consists of respiratory bronchioles, alveolar
ducts and alveoli. The alveoli are small sac-like
structures with very thin walls wrapped by
capillaries (Fig. 2). The 300 million alveoli provide a surface area of about 70 m2. Here oxygen (O2) diffuses
from the air space to the blood and carbon dioxide (CO2) diffuses from the blood to the air space. The
distance that gas has to diffuse is very short, about 0.2 microns, making the alveolus-capillary unit ideally
suited for gas exchange

TYPE I CELLS are thin epithelial cells that line about 90% of the surface area of the alveoli. Gases diffuse across
the type I cells to and from the blood (Fig. 2).

TYPE II CELLS are interspersed among the type I cells. Type II cells synthesize, secrete, and metabolize alveolar
surfactant. Surfactant is a lipid-rich substance that lines the alveoli and helps keep lungs from collapsing.

ALVEOLAR MACROPHAGES are the third type of cell found in alveoli. Macrophages engulf inspired particles
such as bacteria. These cells are mobile and are attracted to areas of either infection or trauma.
Pulmonary function
Inspiration begins when the diaphragm and the intercostal muscles of the chest wall contract in
response to neural impulses from the brain stem (Fig. 3). Contraction of the diaphragm causes it to descend and
contraction of the intercostal muscles raises the ribs; the chest cavity expands. Because the lungs are functionally
connected to the chest wall by the pleural sac, the lungs also expand (Fig. 3). This increase in lung volume reduces the air
pressure in the alveolar ducts and alveoli. When the pressure in the alveoli (P A) becomes less than the pressure at the
mouth, which is ordinarily atmospheric pressure (Patm), air flows in until PA= Patm.
Exhalation occurs when the muscles of inspiration relax. The lung returns passively to its pre- inspiratory volume due to its
elastic properties. This reduction in volume raises the pressure in the lung causing air to flow out.

VENTILATION CYCLE is one inspiration and exhalation. Ventilation rate (f) is in the range of 10- 18 breaths per
min. Both the rate and depth can be changed by output from the respiratory centers in the brain stem
(medulla oblongata). During heavy exercise air flow can increase 20-fold and blood flow 3-fold. To expel such
increased volumes, active exhalation is required in which abdominal muscles and internal intercostals muscles
contract. These actions actively decrease the size of the thorax (chest cavity).

Lung volumes and compliance

LUNG VOLUMES are determined by the interaction of the lung and chest wall. The lungs are elastic like a rubber band.
They expand during inspiration and recoil passively during exhalation. Functional residual capacity (FRC) is the resting
volume of the lung and chest wall. It occurs when the elastic recoil of the lung (pulling inward balances the pressure of
the chest wall to expand (pulling outward). When chest wall muscles are weak, FRC decreases. Lung volumes play a
major role in gas exchange and in the work of breathing. They are measured under dynamic and static conditions.
Dynamic volumes refer to measurements made when volumes are changing, i.e., during gas flow. Static volumes can be
measured between two points where there is no flow, for example before and after inspiration.

Residual volume (RV): Amount of air in the lungs at the end of maximal exhalation (~ 1.5 L young men).
Tidal volume (TV): Volume of air inhaled or exhaled with each breath (in adult males ~ 0.5L; in females usually
about 20- 25% less).
Inspiratory reserve volume (IRV): Volume of air that can be inspired after a normal inspiration (~ 3.0 L in males).
Expiratory reserve volume (ERV): Maximal volume of air that can be expired (exhaled) from resting expiratory
level (~1.0 L in males).
Inspiratory capacity (IC=TV+IRV): Max volume of air that can be inspired from resting expiratory level (~3.5 L in
males).
Functional residual capacity: (FRC=RV+ERV): Volume of air in lungs at end of a normal exhalation. (~2.5 L in males)
Vital capacity (VC=ERV+TV+IV): Volume of air that can be exhaled after maximal inspiration (~ 4.5 L)
Total lung capacity (TLC=RV+ERV+TV+IRV): Volume in lungs at end of maximal inspiration (~6 L).
Pulmonary volumes

LUNG CAPACITIES
Inspiratory capacity is the sum of tidal volume and inspiratory reserve volume
Inspiratory capacity in males = 500 mL + 3100 mL = 3600 mL
Inspiratory capacity in females = 500 mL + 1900 ml 2400 mL

Functional residual capacity is the sum of residual volume and expiratory reserve volue
Functional residual capacity in males = 1200 mL +1200 mL = 2400 mL
Functional residual capacity in females =1100 mL +700 mL = 1800 mL

Vital capacity is the sum of inspiratory reserve volume, tidal volume, and expiratory reserve volume
Vital capacity in male = 3600 mL + 500 mL + 1200 mL = 4800 mL
Vital capacity in females = 1900 mL + 500 mL + 700 = 3100 mL

Total lung capacity is the sum of vital capacity and residual volume
Total lung capacity in males = 4800 mL + 1200 mL = 6000 mL
Total lung capacity in females = 3100 mL +1100 mL = 4200

LUNG COMPLIANCE is defined as the stretchability of the lung for any 1-cm change in
pressure across the lung.
CL=  VL/ (PA - Pip)
The greater the compliance, the easier it is to expand the lungs at any given change in trans-
pulmonary pressure. Compliance is the inverse of elastic recoil or stiffness.
The most common way to obtain a compliance curve is to have an individual inspire to total
lung capacity and then exhale slowly in small increments. When airflow is temporarily stopped,
volume and transpulmonary pressure are recorded. A pressure-volume curve is constructed (Fig. 5). The slope
of the pressure - volume curve at any given point is lung compliance at that point.

Transpulmonary pressure = PA - Pip

Lung compliance is determined in part by the elastic tissue of the lung. A lung with high compliance is easy to
stretch. The disease emphysema destroys this elastic tissue and thus increases lung compliance. A lung with
low compliance is stiff and hard to stretch and so is hard to fill with air. This is seen in the disease fibrosis .
The lungs of many premature babies are unable to
produce adequate amounts of functional surfactant.
Approximately 50% of babies born before the 31st
week of gestation will suffer from Respiratory Distress
Syndrome. Because of the lack of surfactant, the
surface tension in their lungs is high, which increases
the tendency of the lungs to collapse. Do these lungs
have high or low compliance?
Surfactant stabilizes the alveoli. The surface tension
of the alveoli tends to pull inward creating
a pressure. The relationship between surface tension and pressure is shown in Figure 6 and is
defined by the law of Laplace.

According to Laplace, transmural pressure is equal to twice the surface tension divided by the radius:
Transmural Pressure = 2T/r

If surface tension were equal in alveoli of different sizes, the pressure in the smaller alveolus
would be greater than the pressure in the large alveolus and the smaller alveolus would
collapse into the larger one.

Alveolar collapse does not normally happen because the surface tension in a lung with surfactant is not
constant. Instead, surfactant reduces surface tension in a nonlinear fashion; i.e., as area is reduced, surface
tension is reduced even further. By lowering surface tension proportionately more in smaller alveoli,
surfactant makes it possible for alveoli of different radii to coexist and to be stable at low lung volumes.

During normal tidal breathing, the surface area of the lung remains fairly constant and with time the surface
becomes “inactivated” through poorly understood mechanism. A deep sigh or a yawn will increase the surface
area of the lungs and new surfactant will spread at the air-liquid interface.

Pressure changes and resistance

In a normal lung, air flows in and out when a
pressure gradient is created. Gas always flows from
a higher to a lower pressure. During inspiration,
expansion of the thorax causes the intrapleural and
alveolar pressures to decrease, gas flows into the
lung. During exhalation passive recoil of the lung
causes the intrapleural pressure and alveolar
pressure to increase; gas flows out of the lung. Note
that during inspiration and exhalation the pleural
pressure is always less than the pressure in the
alveoli.

The transpulmonary pressure (Fig. 7) also increases and decreases with lung volume. By
convention, the transpulmonary pressure is always positive (Ptp = PA - Pip)
At the end of an unforced exhalation when no air is flowing, then the following conditions exist:
alveolar pressure = 0 mmHg
intrapleural pressure (i.e., pressure in pleural cavity) = -5 mmHg
transpulmonary pressure (PA- Pip) = +5mmHg.
Airway resistance determined by driving pressure & flow
Factors that influence airway resistance include airway diameter, lung volume, and elastic recoil of the lung.

1. AIRWAY DIAMETER: It is probably intuitive that the more narrow the airway, the higher the resistance in
that individual airway. What may not be intuitive is that most of the resistance to air flow is found in the
mouth, trachea and large bronchi. The reason for this is that as the airways divide and become narrower, they
also become more numerous. The small airways divide more rapidly than their diameter decreases, therefore,
the resistance of each individual airway is relatively high, but their total-cross sectional area is so great that
their combined resistance is low.
2. LUNG VOLUME: The diameter of the airway lumen is affected by lung volume. The airways are not rigid and
are capable of being distended and compressed. At high lung volumes, the airways such as bronchi and
bronchioles, are "pulled" open and their resistance is lower than at low lung volumes. Patients with increased
airway resistance frequently have high lung volumes in an attempt to compensate.
3. ELASTIC RECOIL: Airway diameter will be affected by the transmural pressure across them
(Fig. 8). Although the airways are embedded in the lung, the pressure that they are exposed to on their
outside wall is close to intrapleural pressure. If elastic recoil is reduced, then intrapleural pressure will be less
negative than normal. The transmural pressure across the airways will be reduced, the airway diameter will be
smaller than normal, and resistance will be higher than normal. Patients with emphysema often have
destruction of lung tissue, decreased elastic recoil (increased compliance), and increased airway resistance.

Pulmonary function tests and alveolar ventilation

FORCED EXPIRATORY VITAL CAPACITY TEST provides an indirect assessment of airway resistance. In this
pulmonary function test, the subject inhales to total lung capacity and then exhales into a spirometer as
forcefully, rapidly, and as completely as possible. The volume expired under these conditions is called the
forced vital capacity (FVC) (Fig. 9).
The forced expiratory vital capacity test also measures the volume exhaled in 1 second, called the 1-second
forced expiratory volume (FEV1). This value is often expressed as a % of FVC (i.e., FEV1/FVC %). Normally FEV1
is at least 80% of FVC (curve Y). Patients with restrictive lung disease will have a normal value of 80% (curve Z).
In patients such as asthmatics, who have obstructed airways, this value will be reduced (<80%) (curve X).
Oxygen transport
The PaO2 and PaCO2 can be measured directly from arterial blood draws. PAO2 is calculated by the alveolar gas
equation. For a patient breathing room air at sea level, this equation simplifies to: PAO2 = 150 - PaCO2/0.8
Notice that alveolar PO, is determined by three factors:
1. PO2 of atmospheric air
2. Alveolar ventilation rate
3. Rate of tissue O2 consumption (RQ).
Each of these factors can change independent of another. For example, a decrease in either PO2 of the
atmospheric air (changes with altitude) or in alveolar ventilation (hypoventilation) will decrease the amount of
fresh air entering the alveoli per unit time. Likewise. an increase in the rate of total body O2 consumption will
decrease PO2 in the alveoli. Because there is essentially no PCO2 in inspired air, only the rate of ventilation and
the rate of tissue metabolism affect the PCO2 levels in the alveoli. In this instance, hypoventilation (Fig. 11)
and/or increased cellular metabolism will increase PCO2 in the alveoli.

Hypoventilation exists when there is an increase in the ratio of CO2 production to alveolar ventilation.
That is the alveolar ventilation cannot keep up with CO2, production resulting in a rise in alvelolar PACO2 > 40
mm Hg. Hypoventilation can be caused by drugs such as barbiturates that depress the part of the central
nervous system that drives breathing, or by damage to the chest wall, lungs, or respiratory muscles and when
the movement of the chest wall is limited (e.g., caused by arthritis or deformation of the thoracic cavity).

Hyperventilation exists when there is a decrease in the ratio of CO2 production to alveolar ventilation.
That is the alveolar ventilation is too great for the CO2 produced resulting in PACO2, < 40mmHg (Fig. 11).
Hyperventilation will occur in response to hypoxia, high altitude, or some drugs such as cocaine which can cause
anxiety attacks.
***Notice that hyperventilation is not the increased ventilation that accompanies mild to moderate aerobic
exercise. In aerobic exercise the increase in production of CO2 is matched to increased alveolar ventilation
(depth and rate of breathing)

Transport of Oxygen and Carbon Dioxide

Oxygen is not very soluble in water and therefore requires the carrier, hemoglobin (Hb), for transport in blood.
Blood normally contains about 15 g of Hb per 100 ml. This effectively raises the solubility of O2 from 3ml/L of
plasma (blood minus the red blood cells) to 200 ml/L plasma.
Since oxygen consumption ranges from 250 to 1500 L/min, this extra O2 carrying capacity of Hb enables the
heart and lungs to provide for the O2 needs of the body. Hemoglobin binds up to 4 molecules of O2 tightly,
cooperatively, and reversibly.
Normally Hb is almost completely saturated (96%) when exposed to room air (FiO2 = 21%). This occurs
because of the transit time (0.75 seconds) for the red blood cell through the alveolus-capillary unit and the
rapid equilibration (0.3 seconds) for both carbon dioxide and oxygen within this region of the lung.
This rapid equilibration reflects the driving pressure for diffusion and the solubility of the gas. The driving
pressure for diffusion of CO2 in the alveolus-capillary unit is lower (PMVCO2-PaCO2 = 46 mm Hg - 40mm Hg =
6 mm Hg) than that for O2 (PaO2 - PMVO2 = 100 - 40 = 60 mm Hg), but the solubility of CO2 in plasma is much
greater. The net result is that the rates of diffusion for CO2 and O2 are approximately equal in the alveolus-
capillary unit. This means that in normal lungs there is ALWAYS adequate time to saturate Hb with O2,
regardless of ventilatory rate.
Oxygen concentration in the blood is dependent on the Hb concentration in the red blood cells, the number of
red blood cells (hematocrit), and on the adequacy of perfusion of the lungs rather than on diffusion rate itself.
Not all of the O2bound to Hb is released in the tissues. At rest only about 25% of the O2 in blood is called upon
when needed as in exercise.
The Hb-O2 dissociation curve (Fig. 12) is S-shaped because the interaction of oxygen with hemoglobin is
cooperative. That is, when one oxygen molecule binds, it increases the affinity of the hemoglobin for the next
oxygen molecule. Each hemoglobin molecule can bind four oxygen molecules.

The plateau of the Hb-O2 dissociation curve is called the "association part" of the curve, because oxygen is
loaded in the lungs at relatively high partial pressures. Increasing the partial pressure above 100 or down to
about 80 mm Hg, does not result in a large change in the % saturation. This tends to stabilize arterial O2
content, making it relatively insensitive to moderate changes in breathing or altitude

The "dissociation part' of the curve is the steep part of the curve (Fig. 12). In this region a small change in PO2,
results in a large change in % saturation which allows for large quantities of oxygen to be dumped in the tissues.

The P50 is the partial pressure of oxygen required to saturate 50% of the hemoglobin. A normal P50 is about
26-27 mm Hg. This value is a useful measure of the affinity of hemoglobin for O2.

Ventilation & Perfusion

Ventilation is the process of bringing air in and out of the lungs. Perfusion is the process of bringing blood in
and out of the lung capillary bed to allow for gas exchange. The right ventricle delivers blood to the lungs at
relatively low pressures (mean pressure of 15 mmHg). However lung perfusion pressure can increase for
multiple reasons including obstruction of vessels (i.e embolism) or increased resistance to flow (i.e., fibrosis).
The lung will compensate for lowered blood flow (1) by recruiting other capillary beds within the lung and (2)
by distention of small vessels. If these responses are inadequate, then pressure within the pulmonary artery
will rise causing a rise in right ventricular pressure. This is called pulmonary hypertension.

Under normal conditions, regulatory mechanisms within the lung match ventilation (V) to perfusion (Q) to
optimize the oxygenation of the blood. V/Q mismatch can occur when ventilated alveoli are not perfused
giving a V/Q ratio of infinity and conversely, when unventilated alveoli are perfused, giving a V/Q ratio of zero.
This latter condition is equivalent to shunting venous blood from the right to the left side of the heart
bypassing the lungs. Usually lung disease is progressive. It leads to a gradual worsening of either ventilation or
perfusion and therefore the V/Q mismatch is intermediate between zero and infinity. Many believe that V/Q
mismatching is the most common cause of low PaO2.

In a normal individual at the level of the lung, alveolar ventilation is about 4.0 L/min and pulmonary blood
flow is about 5.0 L/min. This gives a V/Q = 0.8 overall.
Note that V/Q mismatch occurs within the normal lung because blood flow is never perfectly uniform in this
organ. In a normal person while standing, gravitational pull causes the apex of the lung to be more expanded
than within the base thereby compressing the capillaries and reducing perfusion; V/Q ratios are greater than 1
in the apex (Fig. 14). In contrast, perfusion is greater than ventilation at the base of the lung in an upright
individual; V/Q ratios are less than 1 (Fig. 14).
One mechanism that compensates for V/Q mismatch is the vasoconstriction of the lung vasculature in
response to hypoxia (low O2). [Note that this is in contrast to the smooth muscle of the systemic vasculature
which dilates in response to low O2 conditions.] Vasoconstriction of the lung vasculature to hypoxia enables
the blood to be shunted away from poorly ventilated areas. This occurs without an increase in pulmonary
artery perfusion pressure because of the large capacity of the pulmonary capillaries.

A second compensation that compensates for V/Q mismatch occurs when PACO2 falls (e.g. when V/Q ratio
increases). In this instance, the concentration of hydrogen ions (H+) in and around the smooth muscle of the
airways (bronchioles) decreases. This reduction in H+ results in airway constriction and a shift of ventilation
away from the areas which are over ventilated (i.e., not perfused).
Regulation of breathing
Control of Respiration
Breathing is essentially automatic and can only be altered temporarily by voluntary efforts. You cannot
consciously stop breathing for long. You breathe when you are asleep, awake, or even anesthetized. Breathing
is finely tuned to meet metabolic demands, such that during exercise ventilation increases to maintain arterial
PO2, PCO2 and pH within a narrow range. To achieve this tight regulation, peripheral receptors send
information to a CNS respiratory center whose output adjusts initiation, duration, depth, and rate of breathing.

The intercostal muscles and diaphragm are skeletal muscles that will not contract unless stimulated. Thus
breathing depends on cyclical excitation of the motor neurons that innervate these muscles. Destruction of
these nerves by the polio virus for example results in paralysis and death if the individual is not ventilated.
The underlying respiratory rhythm is established by respiratory centers in the medulla of the brain stem. The
general term for this integration center is the respiratory rhythm generator. Inspiratory neurons located in the
respiratory center initiate respiratory rhythm by sending signals to the motor neurons that innervate the
effector skeletal muscles (intercostals and diaphragm). This rhythm is modified by input from peripheral
sensors (chemoreceptors and mechanoreceptors) located in blood vessel walls and by central receptors
(chemoreceptors) in the brain.

Inspiration is limited by several inputs including stretch of the lungs and innate rhythm generators within the
brain stem (medulla). The medullary inspiratory neurons are quite sensitive to drugs such as barbiturates and
morphine. Death from an overdose of these drugs is often due to cessation of breathing.

Inspiratory receptors in the lung include:

1. Pulmonary stretch receptors located in the smooth muscle of the large and small airways of the lung are
mechanoreceptors that fire with the inflation of the lung. These receptors stop inspiration as part of the
Hering-Breuer reflex. In the adult this reflex is evoked only under conditions of large tidal volumes as in
rigorous exercise.
2. J Receptors located in the walls of the pulmonary capillaries which are stimulated by pulmonary vascular
congestion, edema, air emboli (air in the blood), and low lung volumes. Stimulation of these receptors can
result in rapid breathing (hyperpnea), and or labored breathing (dyspnea).
3. Pulmonary irritant receptors located in airway epithelium and the nasal mucosa. Mechanical or chemical
irritation elicits a cough reflex and bronchoconstriction.

Ventilation is regulated by Chemoreceptors

Peripheral chemoreceptors are the carotid receptors and aortic bodies. They are stimulated by:
a. decrease in PaO2 (hypoxia)
b. increase in PaCO2 (respiratory acidosis)
c. decrease in pH within the arterial blood (metabolic acidosis).
Of the two, the carotid receptor is the predominate input in controlling respiration.

Central chemoreceptors are widely distributed throughout the brain stem. They respond to an increase in
blood PCO2. These receptors actually sense H+ concentration in the interstitial fluid of the brain. They are not
affected by changes in arterial pH because the blood brain-barrier is not permeable to H+ or HCO3-. Instead,
CO2 equilibrates across this barrier, causing a change in the interstitial fluid pH. Because the interstitial fluid
and the adjoining cerebrospinal fluid contain little protein, they are not well buffered. Hence small changes in
PCO2 produce large changes in pH in this area.
Ventilatory Response to Oxygen
The ventilatory response to hypoxia is shown in the graph below (Fig.15). PaO2 must decrease to about 50-60
mmHg before respiration is increased. It has been suggested that the carotid chemoreceptors (which respond
to changes in PaO2), are designed to protect the organism against hypoxia rather than to regulate respiration.
Note that the stimulation to hypoxia is arterial PO2, not arterial O2 content. That means that individuals with
anemia do not have increased ventilation because their PaO2 is normal.

A very small increase in PaCO2 (2-4 mm Hg) provides a powerful stimulus to increase respiration (doubles
alveolar ventilation) (Fig. 16). What is the physiologic role of this response? Recall that changes in PaCO2 have
profound effects on pH. Thus this tight regulation of PaCO2 allows for tight control of acid-base balance. For
example, in emphysema patients retention of CO2, occurs because of the decrease in the elastic recoil. This
raises their PaCO2 leading to increased minute ventilation (Le, "blowing down" the CO2 in the blood). Of the
two sets of receptors involved in this reflex response to elevated PaCO2, the central chemoreceptors are more
important accounting for ~70% of the increased ventilation.

Hypoxia (low PO2) potentiates the effects of CO2. The response curve is shifted to the left and has a steeper
slope. Thus a lower PaO2 will result in a stronger ventilatory response for the same arterial PCO2.

Very high levels of carbon dioxide (greater than 70-80 mm Hg) can depress respiration, cause headaches,
restlessness, faintness, and even unconsciousness or coma.

Changes in pH without changes in PaCO2

Excess retention or elimination of CO2 causes respiratory acidosis or alkalosis, respectively. However, many
normal and pathological conditions can change arterial H+ levels in which the primary cause is not a change in
PCO2. These conditions are called metabolic acidosis (increased H+ concentration) and metabolic alkalosis
(decreased H+ concentration). Which chemoreceptors play a major role in these instances, central or
peripheral? Why?

For example, in strenuous exercise, lactic acid is released by the working muscle. The addition of lactic acid to
the blood lowers the pH and causes hyperventilation almost entirely by stimulating the peripheral
chemoreceptors. Recall that H+ do not cross the blood brain barrier, but CO2 does and is converted in the
interstitial fluid to H+ and HCO3-.

Predict what happens when arterial H+ concentration is decreased by vomiting (loss of acid from the
stomach). Is ventilation increased or decreased? Answer: The peripheral chemoreceptors will reflexively
decrease ventilation to conserve CO2 in the blood.
Thus the respiratory system compensates for metabolic acidosis by increasing ventilation (hyperventilation)
and for metabolic alkalosis by decreasing ventilation (hypoventilation). Notice that maintenance of PCO2
levels is not as important as maintenance of H+ concentration in the blood. This is because most enzymes of
the body function best at physiological pH (pH = 7.4).
 SPIROMETRY  Due to increases in sinus and middle ear
pressures -> Sinus surgery or middle ear
o is a physiological test surgery or infection within 1 wk
o measures the maximal volume of air that an  Due to increases in intrathoracic and
individual can inspire and expire with maximal effort. intraabdominal pressure
Spirometry assesses the integrated mechanical — Presence of pneumothorax
function of the lung, chest wall, and respiratory — Thoracic surgery within 4 wk
muscles by measuring the total volume of air — Abdominal surgery within 4 wk
exhaled from a full lung (total lung capacity [TLC]) — Late-term pregnancy
to maximal expiration (residual volume [RV])  Infection control issues -> Active or suspected
transmissible respiratory or systemic infection,
INDICATIONS including tuberculosis
Spirometry tests are used to diagnose these
conditions: PREPARATION
o COPD  a quiet and comfortable environment that is
o asthma separated from the waiting room and other
o restrictive lung disease (such as interstitial patients being tested
pulmonary fibrosis)  The patient should be seated with shoulders
o other disorders affecting lung function slightly back and chin slightly elevated.
 A chair with arms (to prevent falling sideways
 To assess response to therapeutic intervention should syncope occur), without wheels, and
 To monitor disease progression with a height adjustment so that the feet are
 To monitor patients for exacerbations of flat on the floor should be used.
disease and recovery from exacerbations  A nose clip or manual occlusion of the nostrils
 To monitor people for adverse effects of should be used.
exposure to injurious agents
 To watch for adverse reactions to drugs with PREPARE TO TEST
known pulmonary toxicity  shouldn’t smoke and /or vaping one hour
 Research and clinical trials before a spirometry test.
 Epidemiological surveys  avoid alcohol that day
 Derivation of reference equations  Performing vigorous exercise within 1 h
 Preemployment and lung health monitoring before testing (to avoid potential exercise-
for at-risk occupations induced bronchoconstriction)
 To assess health status before beginning at-  Eating too large of a meal could also impact
risk physical activities the ability to breathe.
 Don’t wear clothing that’s so tight that it could
CONTRAINDICATIONS restrict your breathing.
o Due to increases in myocardial demand or  should avoid using inhaled breathing
changes in blood pressure medications or other medications prior to
— Acute myocardial infarction within 1 week your test.
— Systemic hypotension or severe hypertension
— Significant atrial/ventricular arrhythmia Inhaled medication
— Noncompensated heart failure Bronchodilator medication Withholding
— Uncontrolled pulmonary hypertension time
— Acute cor pulmonale SABA(e.g albuterol or 4-6 h
— Clinically unstable pulmonary embolism salbutamol)
— History of syncope related to forced SAMA (e.g., ipratropium 12h
expiration/cough bromide)
LABA (e.g., formoterol or 24h
o Due to increases in intracranial/intraocular salmeterol)
pressure Ultra-LABA (e.g., indacaterol, 36h
vilanterol, or olodaterol)
— Cerebral aneurysm
LAMA (e.g., tiotropium, 36-48h
— Brain surgery within 4 weeks umeclidinium, aclidinium, or
— Recent concussion with continuing symptoms glycopyrronium)
— Eye surgery within 1 week

INHALED MEDICATION
• LABA = long-acting β2-agonist;
• LAMA = long-acting muscarinic antagonist;
• SABA = short-acting β2-agonist;
• SAMA = short-acting muscarinic antagonist.
SPIROMETRY
 all initial spirometry done for diagnostic
reasons should be performed before and after
bronchodilator administration.
 Thereafter the clinician may choose to perform
spirometry without bronchodilator
responsiveness testing, but
 it is important to consider baseline variability
in lung function when making this decision.
PREPARATIONS
 The use of disposable, in-line filters for
spirometers has become standard practice
 the mouthpiece is usually an integral part of
the filter and will reduce contamination of the
spirometer.
 All disposable items, including filters,
mouthpieces, nose clips, and gloves, must be
disposed of at the end of testing session.
CURVES
o For optimal quality control, both volume–
time and flow–volume real-time displays are
required, and operators must visually inspect
the performance of each maneuver for quality
assurance before proceeding with another
maneuver.
o For the flow–volume graph, expiratory flow
must be plotted upward, and expiratory
volume must be plotted toward the right.
o A 2:1 aspect ratio must be maintained
between the flow and volume scales; that is, 2
L/s of flow and 1 L of volume must be the
same distance on their respective axes.
DAILY CALIBRATION: POTENTIAL
REASONS FOR FAILURE
A slight change in spirometer function that
requires a subsequent recalibration procedure to
adjust the calibration factor
 A leak in the connection of the spirometer to
the calibration syringe
 Air flow through the spirometer during the
zero-flow setting procedure
 Failure to fully fill and empty the calibration
syringe in one smooth action
 Calibration syringe malfunction (e.g., piston
leak or displacement of the piston stop or
syringe damaged by dropping)
 Spirometer blockage either by debris in the
spirometer sensor or by the operator’s hand
while holding the spirometer in place
 Improper assembly of the sensor, mouthpiece,
filter, and/or breathing tube
 Differences between room temperature and
calibration syringe temperature
 Data entry errors in the ambient temperature
and/or pressure
INSTRUCT THE PATIENT AND
DEMONSTRATE THE TEST
 Position of the mouthpiece and noseclip
 Correct posture with head slightly elevated
 Inspire rapidly until completely full
 Expire with maximal effort until completely
empty
 Inspire with maximal effort until completely full
 Confirm that patient understands the instructions
and is willing to comply
Calibration of the equipment => 3-L syringe used
to calibrate
SPIROMETRY
 The patient’s age, height, and weight
(wearing indoor clothes and without shoes) are
recorded
 Ethnicity !!!
 It is preferable to calculate age using the date
of birth and the date of the test.
PREDICTIVE VALUES Ethnicity (Race)
categories for the Global Lung Function Initiative
(GLI) reference values are: white (i.e., European
caucasian), African American, Northeast Asian,
Southeast Asian, other/mixed
 INTERPRETATION OF SPIROMETRY :
PULMONARY DYSFUNCTION
• NORMAL
• OBSTRUCTION
• RESTRICTIVE pattern
• Mixed

SPIROMETRY: MANOUVERS
— Have patient assume the correct posture
— Attach noseclip, place mouthpiece in mouth, and
close lips around the mouthpiece
— Breathe normally
— Inspire completely and rapidly with a pause of
≤2 s at TLC
— Expire with maximal effort until no more air can
be expelled while maintaining an upright posture
— Inspire with maximal effort until completely full
— Repeat instructions as necessary, coaching
SPIROMETRY:VARIABLES vigorously
variable units — Repeat for a minimum of three maneuvers,
FVC Liters usually no more than eight for adults
FEV1 Liters — Check FEV1 and FVC repeatability and perform
FEV1/FVC Decimal fraction to more maneuvers as necessary
two decimal places
PEF Liters per second EQUIPMENTS: Pneumotahograf, vitalograf
FET Seconds
FIVC Liters LUNG VOLUMES:
For children ≤6 yr
FEV0.75 Liters Tidal Volume (TV): volume of air inhaled or
FEV0.75/FVC Decimal fraction to exhaled with each breath during quiet breathing
two decimal places (6- 8 ml/kg)
Inspiratory Reserve Volume (IRV): maximum
• FET = forced expiratory time; volume of air inhaled from the end-inspiratory
• FVC = forced vital capacity tidal position. (1900-3300ml)
• FEV0.75 = forced expiratory volume in the first Expiratory Reserve Volume (ERV): maximum
0.75 seconds; volume of air that can be exhaled from resting
• FIVC = forced inspiratory VC end-expiratory tidal position.( 700-1000ml).
• PEF = peak expiratory flow. Residual Volume (RV): Volume of air remaining
in lungs after maximium exhalation (20-25 ml/kg)
(1700-2100ml)
— Indirectly measured (FRC-ERV)
— It can not be measured by spirometry
FORCED VITAL CAPACITY (FVC) = The
volume of air that can be forcefully exhaled after a
maximal inhalation.
 The majority of FVC can be exhaled in less
than three seconds of exhalation in normal DEBITE EXPIRATORII INSTANTANEE
people, however it may be prolonged in people • FEFX% x% din FVC expirata
with obstructive lung diseases. • MEFX% x% din FVC ramasa a fi expirata

FORCED EXPIRATORY VOLUME in 1 PARAMETERS

second (FEV1)-The volume of air exhaled in the
first second of FVC.
 Normal subjects can exhale 75- 80% of their
FVCin the first second, hence the FEV1/FVC
ratio is an important determinant in assessing
lung disease.

FEV1 - Mecanisme ce produc scaderea FEV1:

- Micsorarea calibrului cailor aerifere (edem,
infiltratie, hipersecretie, bronhospasm,
compresiune etc.): afectiuni obstructive
- Diminuarea reculului elastic pulmonar OBSTRUCTION – use spirometry to establish
(emfizemul pulmonar) airflow obstruction
- Scaderea fortei musculare in opozitie : Atentie!!! FEV1/FVC < 70%
pacienti bine antrenati
- Scaderea volumului pulmonar (afectiuni
restrictive!!!), dar FEV1/VC% normal sau crescut

 To express the degree of the improvement

o Calculate the absolute changes in
FEV1
o Calculate the absolute changes in
FEV1 from base line
 % Improvement in FEV1 =
𝐹𝐸𝑉1 (𝑝𝑜𝑠𝑡𝐵𝐷)−𝐹𝐸𝑉1 (𝑏𝑎𝑠𝑒 𝑙𝑖𝑛𝑒)
x 100
𝐹𝐸𝑉1 (𝑏𝑎𝑠𝑒 𝑙𝑖𝑛𝑒)

Reversibility test
• FEV1

• + 200 ML AND 12%

CV,m, astm bronsic persistent forma moderat- STENOZA VARIABILA EXTRATORACICA
severa
Aspecte functionale:
 Diminuarea debitelor instantaneee maxime numai
pe ramura inspiratorie a buclei flux / volum
 In cea mai mare parte a capacitatii vitale inspirate
curgerea aerului se face la debit mic si egal
 “stergerea” PIF; VIMS scazut
 Ramura expiratorie a curbei flux / volum are
aspect normal; VEMS normal

Cauze:
- Stenoza de laringe
- Paralizie unilaterala de corzi vocale

SPIROMETRY INTERPRETATION:
1. Assess validity
2. Determine ventilatory pattern
3. Grade severity
4. Grade response to BD challenge

Criterii de validitate a curbelor flux / volum

• CV forţată (măsurată pe axa volumelor) trebuie să
fie maximă şi să nu difere cu mai mult de 5% de CV
inspiratorie lentă;
• Curba expiratorie trebuie să înceapă din punctul zero
al graficului şi să fie cât mai aproape de verticală în
prima sa porţiune;
• Curba expiratorie trebuie să prezinte un vârf
HRB la effort corespunzător PEF, situat la un volum cât mai
aproape de CPT;
• Pe curba inspiratorie debitul trebuie să crească
progresiv până la valoarea PIF pentru ca după un
mic platou să tindă progresiv către zero;
• CV inspiratorie forţată să fie egală cu CV
expiratorie forţată;
• Graficul să fie continuu, fără incizuri sau întreruperi;
• Excepţie fac cei cu tulburări severe obstructive, mai
ales cei cu recul elastic pulmonar diminuat, la care
CV forţată poate diferi cu mai mult de 5% de CV
inspiratorie lentă.
Step 1: look at the Flow-Volume loop to
determine acceptability of the test, and look for
upper airway obstruction pattern
Step 2: look at the FEV1 to determine if it is
normal (>= 80% predicted)
Step 3: look at FVC to determine if it is normal
limits (>= 80% predicted)
Step 4: look at the FEV1/FVC ratio to determine
if it is within normal limits (>=70%)

Modificările volumelor si capacitătilor

pulmonare

Interpretarea testelor
Ex.: Pt. CAPACITATE VITALĂ - ♂, 180 cm, 51
ani = 6,10 × I - 0,028 × V - 4,65 ± DS (0,91)

Inducerea sentimentului de boală este la fel de

gravă ca si minimalizarea diagnosticului.

Raportarea la valoarea medie se face în mod curent

pentru realizarea unui consens al interpretării. În
particular raportarea se poate face la limita superioară
a fiziologicului (în cazul tinerilor, a subiecților cu o
condiție biologică buna) sau la limita inferioară a
fiziologicului (când statusul biologic este precar, vârsă
înaintată etc).
 ASTHMA

History
• Asthma: derived from the Greek aazein, meaning "sharp breath." The word first appears in Homer's lliad.
• In 450 BC. Hippocrates: more likely to occur in tailors, anglers, and metalworkers.
• Six centuries later. Galen: caused by partial or complete bronchial obstruction.
• 1190 AD. Moses Maimonides: wrote a treatise on asthma, describing its prevention, diagnosis, and
treatment
• 17th century, Bernardino Ramazzini: connection between asthma and organic dust.
• 1901: The use of bronchodilators started.
• 1960s: inflammatory component of asthma was recognized and anti-inflammatory medications were added
to the regimens.

What is asthma?
 Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined
by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough
that vary over time and in intensity, together with variable expiratory airflow limitation. Airflow
limitation mav later become persistent.
 Recognizable clusters of demographic, clinical and/or pathophysiological characteristics are often called
'asthma phenotypes'; however, these do not correlate strongly with specific pathological processes or
treatment responses.
 Asthma is usually associated with airway hyperresponsiveness and airway inflammation, but these are
not necessary or sufficient to make the diagnosis.

How is asthma diagnosed?

 The diagnosis of asthma is based on the history of characteristic symptom patterns and evidence of
variable expiratory airflow limitation. This should be documented from bronchodilator reversibility
testing or other tests.
 Test before treating, wherever possible, i.e. document the evidence for the diagnosis of asthma
before starting controller treatment, as it is often more difficult to confirm the diagnosis afterwards.
 Additional strategies may be needed to confirm the diagnosis or asthma in particular populations,
Including patents already on controller treatment. the elderly, and those in low-resource settings

DEFINITION OF ASTHMA
 Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined
by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough
that vary over time and in intensity, together with variable expiratory airflow limitation.
 This definition was reached by consensus, based on consideration of the characteristics that are typical of
asthma before controller treatment is commenced, and that distinauish it from other respiratory
conditions, however airflow limitation may become persistent later in the course or the disease.
o Chronic inflammatory condition of the airways characterized by;
- airflow limitation (reversible with treatment)
- airway hyper-responsiveness to a wide range stimuli
- inflammation of the bronchi
o In chronic asthma, inflammation maybe accompanied by irreversible airflow limitation
o Symptoms are cough, wheeze, chest tightness, and shortness of breath which often worse at night

Asthma/ Triggers
• Irritants-household sprays paint fumes
• Occupational factors
• Hormonal factors-fall in progesterone thyrotoxicosis
• Gastrointestinal reflex
• stres
Types of asthma
1. Allergic asthma
2. Occupational (allergic)
3. ABPA (allergic)
4. Intrinsic (non-allergic)
5. Exercise-induced
6. Steroid-resistant

Pathologic features of asthma

• Inflammatory cell infiltration of the airways
• Increased thickness of the bronchial smooth muscle
• Partial or full loss of the respiratory epithelium
• Subepithelial fibrosis
• Hypertrophy and hyperplasia of the submucosal glands and goblet cells
• Partial or full occlusion of the airway lumen by mucous plugs
• Enlarged mucous glands and blood vessels

Pathophysiology
• Smooth muscle contraction
• Thickening of airway -cellular infiltration and inflammation
• Excessive secrection of mucus
Genetic factor
• Cytokine gene complex (chromosome 5)-IL-4 gene cluster control IL-3, IL-4, IL-5 and IL-13
Environment factor
• Childhood expose irritants or childhood infection

•Vasodilatation and leakage

• Angiogenesis
• Lung parenchyma not affected

Dendritic cell antigen presentation

Takes up antigen -> peptide processing -> migrate to lymph node -> peptide presentation to T cell ->
allergic specific T cell production

Asthma/type 2 inflammation
SYMPTOMS OF ASTHMA

Patterns of respiratory symptoms that are

characteristic of asthma
The following features are typical of asthma and, if
present, increase the probability that the patient has
asthma:
Respiratory symptoms of wheeze, shortness of breath,
cough and/or chest tightness:
o Patients (especially adults) experience more than
one of these types of symptoms
o Symptoms are often worse at night or in the
early morning.
o Symptoms vary over time and in intensity.
o Symptoms are triggered by viral infections (colds), exercise, allergen exposure, changes in weather,
laughter, or irritants such as car exhaust fumes, smoke or strong smells
Definition
— Palpable and audible vibrations
— Musical in character
— Produced when airflow is restricted
Wheeze = high pitched continuous sounds with a dominant frequency of 400 HZ or more
MC: expiratory wheeze
— Typically reflect lower airway obstruction
MC found with asthma & bronchiolitis
— Other causes: CHF & foreign body aspiration

Polyphronic Monophonic
Various pitch Single-pitch sound
Widespread narrowing of airways Narrowing of larger airway
Asthma Tracheomalacia,bronchomalacia

Phenotypes in asthma
Many clinical phenotypes of asthma have been identified.&-10 Some of the most common are:
 Allergic asthma: this is the most easily recognized asthma phenotype, which often commences in
childhood and is associated with a past and/or family history of allergic disease such as eczema,
allergic rhinitis, or food or drug allergy. Examination of the induced sputum of these patients before
treatment often reveals eosinophilic airway inflammation. Patients with this asthma phenotype
usually respond well to inhaled corticosteroid (ICS) treatment.
 Non-allergic asthma: some patients have asthma that is not associated with allergy. The cellular
profile of the sputum of these patients may be neutrophilic, eosinophilic or contain only a few
inflammatory cells (paucigranulocytic). Patients with non-allergic asthma often demonstrate less
short-term response to ICS.
 Adult-onset (late-onset) asthma: some adults, particularly women, present with asthma for the first
time in adult life. These patients tend to be non-allergic, and often require higher doses of IS or are
relatively refractory to corticosteroid treatment. Occupational asthma (i.e. asthma due to exposures at
work) should be ruled out in patients presenting with adult-onset asthma.
 Asthma with persistent airflow limitation: some patients with long-standing asthma develop airflow
limitation that is persistent or incompletely reversible. This is thought to be due to airway wall
remodeling.
 Asthma with Obesity: some obese patients with asthma have prominent respiratory symptoms and
little eosinophilic airway inflammation
FAMILY HISTORY AND SIGNS

History and family history

Commencement of respiratory symptoms in childhood, a history of allergic rhinitis or eczema, or a family
history of asthma or allergy, increases the probability that the respiratory symptoms are due to asthma.
However, these features are not specific for asthma and are not seen in all asthma phenotypes. Patients with
allergic rhinitis or atopic dermatitis should be asked specifically about respiratory symptoms.

Physical examination
Physical examination in people with asthma is often normal. The most frequent abnormality is expiratory
wheezing (rhonchi) on auscultation, but this may be absent or only heard on forced expiration. Wheezing
may also be absent during severe asthma exacerbations, due to severely reduced airflow (so called silent
chest'), but at such times, other physical signs of respiratory failure are usually present. Wheezing may also
be heard with inducible laryngeal obstruction, chronic obstructive pulmonary disease (COPD), respiratory
infections, tracheomalacia, or inhaled foreign body. Crackles (crepitations) and inspiratory wheezing are not
features of asthma. Examination of the nose may reveal signs of allergic rhinitis or nasal polyposis
VARIABLE EXPIRATORY AIRFLOW LIMITATION

Asthma is characterized by variable expiratory airflow limitation, i.e. expiratory lung function varies over
time and in magnitude, to a greater extent than in healthy populations. In asthma, lung function may vary
between completely normal and severely obstructed in the same patient. Poorly controlled asthma is
associated with greater variability in lung function than well-controlled asthma.

In clinical practice, once an obstructive defect has been confirmed, variation in airflow limitation is
generally assessed from variation in FEV+ or PEF. Variability' refers to improvement and/or deterioration in
symptoms and lung function.
Excessive variability may be identified over the course of one day (diurnal variability), from day to day,
from visit to visit, or seasonally, or from a reversibility test. 'Reversibility' (also called 'responsiveness")15
generally refers to rapid improvements in FEV1 (or PEF), measured within minutes after inhalation of a
rapid-acting bronchodilator such as 200-400 mcg salbutamol, or more sustained improvement over days or
weeks after the introduction of effective controller treatment such as ICS

In a patient with typical respiratory symptoms, obtaining evidence of excessive variability in expiratory lung
function is an essential component of the diagnosis of asthma. Some specific examples are:
 An increase in lung function atter administration of a bronchodilator, or atter a trial of controller
treatment
 A decrease in lung function after exercise or during a bronchial provocation test
 Variation in lung function beyond the normal range when it is repeated over time, either on separate
visits, or on home monitoring over at least 1-2 weeks

ASTHMA CONTROL

Asthma symptoms such as wheeze, chest tightness, shortness of breath and cough typically vary in
frequency and intensity, and contribute to the burden of asthma for the patient. Poor symptom control is also
strongly associated with an increased risk of asthma exacerbations.

Asthma symptom control should be assessed at every opportunity, including during routine prescribing or
dispensing Directed questioning is important, as the frequency or severity of symptoms that patients regard
as unacceptable or bothersome may vary from current recommendations about the goals of asthma
treatment, and differs from patient to patient. For example, despite having low lung function, a person with a
sedentary lifestyle may not experience bothersome symptoms and so may appear to have good symptom
control.

BRONCHIAL PROVOCATION TESTS

One option for documenting variable expiratory airflow limitation is to refer the patient for bronchial
provocation testing to assess airway hyperresponsiveness. Challenge agents include inhaled methacholine,
histamine, exercise,eucapnic voluntary hyperventilation or inhaled mannitol. These tests are moderately
sensitive for a diagnosis of asthma but have
limited specificity.For example, airway hyperresponsiveness to inhaled methacholine has been described in
patients with allergic rhinitis, cystic fibrosis, bronchopulmonary dysplasia and COPD.This means that a
negative test in a patient not taking ICS can help to exclude asthma, but a positive test does not always mean
that a patient has asthma - the pattern of symptoms (Box 1-2, D.23) and other clinical features (Box 1-3,
D.26) must also be considered.
ASTHMA CONTROL IN CHILDREN 6-11 YEARS OLD
TEST RESULTS
A low FEV1 percent predicted:
 Identifies patients at risk of asthma exacerbations, independent of symptom levels, especially if
FEV1 is <60% predicted
 Is a risk factor for lung function decline, independent of symptom levels
 If symptoms are few, suggests limitation of lifestyle, or poor perception of airflow limitation, which
may be due to untreated airway inflammation.
A 'normal' or near-normal FEV1 in a patient with frequent respiratory symptoms (especially when
symptomatic):
 Prompts consideration of alternative causes for the symptoms; e.g. cardiac disease, or cough due to post-
nasal drip or gastroesophageal reflux disease (Box 1-3, p.26).
Persistent bronchodilator reversibility.
 Finding significant bronchodilator reversibility (increase in FEV1 >12% and >200 mL from baseline18)
in a patient taking controller treatment, or who has taken a short-acting beta2-agonist within 4 hours, or a
LABA within 12 hours (or 24 hours for a once-daily LABA), suggests uncontrolled asthma.
In children. Spirometry cannot be reliablv obtained until age 5 ears or more and it is less useful than in
adults. Many children with uncontrolled asthma have normal lung function between flare-ups
(exacerbations).

Diagnosis
CONFIRM THE DIAGNOSIS

DIAGNOSIS OF ASTHMA IN OTHER CONTEXTS

Patients presenting with persistent non-productive cough as the only respiratory symptom

Diagnoses to be considered are chronic upper airway cough syndrome (often called 'postnasal drip'), cough
induced by angiotensin converting enzyme (ACE) inhibitors, gastroesophageal reflux, chronic sinusitis, and
inducible laryngeal obstruction.37,38 Patients with so-called 'cough-variant asthma' have persistent cough as
their principal or only symptom, associated with airway hyperresponsiveness. It is often more problematic at
night. Lung function may be normal, and for these patients, documentation of variability in lung function
(Box 1-2, p.23) is important 39 Cough-variant asthma must be distinguished from eosinophilic bronchitis in
which patients have cough and sputum eosinophilia but normal spirometry and airway responsiveness.

Asthma acquired in the workplace

Asthma acquired in the workplace is frequently missed. Asthma may be induced or (more commonly)
aggravated by exposure to allergens or other sensitizing agents at work, or sometimes from a single, massive
exposure. Occupational rhinitis may precede asthma by up to a year and early diagnosis is essential, as
persistent exposure is associated with worse outcomes.
An estimated 5-20% of new cases of adult-onset asthma can be attributed to occupational exposure 40
Adult-onset asthma requires a systematic inquiry about work history and exposures, including hobbies.
Asking patients whether their symptoms improve when they are away from work (weekends or vacation) is
an essential screening question.

Athletes
The diagnosis of asthma in athletes should be confirmed by lung function tests, usually with bronchial
provocation testing. Conditions that may either mimic or be associated with asthma, such as rhinitis,
laryngeal disorders (e.g. inducible laryngeal obstruction), dysfunctional breathing, cardiac conditions and
over-training, must be excluded.
Pregnant women
Pregnant women and women planning a pregnancy should be asked whether they have asthma so that
appropriate advice about asthma management and medications can be given (see Chapter 3: Managing
asthma in special populations or settings, p.97). If objective confirmation of the diagnosis is needed, it
would not be advisable to carry out a bronchial provocation test or to step down controller treatment until
after delivery.

The elderly
Asthma is frequently undiagnosed in the elderly, 46 due to poor perception of airflow limitation; acceptance
of dyspnea as being 'normal' in old age; lack of fitness; and reduced physical activity. The presence of
comorbid diseases also complicates the diagnosis. In a large population based survey of asthma patients
older than 65 years, factors associated with a history of asthma hospitalization included co-diagnosis of
COPD, coronary artery disease, depression, diabetes mellitus, and difficulty accessing medications or
clinical care because of cost. Symptoms of wheezing, breathlessness and cough that are worse on exercise or
at night can also be caused by cardiovascular disease or left ventricular failure, which are common in this
age group. A careful history and physical examination, combined with an electrocardiogram and chest X-
ray, will assist in the diagnosis. Measurement of plasma brain natriuretic polypeptide (BNP) and
assessment of cardiac function with echocardiography may also be helpful. In older people with a history of
smoking or biomass fuel exposure, COPD and overlapping asthma and COPD (asthma-COPD overlap)
should be considered.

Smokers and ex-smokers

Asthma and COPD may be difficult to distinguish in clinical practice, particularly in older patients and
smokers and ex- smokers, and these conditions may overlap (asthma-COPD overlap). The Global Strategy
for Diagnosis, Management and Prevention of COPD (GOLD) defines COPD based on chronic respiratory
symptoms, exposure to a risk factor such as smoking, and post-bronchodilator FEV1/FVC <0.7. Clinically
important bronchodilator reversibility (>12% and >200 mL) is often found in COPD. Low diffusion capacity
is more common in COPD than asthma. The history and pattern of symptoms and past records can help to
distinguish these patients from those with long-standing asthma who have developed persistent airflow
limitation (see Chapter 5, p.135). Uncertainty in the diagnosis should prompt early referral for specialized
investigation and treatment recommendations, as patients with asthma-COPD overlap have worse outcomes
than those with asthma or COPD alone.

Obese patients
While asthma is more common in obese than non-obese people,respiratory symptoms associated with
obesity can mimic asthma. In obese patients with dyspnea on exertion, it is important to confirm the
diagnosis of asthma with objective measurement of variable expiratory airflow limitation. One study found
that non obese patients were just as likely to be over-diagnosed with asthma as obese patients (around 30%
in each group) Another study found both over- and under-diagnosis or asthma in obese patients
Treatment
Treatment of children (6-11 years)
Anti IL4 and anti IL13 (dupilumab)

Anti IL5Rα (Benralizumab)

Anti IL5 (Mepolizumab, Reslizumab)
One such target is IL-5, a type-1 cytokine that is
central to the initiation and sustenance of
eosinophilic airway inflammation.
Mepolizumab and reslizumab are humanized
monoclonal antibodies (mAb) targeting circulating IL-5 and thus preventing IL-5 binding to its receptor
MEPOLIZUMAB
• Mepolizumab subcutaneous injection with a dose of 100 mg every 4 weeks is registered as a
treatment for severe eosinophilic asthma

STATUS ASTHMATICUS
Introduction
 Status asthmatics is an acute exacerbation of asthma that remains unresponsive to initial treatment with
bronchodilators.
 Status asthmatics can vary from a mild form to a severe form with bronchospasm, airway inflammation,
and mucus plugging that can cause difficulty breathing, carbon dioxide retention, hypoxemia, and
respiratory failure.
 Patients report chest tightness, rapidly progressive shortness of breath, dry cough, and wheezing and
may have increased their beta-agonist intake (either inhaled or nebulized to as often as every few
minutes.

Pathophysiology - The airway obstruction is due to a combination of factors that include:

a. spasm of airway smooth muscle,
b. edema of airway mucosa,
c. increased mucus secretion,
d. cellular (eosinophilic and lymphocytic) infiltration of the airway walls, and
e. injury and desquamation of the airway
f. epithelium.

Status asthmaticus
Risk factors:
— Genetic predisposition
— GERD
— Viral infections
— Air pollutants - Such as dust, cigarette smoke, and industrial pollutants
— Medications - Including beta-blockers, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs)
— Cold temperature
— Exercise
Status asthmaticus
— The first line of therapy is bronchodilator treatment with a beta2- agonist. Handheld nebulizer
treatments may be administered either continuously (10-15 mg/h) or by frequent timing (eg, q5-
20min), depending on the severity of the bronchospasm.
— Salbutamol solution 0.5% or 5 mg/mL nebulized by compressed oxygen or Salbutamol via a spacer 2
puffs repeated every 20-30 minutes
— Oxygen, via a mask or nasal prongs, oxygen therapy can be easily titrated to maintain the patient's
oxygen saturation above 92% (>95% in pregnant patients or those with cardiac disease)
Set up an IV line for rehydration and possible IV medication, Hydration, with intravenous normal saline at a
reasonable rate, is essential. Special attention to the patient's electrolyte status is important.
ASTHMA-DIFFERENTIAL DIAGNOSIS
PNEUMONIA

Pneumonia is defined as inflammation of the substance of the lungs. It is

usually caused by bacteria but can also be caused by viruses and fungi.
Clinically, it usually presents as an acute illness with cough, purulent sputum,
breathlessness and fever, together with physical signs or radiological changes
compatible with consolidation of the lung (Fig. 28.28). However, it can
present with more subtle symptoms, particularly in the elderly.
Pneumonia is usually classified by the setting in which the patient has
contracted the infection, for example:
 community-acquired pneumonia in a person with no underlying
immunosuppression or malignancy
 hospital-acquired pneumonia (sometimes called ‘healthcare- associated pneumonia’, reflecting the role
of other institutions such as nursing homes)
 aspiration pneumonia, associated with the aspiration of food material or stomach contents into the
lungs, and caused by im- paired swallowing
 pneumonia in immunocompromised patient, acquired through either a genetic defect,
immunosuppressive medication or acquired immunodeficiency, as in human immunodeficiency virus
(HIV) infection
 ventilator-acquired pneumonia, acquired through mechanical ventilation on a critical care unit.

COMMUNITY-ACQUIRED PNEUMONIA
Community-acquired pneumonia (CAP) occurs across
all ages but is more common at the extremes of age.
Streptococcus pneumoniae is the most common cause
overall; however, in 30–50% of cases no organism is
identifiable, while in about 20% more than one
organism is present. Infection can be localized, when
the whole of one or more lobes is affected (‘lobar
pneumonia’), or diffuse, when the lob- ules of the lung
are mainly affected, often due to infection centred on the bronchi and bronchioles (‘bronchopneumonia’).
Factors that increase the risk of developing CAP are shown in Box 28.33.

CLINICAL FEATURES
The clinical presentation varies according to the immune
state of the patient and the infecting agent. Features
include:
 a dry or productive cough, sometimes with haemoptysis
 breathlessness
 fevers, which, if swinging, may indicate empyema (see
p. 965)
 chest pain may be experienced, commonly pleuritic in
nature and due to inflammation of the pleura; a pleural
rub may be heard early on in the illness
 extrapulmonary features (Box 28.34).
In the elderly, CAP can present with confusion or non-specific symptoms such as recurrent falls. CAP should
always be considered in the differential diagnosis of sick elderly patients, given their frequently atypical
presentation.
INITIAL ASSESSMENT
The type and extent of investigations depend on the severity of the illness, which also guides where the
patient should be managed and predicts their outcome. Diagnostic microbiological tests are not needed in
mild infection, which should be treated at home with standard oral antibiotics (amoxicillin, or clarithromycin
for those with a history of penicillin allergy). Where patients have mild dis- ease, chest X-ray is not routinely
recommended unless they fail to improve after 48–72 hours.
Severity is commonly assessed by the CURB-65 or the CRB- 65 score; the CRB-65 score is used in the
community where the serum urea level is not usually available (Box 28.35). These give a guide to the likely risk
of fatal outcome but antibiotic choice must always be tempered by clinical assessment and judgement, taking
into account other factors associated with increased rates of mortality (see Box 28.27).

INVESTIGATIONS
All patients admitted to hospital with suspected CAP should have a chest X-ray, blood tests and microbiological
tests.

Chest X-ray
Radiological abnormalities can lag behind clinical signs. A normal chest X-ray on presentation should be
repeated after 2–3 days if CAP is suspected clinically. The chest X-ray must be repeated 6 weeks later to rule
out an underlying bronchial malignancy causing pneumonia due to bronchial obstruction.

Blood tests
Full blood count, serum creatinine and electrolytes, biochemistry and C-reactive protein (CRP) are helpful.
 Strep. pneumoniae. White cell count is usually >15 × 59/L (90% leucocytosis neutrophils). Inflammatory
markers are significantly elevated: erythrocyte sedimentation rate (ESR) >100 mm/h; CRP >100 mg/L.
 Mycoplasma. White cell count is usually normal. In the presence of anaemia, haemolysis should be ruled
out (direct Coombs’ test and measurement of cold agglutinins, see p. 965).
 Legionella. There is lymphopenia without marked leucocytosis, hyponatraemia, hypoalbuminaemia and
high serum levels of liver aminotransferases.

Other tests
 Sputum culture and blood cultures are required for all patients who have moderate to severe CAP, ideally
before antibiotics are administered. In Strep. pneumoniae infection, positive blood cultures indicate more
severe disease with greater mortality.
 Arterial blood gas analysis is necessary if oxygen saturation is <94%.
 An HIV test should be offered to all patients with pneumonia since it is a common initial presenting illness
in previously undiagnosed HIV infection.
GENERAL MANAGEMENT
Initial management and assessment should follow the guidelines for management of sepsis (see p. 157),
particularly when a patient appears to have a moderate to severe pneumonia. In general:
 Oxygen. Supplemental oxygen should be administered to maintain saturations between 94% and 98%
(provided the patient is not at risk of carbon dioxide retention, due to loss of hypoxic drive in COPD). In
patients with known COPD, oxygen saturations should be maintained between 88% and 92%.
 Intravenous fluids. These are required in hypotensive patients showing any evidence of volume
depletion and hypotension.
 Antibiotics. The first dose of antibiotic should be administered within 1 hour of identifying any high-risk
criteria and treatment should not be delayed while investigations are awaited. Parenteral antibiotics
should be switched to oral once the temperature has settled for a period of 24h, provided there is no
contraindication to oral therapy. If patients fail to respond to initial treatment, microbiological advice
should be sought and alternative diagnoses considered. The antibiotic regimen should be adjusted
specifically once culture and sensitivity results are available (Fig. 28.29).
 Thromboprophylaxis. If the patient is admitted for >12h, sub- cutaneous low-molecular-weight heparin
should be prescribed and thromboembolus deterrent (TED) stockings should be fitted, unless
contraindications exist.
 Physiotherapy. Chest physiotherapy is not needed unless sputum retention is an issue.
 Nutritional supplementation. Need is assessed by a dietician, particularly in severe disease.
 Analgesia. Simple analgesia, such as paracetamol or an NSAID, helps treat pleuritic pain, thereby
reducing the risk of further complications due to restricted breathing because of pain (e.g. sputum
retention, atelectasis or secondary infection).
Causes of a slow-resolving pneumonia are outlined in Box 28.36.
PREVENTION
Cigarette smoking is an independent risk factor for CAP; if the
patient still smokes, cessation advice and support should be given.
Vaccination against influenza is recommended for at-risk groups.
All patients over the age of 65 who have not previously been
vaccinated and are admitted with CAP should have the
pneumococcal vaccine before discharge from hospital.

PARAPNEUMONIC EFFUSION AND EMPYEMA

Pleural effusions are common with pneumonia and complicate around one-third to one-half of cases of CAP.
The majority of these are simple exudative effusions but empyema may also develop (purulent fluid in the
pleural space). Early indications of empyema are ongoing fever and rising or persistently elevated inflammatory
markers, despite appropriate antibiotic therapy.
Pleural aspiration should be performed under ultrasound guidance to make a diagnosis and fluid sent for Gram
stain, culture, fluid protein, glucose and LDH (with comparison to serum levels). Light’s criteria (see p. 973)
can be applied to assess whether an effusion is transudative or exudative. An exudative effusion with pleural
fluid pH of <7.2 is strongly suggestive of empyema. Pathogens are often detectable; sensitivity analysis will
help guide antimicrobial therapy.
If an empyema develops, the fluid should be urgently drained to prevent further complications, such as
development of a thick pleural rind or prolonged hospital admission. The presence of empyema further
increases mortality risk. The duration of antibiotic administration will usually need to be extended. Whenever
possible, the choice of antimicrobial should be guided by the results of cultures. Thoracic surgical intervention
is necessary in severe cases.

LUNG ABSCESS
This term is used to describe severe localized suppuration within
the lung associated with cavity formation visible on the chest X-
ray or CT scan, often with a fluid level (which always indicates an
air–liquid interface). There are several causes of lung abscess
(Box 28.38). Clinical features usually include persisting or
worsening pneumonia associated with the production of large
quantities of sputum, which is often foul-smelling owing to the
growth of anaerobic organisms. There is usually a swinging fever;
malaise and weight loss frequently occur. There may be few signs
on physical examination, although clubbing occurs in chronic
suppuration. Patients have a normocytic anaemia and raised inflammatory markers (ESR/CRP). CT scanning is
essential and bronchoscopy can be undertaken to obtain samples or remove foreign bodies. Treatment should be
guided by available culture results or clinical judgement, and is often prolonged (4–6 weeks). Surgical drainage
is sometimes necessary.

HOSPITAL-ACQUIRED PNEUMONIA
Hospital-acquired pneumonia (HAP) is defined as new
onset of cough with purulent sputum, along with a
compatible X-ray demonstrating consolidation, in patients
who are beyond 2 days of their initial admission to hospital
or who have been in a healthcare setting within the last 3
months (including nursing or residential homes, as well as
acute care facilities such as hospitals). HAP is the second most common form of hospital-acquired infection
after urinary tract infections and carries a significant mortality risk, particularly in the elderly or those with co-
morbidities such as stroke, respiratory dis- ease or diabetes. In HAP, the causative organisms differ from those
causing CAP (Box 28.39). Viral or fungal pathogens only affect immunocompromised hosts.
VENTILATOR-ASSOCIATED PNEUMONIA
This occurs in the context of mechanical ventilation in a critical care setting. Often multidrug-resistant Gram-
negative organisms (such as Acinetobacter baumanii) are responsible, requiring careful selection of an
appropriate antibiotic in association with a clinical microbiologist.

ASPIRATION PNEUMONIA
Acute aspiration of gastric contents into the lungs can produce an extremely severe and sometimes fatal
illness owing to the intense destructiveness of gastric acid. This can complicate anaesthesia, particularly during
pregnancy (Mendelson’s syndrome). Because of the bronchial anatomy, the most usual sites for aspirated
material to end up are the right middle lobe and the apical or posterior segments of the right lower lobe.
Persistent pneumonia is often due to anaerobes and may progress to lung abscess or even bronchiectasis if
protracted. It is vital to identify any underlying problem, as aspiration will recur without appropriate corrective
measures.
Treatment should be directed specifically against positive cultures if available. If not, then co-amoxiclav is used
for mild to moderate disease, which covers Gram-negative and anaerobic bacteria. Treatment needs to be
escalated when there is a lack of response or cases are severe.

PNEUMONIA IN IMMUNOCOMPROMISED PATIENTS

Patients who are immunosuppressed (either iatrogenically or due to a defect in host defences) are at risk not
only from all the usual organisms that can cause pneumonia but also from opportunistic pathogens that would
not be expected to cause disease. These opportunistic pathogens can be commonly occurring microorganisms
(that are ubiquitous in the environment) or bacteria, viruses and fungi that are less common (see Box 37.21).
The symptom pattern may resemble CAP or be more non-specific. A high degree of clinical suspicion is
therefore necessary when assessing an ill patient who is immunocompromised.

PNEUMOCYSTIS JIROVECII PNEUMONIA

Pneumocystis pneumonia is one of the most common opportunistic
infections encountered in clinical practice. It affects patients on immunosuppressant therapy, such as long-
term corticosteroids, mono- clonal antibodies or methotrexate for autoimmune disease; those on anti-
rejection medication after a solid organ or haemopoietic stem cell transplantation; and those infected with
HIV. Individuals with CD4 counts of less than 200/mm3 are at particular risk. Pneumocystis jirovecii is found in
the air, and pneumonia arises from re-infection rather than reactivation of persisting organisms acquired in
childhood.
Clinically, the pneumonia is associated with a high fever, breath- lessness and dry cough. A characteristic
feature on examination is rapid desaturation on exercise or exertion. The typical radiographic appearance is
one of diffuse bilateral alveolar and interstitial shadowing beginning in the perihilar regions and spreading out
in a butterfly pattern. Other chest X-ray appearances include localized infiltration, nodules, cavitation or a
pneumothorax. Empirical treatment is justified in very sick high-risk patients; wherever possible, however, the
diagnosis should be confirmed by indirect immunofluorescence on induced sputum or bronchoalveolar lavage
fluid. First-line treatment of Pneumocystis pneumonia is with high-dose co-trimoxazole (see p. 1443), with
adjunctive corticosteroids in patients with HIV infection.
 COPD - CHRONIC OBSTRUCTIVE PULMONARY DISEASE

 has been described as ‘a disease state characterized by airflow limitation that is not fully reversible.
The airflow limitation is usually both progressive and associated with an abnormal inflammatory
response of the lungs to noxious particles or gases.’
 is an overarching diagnosis that brings together a variety of clinical syndromes (emphy- sema, small
airways disease and chronic bronchitis) associated with airflow limitation and destruction of the lung
parenchyma. There is resultant hyperinflation of the lungs, ventilation/perfusion mismatch, increased
work of breathing and breathlessness.The condition is associated with a number of comorbidities, such
as:
o ischaemic heart disease,
o hypertension,
o diabetes,
o heart failure and
o cancer,
suggesting that it may be part of a generalized systemic inflammatory process.

EPIDEMIOLOGY AND AETIOLOGY

 caused by long-term exposure to toxic particles and gases.

 In developed countries, cigarette smoking accounts for over 90% of cases.
 In developing countries, other factors are also implicated, such as
o inhalation of smoke from biomass heating fuels
o cooking in poorly ventilated areas.
 Only 10–20% of smokers develop COPD, which suggests that there is an underlying individual
susceptibility.
 Urbanization, air pollution, socioeconomic class and occupation may also play a part in the aetiology
but these effects are difficult to separate from that of smoking.
 Some animal studies suggest that diet could be a risk factor for COPD but this has not been proven in
humans.
 The economic burden of COPD is considerable. In the UK COPD causes approximately 18 million lost
working days annually for men and 2.1million lost working days for women, accounting for about 7% of
all days of absence from work due to sickness. Nevertheless, the number of COPD admissions to UK
hospitals has been falling steadily since the mid-1980s.

PATHOPHYSIOLOGY
 Pathologically, there is evidence of airways inflammation and structural changes within the airways
and the lung parenchyma.

STRUCTURAL CHANGES
Structurally, there may be evidence of emphysema and small air- ways disease, with increased mucus-
producing goblet cells in the bronchial mucosa, which may lead to chronic bronchitis (Figs 28.20 and 28.21).
The physiological consequence of these changes is the development of airflow limitation.
Pathologically, there is evidence of both acute and chronic inflammation; endobronchial biopsies demonstrate
a predominance of neutrophils, CD8-predominant lymphocytes and macrophages. This chronic inflammation
results in scarring and fibrosis of the small airways. In addition, there is destruction of the alveolar walls, which
results in emphysema. The phenotype of COPD will differ, depending on the predominance of small airways
disease, emphysema or chronic bronchitis.
CHRONIC BRONCHITIS
Chronic bronchitis, one of the clinical syndromes of COPD is classically defined as a daily productive cough for
3 months per year for 2 consecutive years (p. 955)

EMPHYSEMA
Emphysema is defined as abnormal and permanent enlargement of air spaces distal to the terminal
bronchiole, accompanied by destruction of their walls. It is classified according to the distribution:
 Centri-acinar emphysema. Distension and damage of lung tis- sue are concentrated around the
respiratory bronchioles, while the more distal alveolar ducts and alveoli tend to be well pre- served. This
form of emphysema is extremely common.
 Pan-acinar emphysema. This is less common but is
the type associated with α1-antitrypsin deficiency
(see later). Distension and destruction affect the
whole acinus, and in severe cases the lung is just a
collection of bullae. Severe airflow limitation and
mismatch occur.
 Irregular emphysema. There is scarring and damage
that affect the lung parenchyma patchily,
independent of acinar structure. Emphysema leads
to expiratory airflow limitation and air trap- ping.
The loss of lung elastic recoil results in an increase
in TLC. Premature closure of airways limits
expiratory flow while the loss of alveoli decreases capacity for gas transfer.

The classic Fletcher and Peto studies (Fig. 28.22) showed a loss of
50mL per year in FEV1 in patients with COPD compared with 20mL
per year in healthy people. A more recent study has shown a 40 mL
loss per year but in only 38% of the patients stud- ied. Reliable
biomarkers to predict the rate of decline have not been identified.
PATHOGENESIS

Cigarette smoking
Bronchoalveolar lavage and biopsies of the airways of smokers show increased numbers of neutrophil
granulocytes. These granu- locytes can release elastases and proteases; an imbalance between protease and
antiprotease activity is a causative factor in the devel- opment of emphysema.
Mucous gland hypertrophy in the larger airways is thought to be a direct response to persistent irritation
resulting from the inhalation of cigarette smoke. The smoke has an adverse effect on surfactant, favouring
over-distension of the lungs.

Infections
Respiratory infections are often the precipitating cause of acute exacerbations of the disease. It is less clear
whether infection is responsible for the progressive airflow limitation that characterizes disabling COPD.
Prompt use of antibiotics and routine vaccinations against influenza and pneumococci are appropriate.
Alpha -antitrypsin deficiency 1
Alpha1-antitrypsin is a proteinase inhibitor produced in the liver; it is secreted into the blood and diffuses into
the lung. Here it inhibits proteolytic enzymes such as neutrophil elastase, which are capable of destroying
alveolar wall connective tissue. In α1-antitrypsin defi- ciency, the protein accumulates in the liver, leading to
low levels in the lung.
More than 75 alleles of the α1-antitrypsin gene have been described. The three main phenotypes are MM
(normal), MZ (het- erozygous deficiency) and ZZ (homozygous deficiency). Hereditary deficiency of α1-
antitrypsin accounts for about 2% of UK emphysema cases. Deficiency can also cause liver disease (see p.
1302).

CLINICAL FEATURES

Symptoms
The characteristic symptoms of COPD are productive cough with white or clear sputum, wheeze and
breathlessness. Individuals will be more prone to lower respiratory tract infections. Systemic effects include
hypertension, osteoporosis, depression, weight loss and reduced muscle mass with general weakness and
right heart failure.

Signs
In mild COPD there may be no signs or just quiet wheeze throughout the chest. In severe disease the patient is
tachy- pnoeic, with prolonged expiration. The accessory muscles of respiration are used and there may be
intercostal indrawing on inspiration and pursing of the lips on expiration (see p. 932). The cricosternal distance
is reduced. Chest expansion is poor, the lungs are hyperinflated and there is loss of the normal cardiac and
liver dullness.
Patients who remain responsive to CO2 are usually breathless and rarely cyanosed. Heart failure and oedema
are rare features, except as terminal events. In contrast, patients who become insen- sitive to CO2 are often
oedematous and cyanosed but not par- ticularly breathless. Those with hypercapnia may have peripheral
vasodilation, a bounding pulse, and a coarse flapping tremor of the outstretched hands. Severe hypercapnia
causes confusion and progressive drowsiness. Papilloedema may be present but this is neither specific nor
sensitive as a diagnostic feature.
Patients in the later stages may develop respiratory failure, pul- monary hypertension and cor pulmonale.
Diagnosis
This is usually clinical and based on a history of breathlessness and sputum production in a chronic smoker. In
the absence of a history of cigarette smoking, asthma is a more likely explanation, unless there is a family
history suggesting α1-antitrypsin deficiency.
No individual clinical feature is diagnostic. The patient may have signs of hyperinflation and typical pursed lip
respiration. There may be signs of over-inflation of the lungs (e.g. loss of liver dullness on percussion) but this
also occurs in other diseases such as asthma. Conversely, centri-acinar emphysema may be present without
signs of over-inflation. The chest may become ‘barrel-shaped’ but this can also result from osteoporosis of the
spine in older men without emphysema.
The degree of breathlessness may be recorded using the Medical Research Council (MRC) dyspnoea score,
while the COPD Assessment Test (CAT) is a patient scored symptom tool that measures the impact of the
disease on the individual’s health and wellbeing (Box 28.22).

INVESTIGATIONS
 Lung function tests show evidence of airflow
limitation (see Fig. 28.23). The FEV1:FVC ratio
is reduced and the PEFR is low. In many patients
the airflow limitation is partly reversible (usually
a change in FEV1 of <15%). Lung volumes may
be normal or increased; carbon monoxide gas
transfer factor is low when significant
emphysema is present.
 Chest X-ray is often normal, even when disease is
advanced. The classic features are over-inflation
of the lungs with low, flattened diaphragms, and
sometimes the presence of large bullae. Blood
vessels may be ‘pruned’, with large proximal vessels and relatively little blood visible in the peripheral lung
fields.
 HRCT scans are useful, particularly when the plain chest X-ray is normal.
 Haemoglobin level and packed cell volume can be elevated as a result of persistent hypoxaemia (secondary
polycythaemia; see p. 356).
 Blood gases may be helpful to determine if there is any evidence of respiratory failure.
 Sputum examination may reveal Strep. pneumoniae, H. influenzae and Moraxella catarrhalis, which can
cause infective exac- erbations. Many acute episodes are viral in origin.
 ECG is often normal. If a patient has pulmonary hypertension secondary to COPD, the P wave is tall (P
pulmonale), and there may be a right bundle branch block and evidence of right ventricular hypertrophy
(see p. 1055).
 Echocardiography is useful to assess cardiac function where there is disproportionate dyspnoea.
 α1-Antitrypsin levels and genotype are worth measuring in premature disease or life-long non-smokers.
MANAGEMENT
See Fig. 28.23 for management strategies.

Smoking cessation
 The single most useful measure is to persuade the patient to stop smoking. Even in advanced disease, this
may slow down the rate of deterioration and prolong the time before disability and death occur (see Fig.
28.22). Smoke from burning biomass fuels in poorly ventilated homes should also be reduced.

Drug therapy
 This is used both for the short-term management of exacerbations and for the long-term relief of
symptoms. Many of the drugs used are similar to those employed in asthma (see p. 952).

Bronchodilators
 β-Adrenoceptor agonists. Many patients with mild COPD feel less breathless after inhaling a β-adrenergic
agonist such as salbutamol (200μg every 4–6h). In more severe airway limitation (moderate and severe
COPD) a long-acting β2 agonist should be used.
 Antimuscarinic drugs. Regular use of a LAMA (such as inhaled tiotropium) improves lung function,
symptoms of dyspnoea and quality of life. Use of a LAMA does not prevent the decline in FEV1.
 Theophyllines. Long-acting preparations of theophylline are of little benefit in COPD.

Phosphodiesterase type 4 inhibitors

 Roflumilast is a phosphodiesterase inhibitor with anti-inflammatory properties. It is used as an adjunct to
bronchodilators for maintenance treatment in those patients with an FEV1 of less than 50% and chronic
bronchitis.

Corticosteroids
 Inhaled corticosteroids are recommended in patients with frequent exacerbations or a FEV1 of less than
50% predicted.
 Demonstration of a blood eosinophilia may identify patients who are more likely to have a beneficial
response to inhaled corticosteroid therapy.
 High-dose inhaled steroids are not advised, as their use is linked to increased rates of pneumonia.
 Oral corticosteroids are prescribed in the context of an acute exacerbation.

Antibiotics
 Prompt antibiotic treatment shortens exacerbations and should always be given in acute episodes, as it
may prevent hospital admission and further lung damage. Patients can be given antibiotics to keep at
home, starting them as soon as their sputum turns yellow or green.
 In patients who experience frequent exacerbations, long-term treatment with macrolide antibiotics such
as azithromycin has been shown to reduce exacerbations and improve quality of life.

Mucolytic agents
 These reduce sputum viscosity and can reduce the number of acute exacerbations.
 A meta-analysis showed that mucolytics such as carbocysteine are useful in preventing COPD
exacerbations in those who experience them frequently.
Oxygen therapy
Two controlled trials (chiefly in males) have shown improved
survival with continuous administration of oxygen at 2 L/min via
nasal prongs to achieve an oxygen saturation of more than 90%
for large proportions of the day and night. Survival curves from
these two studies are shown in Fig. 28.24. Only 30% of those not
receiving long-term oxygen therapy survived for more than 5
years. A fall in pulmonary artery pressure was achieved if oxygen
was given for 15 hours daily, but substantial improvement in
mortality was achieved only by the administration of oxygen for
19 hours daily. These results suggest that long-term continuous
domiciliary oxygen therapy will benefit patients who have a:
 PaO2 of <7.3 kPa,(55 mmHg) when breathing air;
measurements should be taken on two occasions at least 3
weeks apart after appropriate bronchodilator therapy (Box
28.24)
 PaO2 of <8kPa with secondary polycythaemia, nocturnal hypoxaemia, peripheral edema or evidence of
pulmonary hypertension
 carboxyhaemoglobin of <3% (i.e. patients who have stopped smoking).
Domiciliary oxygen is best provided via an oxygen concentrator.
Additional measures
 Vaccines. Patients with COPD should receive a single dose of the polyvalent pneumococcal polysaccharide
vaccine and yearly influenza vaccinations.
 α1-Antitrypsin replacement. Weekly or monthly infusions of α1-antitrypsin have been recommended for
patients with serum levels <310mg/L and abnormal lung function. Whether this modifies long-term
progression remains to be determined.
 Heart failure. This should be treated (see p. 1073).
 Secondary polycythaemia. This requires venesection if the packed cell volume is >55%.
 Sensation of breathlessness. Short-acting sedation such as sublingual lorazepam or opiates may be a
helpful palliative measure for intractable dyspnoea. Other useful adjuncts include breathing techniques
and fan therapy.
 Air travel. Commercial aircraft are pressurized to the equivalent of 2000–2400m altitude. In healthy
people, this causes PaO2 to fall from 13.5 to 10kPa, leading to a trivial 3% drop in oxygen saturation, but
patients with moderate COPD may desaturate significantly. The desaturation associated with air travel can
be simulated by breathing 15% oxygen at sea level. Patients whose saturation drops below 85% within 15
minutes should be advised to contact their airline to request supplemental oxygen during their flight.
 Surgery. Some patients have large emphysematous bullae that reduce lung capacity. Surgical bullectomy
can enable adjacent areas of collapsed lung to re-expand, thereby restoring function. In addition, carefully
selected patients with severe COPD (FEV1 <1L) have been treated with lung volume reduction surgery.
Initial studies suggested that ventilation was improved and patients felt less breathless, although
mortality was unchanged. However, a controlled trial in severe emphysema found increased mortality and
no improvement in the patient’s condition. Single lung transplantation (see p. 994) is used for end-stage
emphysema.
 Endobronchial valves. These occlude airways of hyperinflated emphysematous lungs and effectively
achieve lung volume reduction. In selected patients, studies have shown an improvement in quality of life
and exercise tolerance.

COPD exacerbation
Acute exacerbations may be precipitated by a viral or bacterial infection. Patients may have symptoms of
cough, acute broncho- spasm and dyspnoea. Type I and type II respiratory failure may occur as a consequence
of a COPD exacerbation.
Management consists of the following measures:
 Airway, breathing and circulation. These should be assessed (see Ch. 10).
 Oxygen therapy. COPD is by far the most common cause of respiratory failure. In managing respiratory
failure, the main goal is to improve the PaO2 by continuous oxygen therapy. A fixed-percentage mask
(Venturi mask, Fig. 28.25) is used to deliver controlled concentrations of oxygen. Initially, 24% oxygen is
given, and the concentration of inspired oxygen can be gradually increased, provided the PaCO2 does not
rise un- acceptably. In type II respiratory failure, the PaCO2 is elevated and the patient is dependent on
hypoxic drive. In this setting, giving additional oxygen will nearly always cause a further rise in PaCO2.
Patients at risk of hypercapnia should be managed with oxygen therapy to maintain the saturations within
a tar- get range of 88–92%. It is important to monitor arterial blood gases closely if there is any risk of
decompensated type II res- piratory failure. If there is evidence of respiratory acidosis (pH <7.35 with an
elevated PaCO2), despite medical management, the patient should be considered for non-invasive
ventilation unless there are any contraindications (Fig. 28.26).
 Corticosteroids, antibiotics and bronchodilators. These should be administered in the acute phase of an
exacerbation but decisions on long-term use should wait until the patient has recovered (see earlier).
 Removal of retained secretions. Patients should be encouraged to cough up secretions. Physiotherapy is
helpful in achieving adequate chest clearance.
Type II respiratory failure in COPD
 Respiratory support (see p. 227). Non-invasive ventilation should be offered if a patient has a persistent
respiratory aci- dosis with a pH of <7.35. Randomized controlled trials have demonstrated that non-
invasive ventilation (NIV) reduces the need for intubation and lowers mortality. Indications and con-
traindications are shown in Boxes 28.25 and 28.26. Assisted ventilation with an endotracheal tube is
occasionally neces- sary for patients with COPD who have severe respiratory fail ure but only when there is
a clear precipitating factor and the overall prognosis is reasonable. Assessing the likelihood of reversibility
in an acute setting can present a difficult ethical problem

Prognosis of COPD
 Predictors of a poor prognosis are
increasing age and worsening airflow limitation:
that is, decreasing FEV1.
 A predictive index (BODE, body mass index,
degree of airflow obstruction, dyspnoea and
exercise capacity) is used.
 A patient with a BODE index of 0–2 has a 4-
year mortality rate of 10%, compared with 80% in
someone with a BODE index of 7–10.
 This scoring tool may be useful in
determining timing of referral for transplant
consideration.
 VENOUS THROMBOEMBOLIC DISEASE
INTRODUCTION
Pulmonary embolism (PE) is the third most common cause of cardiovascular death after acute myocardial
infarction and stroke. As well as leading to PE, deep vein thrombosis (DVT) frequently results in the post-
thrombotic syndrome, which is a major cause of long-term disability (see p. 1010). Venous thromboembolism
(VTE, the term describing both conditions), is multicausal, often arising as a result of transient provoking
factors, or in individuals with a heritable or acquired predisposition, but in up to 50% of people no cause can be
established.
The clinician must be very familiar with VTE because:
 it is common, particularly in those admitted to hospital or those who have had surgery, suffered trauma or
have other causes of reduced mobility
 it is life-threatening
 it is preventable: PE is the most common avoidable cause of death in patients admitted to hospital, and the
single leading direct cause of death during pregnancy and the puerperium in the UK
 it can be difficult to diagnose: the clinical features and routine initial investigations, particularly for PE, are
often non-specific, and this leads to diagnostic delays with potentially serious consequences
 its treatment can be hazardous: anticoagulant therapy, which may be long-term, is effective but carries the
risk of major, even fatal, bleeding, and can be particularly challenging in patients with co-morbidities

PATHOGENESIS OF THROMBOSIS
Thrombosis is the pathological process by which a localized solid mass of blood constituents (a blood clot or
thrombus) forms within a blood vessel, mostly as a result of fibrin formation with a variable contribution from
platelets and other cells.
This differentiates it from physiological hemostasis, the process in which a fibrin-rich blood clot occurs outside
the vessel-wall lining (or endothelium) as a result of injury. Thrombi form on, and are attached to, the vessel
wall but fragments (emboli) may break off and occlude vessels downstream.
 Thrombosis can occur in both arteries and veins (for example, the usual cause of myocardial infarction is
thrombosis within a coronary artery).
 The pathogenesis of thrombosis in these two sites is different, reflecting the different shear stresses in
arteries and veins, and the contribution that rupture of atheromatous plaques makes to the initiation of
arterial thrombosis.
 Arterial clots are described as white thrombi and venous clots as red thrombi, reflecting the contribution
that platelets, as well as fibrin, make to the former, and fibrin and red cells to the latter.
 Thrombosis is thought to be the cause of about 25% of all deaths worldwide each year.
Terms
Most often, venous thrombosis originates in the deep veins of the leg: hence the term deep vein thrombosis. It is
thought that the process starts within the pocket of one of the valves that line the veins, where flow may be
turbulent and localized hypoxia may develop, resulting in endothelial dysfunction. The thrombus may remain
localized to the leg veins or may embolize through the circulation to result in a pulmonary embolus. A minority
(about 10%) of episodes of venous thrombosis arise in other sites, such as the upper limb, the cerebral venous
sinuses and the splanchnic veins (hepatic, portal and mesenteric veins). Apart from upper limb venous
thrombosis, these unusual-site thromboses are described further in relevant specialty-specific chapters.
If confined to the calf veins, the thrombus is called a calf or distal DVT. Untreated, the thrombus may extend
proximally and, when it reaches the popliteal vein or above, is called a proximal DVT.
Thrombi at this level are larger, and more likely to embolize and be transported with blood flow through the
large veins of the pelvis and abdomen to the right atrium and ventricle. From there, they are pumped into the
pulmonary arteries, which progressively divide into smaller arteries as they course through the lungs to supply
the alveoli. The emboli stop in the pulmonary arteries, where they are no longer physically able to progress,
and, in so doing, obstruct the flow of blood distally. It is thought to take at least several days for venous thrombi
to become clinically evident.

Factors influencing thrombosis

Thrombosis is considered to arise from the interplay between the three factors that make up Virchow’s triad:
 changes in blood flow (stasis or turbulence)
 vessel wall dysfunction
 changes in blood components, leading to hypercoagulability.
The importance of the individual components of Virchow’s triad varies between arterial and venous thrombosis:
 Turbulence and vessel-wall dysfunction caused by atheromatous plaques are factors in arterial thrombosis.
 Stasis and hypercoagulability are more relevant in the pathogenesis of venous thrombosis

Risk factors
Transient
 Surgery, especially major, lower  Oestrogen administration (combined
limb/pelvis or cancer-related hormonal contraception, oral
 Trauma, especially lower limb/pelvis hormone therapy)
 Active cancer  Recent long-haul travel (>4 h)
 Acute medical admission  Central venous catheter
 Immobilization (bed rest >3 days)  Heparin-induced thrombocytopenia
 Plaster cast  Superficial vein thrombosis
 Pregnancy/puerperium
Persistent
 Increasing age
 Body mass index >30 kg/m2
 Ethnicity
 Previous episode of venous thromboembolism
 Inflammatory conditions, e.g. inflammatory bowel disease, systemic lupus erythematosus, Behçet’s
syndrome
 Nephrotic syndrome
 Lower limb paresis, e.g. after stroke
 Heritable thrombophilia (factor V Leiden, prothrombin gene mutation, deficiencies of antithrombin,
protein C or protein S)
 Antiphospholipid syndrome
 Myeloproliferative neoplasms
Deep vein thrombosis – clinical features
 The typical features of DVT include pain and swelling in one leg.
 The leg may be red and warm to the touch.
 There may also be tenderness along the course of the deep veins and
dilation of the superficial
Pulmonary embolism – clinical features
 In about 65% of cases, with pleuritic chest pain and breathlessness,
sometimes accompanied by hemoptysis. Tachypnoea and tachycardia are typically present. Crackles and a
pleural rub over a localized area of pulmonary infarction may be evident on auscultation.
 In another 25%, with isolated breathlessness, sometimes only evident on exertion.
 In the remaining 10%, with more severe features, including syncopal episodes, systolic hypotension or
shock, and myocardial ischemia with associated central chest pain. With this more severe presentation the
patient is tachypnoeic, and has a tachycardia with peripheral shutdown, a raised jugular venous pulse (JVP)
with a prominent α-wave, right ventricular heave, gallop rhythm and a widely split-second heart sound.
Cardiac arrest may occur, typically with pulseless electrical activity. The severity of presentation depends
on both the thrombus burden and the individual’s cardiopulmonary reserve.

Investigations

ECG

Chest X-ray

Arterial blood gas analysis

Biomarkers of cardiac injury

ECG / Kumar
• A right ventricular strain pattern may be seen, with T
wave inversion in the inferior (II, III, AVF) and right
precordial (V1–V4) leads.
• The classical ECG is of an ‘S1Q3T3’ pattern, with a
prominent S wave in lead I and a prominent Q wave
and inverted T wave in lead III, but this is present in
only a minority of patients.
• It is more common to see a sinus tachycardia.
 Chest X-ray - This may be normal but more often shows non-specific abnormalities, including
• atelectasis,
• parenchymal abnormalities,
• cardiomegaly,
• elevation of the hemidiaphragm
• pleural effusion.

Atelectasis / Clinical case

The patient’s chest radiograph shows small atelectatic changes in the
left lung base (arrow).

Cardiomegaly / Clinical case

Chest x-ray showing moderate cardiomegaly and prominent bibasilar
interstitial markings.

Elevation of hemidiaphragm / Clinical case

Arterial blood gas analysis

• Blood gases typically show hypoxia and hypocapnia, but again these are non-specific findings and are
not always present.

Biomarkers of cardiac injury

• Plasma levels of brain natriuretic peptide (BNP) or its precursor, amino-terminal pro-BNP, may be
elevated because of stretching of the right ventricle, and troponin may be increased because of right
ventricular injury due to strain, but once again these findings are non-specific.
 Diagnosis of DVT and PE
• Risk scoring
• Measurement of D-dimer
• Imaging for DVT
• Imaging for PE
Risk scoring
The diagnostic process starts with assessment of the
clinical probability using a clinical prediction score
that takes account of the individual patient’s clinical
features, the presence or absence of risk factors for
VTE, and whether an alternative diagnosis is likely
to explain the symptoms and signs. There are a
number of clinical prediction scores available, and
NICE recommends the modified two-level Wells
score for DVT (Box 29.3) and the two-level Wells
score for PE (Box 29.4); these categorize patients into groups that are likely or unlikely to have DVT or PE,
respectively. Clinical prediction scores standardize clinical assessment and increase reproducibility among less
experienced clinicians. However, in themselves, they do not confirm or exclude the diagnosis of VTE, and
further assessment is necessary.

Measurement of D-dimer
In those considered unlikely to have VTE based on the
Wells score, the next step is D-dimer testing. D-dimer
is a fibrin degradation product that can be measured
quantitatively in plasma by highly sensitive laboratory
tests, or qualitatively by point-of-care testing of whole
blood. Raised levels indicate activation of the
coagulation system but are not specific for VTE, as
they are also seen, for example, with advanced age,
infection, inflammation, postoperatively, in cancer and
during pregnancy.
The value of D-dimer in VTE diagnosis is based on its
high negative predictive value: that is, VTE is very unlikely in a patient who has a low pre-test probability of
DVT or PE by the Wells score and in whom D-dimer, measured by a sensitive assay, falls below a predefined
cut-off (typically quoted as ‘normal’). Such patients do not need further diagnostic testing for VTE. With this
approach it must be borne in mind that there is a small failure rate (<2% within 3 months) and that it does not
absolutely exclude VTE.
In contrast, patients whose Wells score indicates that VTE is unlikely but whose D-dimer is raised (lies above
the cut-off value) require formal radiological imaging to confirm or exclude VTE. Similarly, imaging is also
required for all patients whose Wells score indicates that VTE is likely.
Imaging for DVT
The diagnosis of DVT is generally confirmed by ultrasonography of the deep venous system, which has long
replaced the historical gold standard of venography, as it is quicker and non-invasive.
At a minimum, ultrasonography involves examination of the proximal venous system. Typically, this includes
compression of the popliteal and femoral veins by the ultrasound probe to determine whether the vein is
compressible or not. This is usually supplemented by direct thrombus imaging with vein enlargement and
assessment of blood flow by Doppler. Ultrasonography is very sensitive for proximal DVTs (>95%) but less so
for distal DVTs (70%).
In general terms, a positive scan will confirm the diagnosis. However, in those with a Wells score indicating
that a DVT is likely, a negative scan, if limited to the proximal venous system, does not exclude the diagnosis,
as it will not identify a proportion of patients who have a distal DVT. Further assessment of these patients is
required (Fig. 29.2)

Ultrasound / Clinical case

• A and B, Ultrasound images of a normal femoral vein without
(A) and with (B) compression. The artery (Art) is anterior to
the vein. After compression, the vein is completely collapsed,
indicating normal compressibility.
• C and D, Ultrasound images of acute femoral vein thrombus
without (C) and with (D) compression after 1 week of follow-
up.
• The acute DVT (* in C) is heterogeneous. It expands the vein.
• After compression (D), the vein does not collapse but has an
oval shape indicating an acute DVT based on the
noncompressible but deformable vein.
Imaging for PE
The approach to the diagnosis of PE is similar in principle (Fig. 29.3). When the Wells score indicates that a PE
is unlikely, a negative D-dimer excludes the diagnosis without further investigation.
However, imaging is essential in those who either have a raised D-dimer level or are categorized as likely to
have a PE based on their Wells score.
The most common imaging technique is computed tomographic pulmonary angiography (CTPA) (Fig.29.5),
which is widely available and sensitive and can provide an alternative diagnosis when PE is excluded. The
alternative is ventilation–perfusion (V˙/Q˙) isotope lung scanning, (Fig. 29.6). This test is performed in two
stages:
• a perfusion phase, in which technetium-labelled albumin aggregates are injected intravenously and blood
flow to the lungs is assessed
• a ventilation phase, in which patients inhale radiolabelled xenon or technetium to assess air delivery to the
lungs.
A diagnosis of PE is made if there are mismatched defects in the perfusion scan, indicating impaired blood flow
to the lungs, but normal ventilation because air entry to the lungs is normal. A normal V˙/Q˙ scan excludes the
diagnosis of PE. This technique has the advantage of a lower radiation dose and is preferred in those with renal
impairment and allergies to intravenous contrast agents.

Imaging of PE / Kumar

Imaging of PE / Clinical cases

Imaging of PE /
Clinical cases

Imaging of PE / Clinical cases

• Proximal acute deep venous thrombosis (DVT) in
a 69-year-old woman.
• Axial CT venogram at the level of the thigh shows
typical findings of DVT in the right groin.
• An endoluminal filling defect is demonstrated in
the right common femoral vein (arrow), which is
enlarged compared with the left normal side.
• Note also extensive peri-focal oedema infiltrating
the fat.
• A clot is also demonstrated in the right greater
saphenous vein (arrowhead)

Differential diagnosis Pulmonary embolism

Deep vein thrombosis • Chest infection/pneumonia
• Exacerbation of chronic obstructive pulmonary
• Ruptured Baker’s cyst
disease
• Musculo-tendinous – trauma, haematoma,
• Asthma
myositis, tendonitis
• Pneumothorax
• Superficial vein thrombosis
• Congestive cardiac failure
• Post-thrombotic syndrome
• Acute coronary syndrome
• Cellulitis
• Costochondritis
• Osteoarthritis, osteomyelitis, synovitis, fracture,
• Musculoskeletal pain or rib fracture
tumour
• Aortic dissection
• Acute arterial occlusion
• Pericardial tamponade
• Lymphoedema
• Lung cancer
• Congestive cardiac failure and
• Primary pulmonary hypertension
hypoalbuminaemia – usually cause bilateral leg
• Anxiety/hyperventilation
swelling
Timescale of investigation
Diagnostic testing for VTE should be
performed urgently and completed within
24 hours of initial presentation. When
imaging is required, a first dose of
anticoagulant should be given if it is
anticipated that it will take more than 1
hour to investigate a suspected PE and 4
hours for a suspected DVT.The approaches
described apply only to patients presenting
to primary care or emergency departments.
Inpatients and pregnant women should be
regarded as high-risk and require
appropriate imaging if DVT or PE is
suspected (see p. 1457)
Management
• Anticoagulant therapy is the standard treatment for VTE. It is traditionally divided into three phases:
o the acute phase, lasting 5–10 days
o a maintenance phase, lasting a minimum of 3 months
o a long-term phase beyond this.
• The aim of treatment in the initial phase is to prevent thrombus extension and hence reduce the risk of
embolization; the goal thereafter is to prevent
thrombus recurrence.
Parenteral anticoagulants

Heparin
Heparin is not a pure substance but a mixture of polysaccharides of different molecular weights of biological
origin. In the UK, all heparins are derived from processed porcine gut mucosa. Heparins are destroyed in the
stomach and must be administered parenterally. Heparin is an indirect anticoagulant because it does not work
directly, but by binding through a specific pentasaccharide sequence to naturally occurring antithrombin in
plasma and inducing a conformational change that increases the inhibitory activity of antithrombin at least
1000-fold. The result is more rapid inhibition of several of the activated serine protease coagulation factors,
particularly thrombin (factor IIa) and factor Xa. Heparins are classed as unfractionated heparin (UFH) or as
low-molecular-weight heparin (LMWH).
Unfractionated (standard) heparin
• For many years, UFH was the only form of heparin available for the treatment and prevention of VTE.
• In VTE treatment it is usually administered as an immediate-acting bolus injection, followed by an initially
weight-based intravenous infusion.
• Its use nowadays in the treatment of VTE is largely restricted to particular high-risk settings where its
short half-life, reversibility and lack of renal excretion are advantageous properties. UFH is rarely used
for thromboprophylaxis because its short half-life means that it needs to be given two or three times daily
by subcutaneous injection.
• It is difficult to use in practice because it is necessary to monitor its effect on the APTT regularly and to
adjust the rate of infusion to maintain the APTT ratio (APTT of patient sample compared to mid-point of the
normal range) within a target range: typically, an APTT ratio of 1.5–2.5.
• UFH has a short half-life of 1 hour and, if necessary, can be rapidly reversed with a specific antidote,
protamine sulphate.
• It is not excreted through the kidneys. It carries a small but significant risk of major bleeding, and of an
uncommon but important immunologically mediated, prothrombotic adverse drug reaction, heparin-induced
thrombocytopenia
Low-molecular-weight heparin
LMWHs are the main type of heparin given
nowadays because their favourable
pharmacokinetic properties facilitate their
use in clinical practice. LMWH is produced
by the chemical or enzymatic degradation
of unfractionated heparin, and results in
polysaccharide chains of shorter length and
molecular weight than UFH. Since long
chains with at least 18 saccharides are
required for inhibition of thrombin by
antithrombin, whereas factor Xa is inhibited by shorter chains, the consequence is that, compared to UFH, the
LMWHs inhibit factor Xa to a greater degree than thrombin. LMWH is administered by subcutaneous injection
and peak activity is seen by 4 hours. The half-life of LMWH is longer than that of UFH at 4 hours. LMWH is
excreted through the kidneys and caution is required in patients with renal impairment. Because of its better
bioavailability than UFH, it has the major advantage of fixed, weight-based dosing, without the need for
laboratory monitoring. As a result, the majority of patients with DVT and many with PE can be treated as
outpatients without
hospital admission. Further advantages of LMWH over UFH are that it is at least as safe and effective and
carries a lower risk of HIT. However, LMWH is only partially reversed by protamine sulphate.
In VTE treatment, standard practice for many years has been to give an initial subcutaneous injection of LMWH
while awaiting confirmation of the radiological diagnosis of DVT or PE, and then continuing it with warfarin
until the latter, with its slower onset of action, is providing sufficient anticoagulation for the LMWH to be
stopped, a process that takes at least 5 days. During this time, LMWH is administered, often by the patients
themselves, by subcutaneous injection once or twice daily. In certain groups, longer-term LMWH is preferred
over oral anticoagulants:
• In pregnant women, LMWH is used throughout because it does not cross the placenta.
• In patients with cancer-associated thrombosis, LMWH is more effective than warfarin.
LMWH is also widely used as thromboprophylaxis in patients admitted to hospital or undergoing surgery and
has the advantages over UFH of once-daily administration and lower risk of HIT. LMWH (or an alternative
anticoagulant) also may be used to reduce morbidity and mortality in acute coronary syndrome, where it is
usually given twice daily.

Fondaparinux
Unlike heparins, fondaparinux is a synthetic Penta saccharide. It binds to antithrombin, and because of its short
chain length it inhibits only factor Xa and not thrombin. It is administered by subcutaneous injection and has a
longer half-life than heparin at around 18 hours. It is renally excreted and cannot be used in those with
significant renal impairment. Its effect is not reversed by protamine sulphate.
Vitamin K antagonists
These agents are indirect anticoagulants that inhibit the
final stage of the synthesis of vitamin K-dependent
proteins in the liver: namely, clotting factors II
(prothrombin), VII, IX and X, and the naturally
occurring anticoagulants, protein C and protein S. The
main vitamin K antagonist used in the UK is warfarin.
The full anticoagulant effect of warfarin takes at least 5
days because it affects only synthesis of new proteins;
those already circulating or fully formed in hepatocytes
are unaffected and decline as a function of their half-
lives, which vary from 6 hours (factor VII) to 60 hours
(prothrombin). Therefore, in the setting of VTE
treatment, where an immediate anticoagulant effect is
desired, it is necessary commence with a quick-acting anticoagulant such as heparin, and to continue the latter
until warfarin is providing sufficient anticoagulation on its own.
The anticoagulant effect of vitamin K antagonists is measured using the prothrombin time (PT), which measures
the extrinsic and common pathways of the coagulation system. Because different laboratories use different
reagents with different sensitivities and normal ranges to measure the PT, a system has been devised to
standardize assessment of the degree of anticoagulation by the vitamin K antagonists. In this system the PT for
each patient test (in comparison to the normal PT of the general population not on anticoagulants) is converted
to a standardized ratio, the International Normalized Ratio (INR), and this enables comparison between results
in different laboratories and target ranges defined in clinical trials to be adopted in routine clinical practice. The
higher the INR is, the greater the intensity of anticoagulation. For most patients on warfarin for VTE treatment,
the target INR is 2.0–3.0. A small proportion of patients – for example, those who have a recurrent VTE
episode while the INR is in the target range – need to be more intensively anticoagulated and the new target
range may be set at 3.0–4.0, reflecting greater prolongation of the PT.
Warfarin is metabolized in the liver and has a half-life of about36 hours. It has a narrow therapeutic index and a
wide range of interactions with dietary factors, alcohol and other drugs. Drug interactions can be either
pharmacokinetic or pharmacodynamic. The former are represented by drugs that either induce or inhibit the
metabolism of warfarin by the cytochrome P450 system, and thereby reduce or increase warfarin levels and the
resulting INR. The latter are exemplified by aspirin and clopidogrel, which do not affect warfarin levels, but
further increase the bleeding risk of warfarin through their antiplatelet effects. For reasons that are partly
genetic, there is considerable variation between individuals in the dose of warfarin required for the same effect
on the INR.
Direct oral anticoagulants (DOACs)
DOACs, also called NOACs (non-vitamin K antagonist oral anticoagulants), are a class of anticoagulants that have been
transforming clinical practice since their introduction around 2010. In view of their increasing use, the clinician should be
aware of their pharmacological properties, which are very different to those of warfarin (Box 29.9).
Four DOACs are currently licensed for treatment of VTE in the UK: three (apixaban, edoxaban and rivaroxaban) are
inhibitors of factor Xa and one (dabigatran) is an inhibitor of factor IIa (thrombin). Unlike heparin and warfarin, they
directly inhibit their target substrates. All are administered orally and peak levels are seen about 2 hours after ingestion.
• They have a wider therapeutic index than warfarin.
• There is no interaction with dietary factors or alcohol.
• There is limited interaction (compared to warfarin) with other drugs.
• They can be given in a fixed dose with no monitoring – a major clinical advantage.
• They are variably eliminated through the kidneys and have a half-life of around 12 hours.
In the event of major bleeding on DOACs, management should, in general, follow established principles:
• The DOAC should be stopped.
• Supportive therapy, e.g. intravenous fluids and blood components like red cells, should be administered as appropriate.
• Consideration should be given to specialty-specific intervention, e.g. endoscopy.
In the event of life-threatening bleeding, specific antidotes are emerging as additional options. In the case of dabigatran, a
monoclonal antibody, idarucizumab, which rapidly binds to and completely reverses dabigatran, is now widely available.
An antidote to the inhibitors of factor Xa, andexanet alfa, is currently undergoing clinical evaluation.

Initial treatment of VTE /Traditional management

The long-established initial treatment of VTE involves a parenteral anticoagulant, most commonly subcutaneous low-
molecularweight heparin (LMWH); alternatively, intravenous unfractionated heparin (UFH) or subcutaneous
fondaparinux may be used. In addition, an oral vitamin K antagonist, such as warfarin, is given.
Parenteral anticoagulants are used initially, as they provide almost
immediate anticoagulant activity, whereas warfarin needs at least 5
days to provide therapeutic anticoagulation, as judged by its
impact on the International Normalized Ratio (INR). Heparin or
fondaparinux can be stopped and warfarin continued alone once
the INR is 2.0 or more on 2 consecutive days, indicating that the
vitamin K antagonist is now providing sufficient anticoagulation.

Initial treatment of VTE/ DOACs

The introduction of the direct oral anticoagulants (DOACs) into
clinical practice around 2010 has had a major impact on the
management of VTE. Four DOACs are currently licensed for VTE
treatment: three direct factor Xa inhibitors (apixaban, edoxaban
and rivaroxaban) and one direct thrombin inhibitor (dabigatran).
There are differences between them in the timing of their
introduction, based on the large randomized clinical trials that led
to approval for their use.
• Edoxaban and dabigatran are preceded by parenteral anticoagulation (such as LMWH) for 5 days prior to starting the
DOAC alone: that is, there is a straight switch from LMWH to edoxaban or dabigatran on day 6 with no overlap.
• Apixaban and rivaroxaban do not require parenteral anticoagulation and the DOAC is used alone from the outset, albeit
at a higher initial dose, for 7 and 21 days, respectively.The different treatment models are shown in Fig. 29.7 and the
drugs are described further on pages 1014–1016.
Initial treatment of VTE/ Ambulatory care
• Many patients with DVT can be managed on an outpatient basis, admission being reserved for those with a
complex presentation or significant co-morbidities.
• Increasingly, too, low-risk PE can be managed on an outpatient basis or with early discharge after 24–48
hours.
• Low-risk patients can be identified using the Pulmonary Embolism Severity Index (PESI) or simplified
PESI (Box 29.5); management as an outpatient or with early discharge might be considered for this group.
• Higher-risk patients need admission for close observation and administration of high-flow oxygen.

Original and simplified PESI scores

Role of thrombolysis

Anticoagulants help prevent thrombus extension and recurrence but do not dissolve blood clots, in contrast to
thrombolytic agents. The latter are seldom used in the treatment of VTE because they carry a higher risk of
major bleeding than anticoagulation, including a 2% risk of intracranial haemorrhage. However, in patients
presenting with massive PE characterized by systolic hypotension (blood pressure ≤90mmHg) there is a high
risk of early death, and systemic thrombolysis administered intravenously, or occasionally by catheter infusion
directly into the thrombus, may be lifesaving by rapidly restoring pulmonary perfusion.
The role of thrombolysis in the management of intermediate risk PE – that is, without systolic hypotension but
with evidence of right ventricular dysfunction and raised pro-BNP or troponin levels – remains controversial.
Thrombolysis – either systemic, catheter directed or pharmaco-mechanical – is occasionally used in the rare
setting of management of limb-threatening ilio-femoral vein thrombosis. Local thrombolysis is also sometimes
used in non-limb threatening ilio-femoral vein thrombosis in an attempt to reduce symptoms and prevent the
post-thrombotic syndrome, although there is limited evidence of long-term benefit.
Interventional approaches
Surgical embolectomy
When patients present with massive PE and thrombolysis is contraindicated, emergency pulmonary
embolectomy can be life-saving.
Inferior vena cava filters
Occasionally, patients with newly diagnosed VTE have a contraindication to anticoagulation – for example,
active bleeding – or a major bleeding risk, such as the need for urgent surgery. In such settings an inferior vena
cava (IVC) filter can be inserted by an interventional radiologist to prevent emboli from the deep veins in the
leg reaching the lungs. Contraindications to anticoagulation are usually temporary, and anticoagulant treatment
should be started as soon as it is safe to do so because filters do not entirely prevent pulmonary emboli and are
independently associated with an increased risk of DVT. IVC filters do not reduce the risk of recurrent PE
compared to anticoagulation alone. As IVC filters can give rise to complications that include migration and
embolization, retrievable filters are preferred over permanent ones and they should be removed as soon as
anticoagulation has been safely established.
Complications: Mortality, Associated cancer , Post-thrombotic syndrome , Pulmonary hypertanesion
Complications / Associated cancer
Cancer-associated thrombosis, the initial description of which is often attributed to Trousseau in the 19th
century (Trousseau’s syndrome), is common and 10–20% of all episodes of VTE are diagnosed in people with
cancer. The pathogenesis is multifactorial and includes:
• hypercoagulability resulting directly from the cancer
• the added impact of surgery and/or chemotherapy
• reduced mobility
• use of indwelling central venous catheters that cause local catheter-associated thrombosis.
The combination of cancer and thrombosis carries a particularly poor prognosis. Up to 5% of patients who
present with a seemingly unprovoked episode of VTE are diagnosed with cancer within 12 months.
Complications / Post-thrombotic syndrome => PTS results from:
• proximal venous occlusion with outflow obstruction
• damage to the venous valves that normally allow blood flow from superficial to deep and distal to
proximal
• development of a collateral circulation
• venous hypertension
• capillary leakage
• localized inflammation
Complications / Pulmonary hypertension
Following PE, up to 5% of patients remain persistently breathless due to chronic thromboembolic pulmonary
hypertension (CTEPH). In this condition there is incomplete resolution of pulmonary emboli. The diagnosis
should be suspected in those with persisting symptoms supported by follow-up perfusion lung scanning, CTPA
showing evidence of residual occlusion, and echocardiography suggesting pulmonary hypertension. Assessment
is undertaken by respiratory specialists and a proportion of patients can be successfully treated surgically with a
pulmonary endarterectomy.
 TUBERCULOSIS

M. tuberculosis is an aerobic, intracellular pathogen. Due to their relative impermeability to acid-based dyes in the
laboratory, these organisms are often termed ‘acid-fast bacilli’. TB is an airborne infection spread by coughing via
respiratory droplets. Only a small number of bacteria need to be inhaled for infection to develop, but not all those who
are infected develop active disease.

Primary tuberculosis

• ‘Primary TB’ describes the first infection with TB. When

the bacteria reach the alveolar macrophages, they are
ingested and the subse- quent inflammatory reaction
results in tissue necrosis and formation of a granuloma.
These granulomatous lesions consist of a central area of
necrotic material called caseation, surrounded by
epithelioid cells and Langhans giant cells.
• Subsequently, the caseated areas heal completely and many become calcified. Some of these calcified nodules
contain bacteria, which are contained by the immune system (and the hypoxic acidic environment created within
the granuloma) and are capable of lying dormant for many years. This is known as the primary focus or the ‘Ghon
focus’ of the disease. On a chest X-ray, the Ghon focus can be evident as a small, calcified nodule.
• On initial contact with infection, less than 5% of patients develop active disease. This increases to 10% within the
first year of exposure.

Reactivation tuberculosis

 In the majority of people who are infected by Mycobacterium spp., the immune system contains the infection and
the patient develops cell-mediated immune memory of the bacteria. This is termed ‘latent TB’.
 The majority of active TB cases are due to reactivation of latent infection, where the initial contact usually
occurred many years or decades earlier.
 Most patients are young and previously healthy but may have one or more of risk factors implicated in the
development of active disease (Box 28.41). In patients with HIV infection, newly acquired TB is also common.
 The majority of active TB occurs in the lung, but extrapulmonary infection occurs with spread to the lymph nodes,
particularly the cervical and intrathoracic chains, where it causes active disease in 20–25% (UK figures) and also
via the blood- stream to more distant sites such as
the brain, bones and skin.

28.41 Factors implicated in the reactivation of latent

tuberculosis

• HIV co-infection
• Immunosuppressant therapy
(chemotherapy/monoclonal antibody
treatment), including corticosteroids
• Diabetes mellitus
• End-stage chronic kidney disease
• Malnutrition
• Ageing

Clinical features and diagnosis

The cardinal symptoms of TB are cough, haemoptysis

and the sys- temic symptoms of fevers, night sweats and
weight loss. However, in extrapulmonary sites,
respiratory symptoms are often absent, and the systemic symptoms are often ignored by patients and med- ical
practitioners alike.

In all cases of suspected TB, it is essential, depending on the site of disease, to obtain sputum, biopsy samples or fluid
for micros- copy, smear and culture, to obtain information on sensitivities. Tis- sue samples should also be sent for
histopathological examination, either dry or in saline.
Pulmonary TB

 Patients are frequently symptomatic with a productive cough and, occasionally, haemoptysis, along with systemic
symptoms.
 Where there is laryngeal involvement, a hoarse voice and a severe cough are found.
 If disease involves the pleura, then pleuritic pain is a frequent presenting complaint.
 The chest X-ray (Fig. 28.30) can show consolidation with or without cavitation, pleural effusion, or thickening or
widening of the mediastinum caused by hilar or paratracheal adenopathy.
 Serial sputum samples should be collected on at least three occasions (ideally, first thing in the morning); if the
patient is unable to produce sputum, it may be necessary to organize an induced sputum or perform bronchoscopy
to obtain samples.
 Patients whose sputum is smear-positive for TB are consid- ered to be infectious and should be isolated in
hospital. Those who are smear-negative but subsequently culture-positive are less infectious and generally so not
need to be isolated, although care should be taken when contacts include immunocompromised individuals.

Fig. 28.30 Chest X-ray demonstrating patchy right mid and up- per zone
consolidation and a cavity at the right apex in a patient with tuberculosis.

Lymph node TB

The lymph nodes are the second most commonly affected organs. Extrathoracic nodes are more commonly involved
than intratho- racic or mediastinal. Usually, presentation is with firm, non-tender enlargement of a cervical or
supraclavicular node. The node becomes necrotic centrally and can liquefy and be fluctuant if peripheral. The
overlying skin is frequently indurated or there can be sinus tract formation with purulent discharge, but characteristi-
cally there is no erythema (‘cold abscess’ formation). Nodes can typically be enlarged for several months prior to
diagnosis. On CT imaging, the central area appears necrotic (Box 28.42). Samples should be obtained via either
ultrasound-guided fine needle aspira- tion (FNA), core biopsy or, if necessary, removal of a whole node.
Miliary TB

 Miliary disease occurs through haematogenous spread of the bacilli to multiple sites, including the central nervous
system (CNS) in 20% of cases.
 It often presents with systemic symptoms and the chest X-ray demonstrates multiple nodules, which appear like
millet seeds: hence the term ‘miliary’.
 Other findings are liver and splenic microabscesses with deranged liver enzymes, cholestasis and gastrointestinal
symp- toms.
 All patients should have brain imaging (MRI), to look for evi- dence of cerebral disease, which can present as an
asymptomatic brain tuberculoma.

INVESTIGATIONS:

Stains -> Auramine–rhodamine staining is more sensitive (though less spe- cific) than Ziehl–Neelsen; as a result, it is
more widely used. It requires fluorescence microscopy and highlights bacilli as yellow– orange on a green
background.

Culture -> The majority of the developed world uses liquid/broth culture of mycobacteria in addition to solid media
(Lowenstein–Jensen slopes or Middlebrook agar), as time to culture is shorter than for solid culture (1–3weeks
compared with 3–8weeks). Using liquid culture in the presence of antimycobacterial drugs (usually first-line ther-
apy) establishes the drug sensitivity for that strain and usually takes approximately 3 weeks.

 Tuberculin skin test (TST; purified protein derivative (PPD) or Mantoux test):
 Intradermal injection of tuberculin antigen
 Can detect active or latent infection
 Measure induration area in 48-72 hours; positive if:
 5 mm in patients with HIV, immunosuppression, or recent contact with TB
 10 mm in patients from high-risk countries, IV drug users, medical and lab workers
 15 mm in patients with no known risk factors for TB
 Interferon-y release assay (IGRA): no distinction between active and inactive TB

Nucleic acid amplification and polymerase chain reaction

Nucleic acid amplification testing (NAAT) is increasingly used for rapid identification of MTb complex and is useful
in differen- tiating between M. tuberculosis complex and non-tuberculous mycobacteria, as well as identifying TB in
smear-negative sputum specimens. It works by using the polymerase chain reaction (PCR) to replicate and then
identify mycobacterium DNA. Culture and staining are still necessary and should not be replaced by PCR. PCR is
useful only at the initial stage of diagnosis, as it frequently remains positive despite treatment, due to the detection of
dead organisms.
Management

All patient should have routine blood tests and a viral hepatitis screen, and be offered an HIV test before treatment.
Patients with active viral hepatitis are much more likely to develop a fatal drug- induced hepatitis and need careful
monitoring and counselling. Those with fully sensitive TB require 6 months
of treatment; the exception is TB infection of the CNS, for which the
recommended duration is at least 12 months. Isoniazid, rifampicin,
pyrazinamide and ethambutol are the first-line TB drugs, known as
quadruple therapy. In CNS and pericardial disease, corticosteroids are used
as an adjunct at treatment initiation to reduce long-term com- plications.
Box 28.43 summarizes the standard recommended regimens.

Isoniazid

 can cause a polyneuropathy due to B6 deficiency, as isoniazid

interacts with pyridoxal phosphate;
 vitamin B6, pyridoxine 10–25mg daily, should be prescribed
concomitantly to prevent this.
 Occasionally, isoniazid gives rise to allergic reac- tions, such as a
skin rash and fever.
 Hepatitis occurs in less than 1% of cases but may lead to liver transplantation or death if the drug is continued.

Rifampicin

 induces liver enzymes, which may be transiently elevated in the serum of many patients. This also means that
con- comitant drug treatment may be made less effective and a careful review of a patient’s therapy will need
to be undertaken, particularly with antidepressants, anticoagulants and antiepileptics (see p. 259).
 Oral contraception will not be effective, so alternative birth-control methods should be used.
 Rifampicin stains body secretions red/ pink and patients should be warned of the change in colour of their
urine, tears (affecting contact lenses) and sweat.
 Thrombocytopenia has been reported.

Pyrazinamide

 may cause hepatic toxicity but its most common side-effects are itching, rash and arthralgia;
 pyrazinamide reduces the renal excretion of urate and may precipitate hyperuricaemic gout.
 May cause hepatic toxicity.

Ethambutol

 can cause a dose-related optic retrobulbar neuritis that presents with:

o colour blindness for green,
o reduction in visual acuity and a
o central scotoma.
 Patients should have their visual acuity and colour vision checked prior to treatment using Snellen and
Ishihara charts. This condition usually reverses, provided the drug is stopped when symptoms develop;
patients should therefore be warned of its effects.
 All patients prescribed the drug should be seen by an ophthalmologist prior to treatment and doses of 15 mg/
kg should be used, with a maximum dose of 1.2 g.
 Healed primary TB
• Following an immune response to primary infection, a
caseating granuloma forms which calcifies over time – this is
known as a ‘Ghon focus’ – TB has gone!
• A Ghon focus is a rounded, well-defined focus of
calcific density (as dense as bone) usually located in the
periphery of the lung
• This chest X-ray shows a large, rounded calcified focus
near the right hilum
• The CT (not usually necessary) shows it is located in the
lung peripherally
• This is a particularly large Ghon focus

Post-primary TB
• Post-primary TB (secondary TB or
reactivation TB) is more common in
immunocompromised individuals – for example
those with HIV/AIDS, those on immunosuppressing
drugs, or those with malnutrition or diabetes
• The upper lobes are more commonly affected
• Consolidation often extends to the hilum
• The hilar structures may be distorted due to
volume loss of the upper lobe

• Post-primary TB – lung cavity - Cavities are

a common finding in mycobacterial infection

Healed post-primary TB
• Following an immune response to post-
primary infection, the affected area often becomes
scarred (fibrotic) and calcified
• The combined fibrosis and calcification can
be described as ‘fibro-calcific change’

Miliary TB
• Miliary TB is due to disseminated spread
of mycobacterial infection
• It can occur either at the time of primary
infection or on disease reactivation –
prognosis is poor
• Very fine nodules are typically seen
scattered throughout the lungs
 THORACENTESIS
Anatomy and physiology
• A potential space exists in the left and right side of the chest cavity
between the inner chest wall and lung.
• A trace amount of fluid is found in this space as part of healthy
lymphatic drainage, providing lubrication between the lung
parenchyma and musculoskeletal structures of the rib-cage during
expansion (inhalation) and recoil (exhale).
• Excess fluid is pathological.

• The pleural space extends inferiorly to level of approximately the 10th intercostal space.
• The intercostal vascular bundles are located along the inferior aspect of the ribs

Thoracentesis – Key points

• Thoracentesis is a percutaneous procedure that is
performed to remove excess fluid, known as a
pleural effusion, from the pleural space to help a
patient breathe easier.
• Diagnostic thoracentesis = removal of a small
volume of pleural fluid for analysis
• Therapeutic thoracentesis = removal of a large
volume of pleural fluid for relief of symptoms (pain,
shortness of breath)
• Evaluation of the fluid remove may determine the
underlying cause of excess fluid in the pleural space.

Indications
1. Diagnostic analysis of pleural effusion:
1) Any new pleural effusion, except in the case of clinically suspected transudate due to heart failure,
hypoalbuminemia, cirrhosis, end-stage renal failure, or in patients with small effusions; in such circumstances treat the
underlying cause, reassess, and consider thoracentesis if effusion does not resolve with treatment.
2) Persistent effusion despite an adequate trial of therapy of the underlying disease, large unilateral effusions
(particularly left-sided), symptoms of pleurisy, dyspnea or fever, or effusion of unknown etiology.
2. Treatment of pleural effusion: Symptomatic lung compression by a pleural effusion.
● Usually the volumes drained during one procedure should not exceed 1500 mL due to risk of reexpansion
pulmonary edema (RPE). Although rare, mortality rate of RPE is as high as 20%.
● Repeated therapeutic thoracentesis may be done several hours later if there is no evidence of RPE and the
patient remains symptomatic.
 Prior to the procedure
• Prior to any invasive procedure like a thoracentesis, informed consent should be obtained from the patient and a
time out procedure observed.
• The hemithorax identified for the procedure should be reconfirmed.
• The effusion should be localized using auscultation, percussion, and tactile fremitus.
• The overlying skin area should then be prepared and draped in a sterile manner.
• The practitioner should also practice maximal sterile precautions throughout the procedure.
• After thorough handwashing, a mask,a sterile cap, gown and gloves should be used.

Upright position
1. Positioning of the patient
• allows access to the posterior approach of thoracentesis
• the patient is leaning forward on a support
• the location of needle placement is best determined by using ultrasound
2. Supine position
• lateral approach to the chest cavity
• may be employed in patients unable to sit up
• the head of the bed should be elevated in this position to facilitate the drainage of
the pleural fluid inferiorly and to accumulate the effusion closer to the location of
standard needle placement
Analgesia
• The thoracentesis site should be in the mid scapular or posterior axillary line (6-10 cm lateral to spine), and one
to two intercostal spaces below the highest level of the effusion.
• In order to minimize potential injury of the diaphragm, the lowest recommended level for thoracentesis is between
the eighth and ninth ribs (eighth intercostals space).
• Use lidocaine with epinephrine (1% lidocaine is 10 mg/mL of solution). Usually 5 to 10 mL is required.
• Inject the subcutaneous tissue with a small-bore (25-gauge) needle and raise a wheal at the superior margin of the
selected rib in the midscapular or posterior axillary line
• Alternating between aspiration and injection, advance to the superior portion of the posterior rib and anesthetize
the periosteum
• Gently advance the needle over the superior portion of the rib while infiltrating with lidocaine
• Slowly advance the needle while aspirating, until pleural fluid is aspirated. Withdraw the needle 1 to 2 mm and
inject 2 to 4 mL of lidocaine to anesthetize the parietal pleura. Though the visceral pleura are not innervated with
pain fibers, the parietal pleura are quite sensitive.
• Mark the depth of the chest wall by grasping the needle at the level of the skin with either your thumb and index
finger or a Kelly clamp and withdraw the needle
Needle insertion
• Make a stab incision parallel to the rib at the marked site for easier insertion of the thoracentesis needle
• Attach a 60-mL syringe to the catheter-clad needle. Insert the thoracentesis needle, with the bevel inferiorly,
through the skin over the selected rib.
• Advance the needle over the superior portion of the posterior rib, aspirating until pleural fluid is encountered
• As the catheter enters the pleural space, angle the needle caudally and push the catheter off the needle into the
pleural space
• Occlude the lumen of the catheter
Drain pleural effusion
• Attach the three-way stopcock to the catheter hub. Set the stopcock valve to occlude the catheter port.
• Attach the 60-mL syringe to one port of the three-way stopcock
• Turn the stopcock valve to connect the syringe with the catheter and withdraw fluid from the pleural space.
• Turn the stopcock to connect the syringe to the intravenous tubing and empty the syringe into the collection bag or
bottle. Continue this procedure until no further fluid drainage is desired.
 Potential complications
• Pain or chest wall numbness
• Wound infection and bleeding
• Subcutaneous emphysema
• Failure to drain collection, requires reattempt
• Trauma to viscera in the thorax or abdomen
• Tension pneumothorax
• New pneumothorax. There is a 10–20% chance of causing a pneumothorax if thoracocentesis is attempted and the
child does not have a pneumothorax

Contraindications
• Absolute: none
• Relative
o Thrombocytopenia
o INR/PTT greater than 2 times upper limit normal
o Cellulitis or herpes zoster overlying needle insertion site
o Mechanical or manual ventilation

Pay attention
• Chest drains require close observations including documentation of the amount and type of fluid drained, colour,
consistency and the presence of oscillation and/or air bubbling
• If there is significant large volume or an unexpected change seek urgent senior advice
• When a patient is mobilised, drain clamps must be carried in case of accidental disconnection of the chest drain
from the UWS for urgent clamping