9

ANATOMY OF THE RESPIRATORY SYSTEM

UPPER AIRWAY The upper airway is the portion of the airway from the nares and the lips to the distal end of the larynx.
Nose breathing is typically through the nose. This confers two
advantages, there is improved filtration by vibrissae hairs and
humidification of inspired gas because the nasal septum and the
turbinates greatly increase the surface area of muscosa available for
evaporation and the turbulent flow improves contact. The
consequence is increased resistance to flow such that at higher flows
(>35 l/min) oral breathing is required.

Superior nasal concha

Middle nasal concha
Inferior nasal concha
Pharyngeal tonsil along with the palatine tonsil is a
frequent cause of obstruction
Hard palate
Soft palate is the movable third of the palate, which is
suspended from the posterior border of the hard palate. The
soft palate is strengthened by the palatine aponeurosis.

Palate and Tongue

During breathing at rest the tongue is pressed

against the hard palate and air flows through the nose, the pharynx in to the
larynx. When oral breathing is used (or when swallowing) the soft palate
becomes rigid and arches up and back under control of the palatine
aponeurosis (tensor and levator palati) to lie against the superior constrictor
the the pharynx known as Passavants ridge to form the palatopharyngeal
sphincter. The pressure of the air in the mouth reinforces the soft palates
movement.

Tongue gleniglossus is the muscle inf to the tongue

Uvula is the conical shape at the end of the soft palate
Palatine tonsil

C2

Epiglottis
Hyoid bone the gleniohyoid and the

C3

mylohyoid are the two muscles attached

C4

The larynx, which lies at the level of the third through sixth cervical vertebrae, serves

as the organ of phonation and as a valve to protect the lower airways from the contents
of the gastrointestinal tract. The structure consists of muscles, ligaments, and a
framework of cartilages. These include the thyroid, cricoid, arytenoids, corniculates, and
the epiglottis. The epiglottis, a fibrous cartilage, has a mucous membrane covering
that reflects as the glossoepiglottic fold onto the pharyngeal surface of the tongue. On
either side of this fold are depressions called valleculae. These areas provide the site for
placement of the curved MacIntosh laryngoscope blade. The epiglottis projects into the
pharynx and overhangs the laryngeal inlet. However, it is not absolutely essential for
sealing off the airway during swallowing.

Larynx is located between the third and sixth cervial

vertebrae. The most distal section marks the end of the
upper airway

C5

Cricoid cartilage (posterior)

Vestibular fold is the false voal cord, superior to the
Ventricle. The Vocal cord is inferior to the ventricle.

C6
C7

Thyroid cartilage
C8

Oesophagous
Cartilaginous rings of the trachea are

T8

incomplete where it articulates with the

oesophageous and therefore flat posteriorly

Airway differences due to age After about 8 years of age, airway differences between adults and
children mainly reflect size differences. The newborn has the most dramatically different anatomy
from the adult, and it persists during the first year of life and then slowly evolves to the adult form.
Differences include a large head that tends to flex the short neck and obstruct the airway and a
disproportionately large tongue that may cause airway obstruction and more difficult laryngoscopy.
The larynx is more cephalad in infants because the cricoid cartilage is opposite the fourth cervical
vertebra (rather than the sixth in adults). The epiglottis is longer and stiffer, and it lies more
horizontally than in adults. The cricoid cartilage is the narrowest point of the airway until about age
8. The shorter trachea also leaves less margin for error in placement of the endotracheal tube. The
angles of the main bronchi take-off points make left-sided endobronchial intubation as likely as
right-sided procedures.

Muscles of respiration

During inspiration negative pressure is created primarily by the retraction of the diaphram. With only a small change in the pressure, the
pharynx would collapse without the relfex contraction of the pharyngeal dilator muscles, glenioglossus and tensor and levator palati. When in the supine position these
muslces are also important in stopping the soft palate falling back against the posterior pharyngeal wall. Failure of these muscles which preserve airway patency may occur
during sleep, hypoxia or anaesthesia.

In the larynx during inspiration the the posterior cricoaryenoid muscles acting by rotating the arytenoid cartilages, abducts the vocal cords to reduce resistance. During
expiration the thyroartenoid muscles adduct the vocal cords, increasing resistance, possibly to prevent lower airway collapse.
The diaphram is a dome shaped membraneous muscle separating the the abdominal
cavity and chest, and in adults has a surface area of approx 900cm2. It is the most
important inspiratory muscle, with motor innervation solely from the phrenic nerves
(C3-5). When it contracts the diaphram acts like a piston as well as flattens out in shape
increasing the volume of the lungs and therefore creating negative pressure. The external
intercostal muscles connect adjacent ribs and project downward and forward. When they
contract the ribs are pulled upward and forward increasing the size of the lung volume
and augmenting the action of the diaphram. The main accessory muscles of inspiration are
the scalene muscles which elevate the first two ribs, and the sternomastoids which raise
the sternum.
Expiration is passive during quiet breathing but during exercise it becomes active. The
most important muscle is the abdominal wall which contracts, increasing intrabdominal
pressure and resulting in the diaphram being pushed upward. The internal intercostal
muscles perform the opposite action of the externals, pulling the ribs downward and
inward thus decreasing intrathoracic pressure. They also stiffen which prevents bulging
outward due to straining.

The trachea, extending from the inferior end of the larynx into the thorax, terminates at the sternal angle,
where it divides into the right and left main bronchi. Deviation of the trachea from the midline often signals the
presence of a pathological process. In adults, the trachea is approximately 2.5 cm in diameter, whereas in infants
it is the diameter of a pencil. The trachea is a fibrocartilaginous tube, supported by incomplete cartilaginous
tracheal rings. They are deficient posteriorly where the trachea is adjacent to the esophagus. The rings keep the
trachea patent. The posterior gap in the tracheal rings is spanned by the involuntary trachealis muscle, smooth
muscle connecting the ends of the tracheal rings. Lateral to the trachea are the common carotid arteries and
thyroid lobes. Inferior to the isthmus of the thyroid gland are the jugular venous arch and the inferior thyroid
veins.
The airways consist of a series of branching tubes. The trachea
divides into the left and right main bronchi, which in turn
divide into lobar then segmental bronchi. This process
continues down to the terminal bronchioles (TB) which are
the smallest airways without aveloi. Since none of the airway
up to this point (the conducting airway) takes part in gas
exchange it is called the anatomical dead space. This acounts
for approximately 150ml in adults. Everything distal the the
TBs is the respiratory zone and from each TB is an acinus. TBs
divide into respiratory bronchioles and alveolar ducts. The
distance from the TB to the most distal alveolus is only a few
millimetres but the respiratory zone makes up most of the
lung, its volume about 2.5-3 litres at rest. Because the area
increases so dramatically the forward velocity drops away
dramatically, as a result most of the gas movement in the
distal airways is by diffusion which is important from a gas
exchange perspective.
Each lung has a large pulmonary artery supplying blood to it and two pulmonary veins draining
blood from it. The right and left pulmonary arteries arise from the pulmonary trunk at the level
of the sternal angle. The pulmonary arteries carry poorly oxygenated (venous) blood to the
lungs for oxygenation. The pulmonary arteries pass to the corresponding root of the lung and
give off a branch to the superior lobe before entering the hilum. Within the lung, each artery
descends posterolateral to the main bronchus and divides into lobar and segmental arteries.
Consequently, an arterial branch goes to each lobe and bronchopulmonary segment of
the lung, usually on the anterior aspect of the corresponding bronchus. The pulmonary
veins, two on each side, carry well-oxygenated (arterial) blood from the
lungs to the left atrium of the heart. Beginning in the pulmonary capillaries,
the veins unite into larger and larger vessels. Intrasegmental veins drain
blood from adjacent bronchopulmonary segments into the intersegmental
veins in the septa, which separate the segments. A main vein drains each
bronchopulmonary segment, usually on the anterior surface of the
corresponding bronchus. The veins from the parietal pleura join the
systemic veins in adjacent parts of the thoracic wall. The veins from the
visceral pleura drain into the pulmonary veins. The bronchial arteries supply
blood to the structures making up the root of the lungs, the supporting
tissues of the lung, and the visceral pleura. The left bronchial arteries arise
from the thoracic aorta; however, the right bronchial artery may arise from
an intercostal artery or bronchial artery. The small bronchial arteries provide
branches to the superior esophagus and then pass along the posterior aspects of the main bronchi, supplying them and their
branches as far distally as the respiratory bronchioles. The most distal branches of the bronchial arteries anastomose with branches
of the pulmonary arteries in the walls of the bronchioles and in the visceral pleura. The bronchial veins drain only part of the blood
supplied to the lungs by the bronchial arteries, primarily that distributed to or near the more proximal part of the root of the lungs
(Fig. 1.22B). The remainder of the blood is drained by the pulmonary veins. The right bronchial vein drains into the azygos vein, and
the left bronchial vein drains into the accessory hemiazygos vein or the left superior intercostal vein.
Insertion of an Intercostal Catheter The layers should be described and are
shown adjacent. Most clinicians insert the chest tube via an incision at the
fourth or fifth intercostal space in the anterior axillary or mid-axillary line.
This is the so-called safe triangle for insertion. For evacuation of a pneumothorax, the second intercostal space in the mid-clavicular line has been
suggested as an alternate site; however, this requires dissection through the
pectoralis muscle and leaves a visible scar. We suggest this approach only for
a loculated anterior pneumothorax with the use of a small bore catheter (10
to 14 Fr) rather than a standard chest tube. For evacuation of a pneumothorax, the chest tube should be directed apically, while for drainage of a
pleural effusion the chest tube should be directed inferiorly and posteriorly.

Tracheostomy A transverse incision through the skin of the neck and anterior wall of the trachea
(tracheostomy) establishes an airway in patients with upper airway obstruction or respiratory failure. The
infrahyoid muscles are retracted laterally, and the isthmus of the thyroid gland is either divided or retracted
superiorly. An opening is made in the trachea between the first and second tracheal rings or through the
second through fourth rings. A tracheostomy tube is then inserted into the trachea and secured.
Cricothyroidotomy On the anterior neck, palpate the laryngeal prominence, which forms the superior edge
of the thyroid cartilage and is popularly called the Adam's apple. It is especially prominent in men. Next,
palpate the trachea and note that it is the caudal continuation of the larynx and no longer palpable as it
enters the mediastinum. The trachea is comprised in large part by a row of C-shaped cartilaginous rings that
are deficient posteriorly where the trachea rests against the anterior esophagus.
Next, identify and palpate the cricoid cartilage, which is a complete cartilaginous ring, shaped like a signet ring, with its widest part found posteriorly.
The boundaries of the cricothyroid membrane are the thyroid cartilage superiorly, the cricoid cartilage inferiorly, and the cricothyroideus muscles laterally on both sides.
Palpate the cricothyroid membrane. It is located about 2 cm caudal to the laryngeal prominence. It can be identified by a slight depression in this area. The anatomical
relationship between the thyroid and cricoid cartilages and the cricothyroid membrane is the most important landmark when performing cricothyroidotomy. The
cricothyroid arteries are branches of the superior thyroid arteries that course along both sides of the cricothyroid membrane and anastomose in the midline, closer to the
superior border of the membrane. Try to avoid these arteries (although this can be difficult) when performing the procedure by incising the membrane in its lower third.

MECHANICS OF BREATHING
Work of breathing work is equal to the product of force applied and the distance moved. This is exactly analogous in the respiratory system, however in this setting it is

the pressure applied and the resultant volume attained. The units are the same, 1 joule = 1 newtown metre (1 newtown moves its point of application 1 metre) = 1 litre
kilopascal (when 1 litre moves in response to a pressure gradient of 1 kilopascal). The work done by the muscles of respiration result in an efficiency of around 10% during
quiet breathing i.e. for every it requires 10 joules of effort to result in the movement of 1 litre kilopascal, the extra work is lost overcoming the impedence in the system.
Luckily at rest the respiratory system uses only about 2% of the metabolic rate, therefore this inefficiency is tolerated. When increased demands are placed on the system or
the impedence is increased in disease states however, the efficiency decreases further and patients may become overwhelmed as any increase O2 from ventilation is entirely
consumed by the muscles of breathing.

500

Elastic Work

Tidal Volume (ml)

Non Elastic Work

Inspiration
Expiration

3.3
Airway Pressure (cm.H2O)

The work of breathing overcomes two main sources of impedence, the elastic recoil of the lungs and the chest
wall, whose energy is stored for further use (expiration) and non elastic resistance of the lung tissues, of the forces
of inertia and of the resistance to airflow whose energy is lost as heat. This is shown graphically adjacent. Note
that during normal breathing expiration does not incur a cost because the stored potential energy from the
elastic work accounts for the non elastic force. For a constant minute volume the work done against elastic forces
is increased when breathing slow and deep, conversely the work performed when there is high non elastic forces
(mainly airways resistance) is increased when breathing. People with high resistance in respiratory system
(asthmatics and emphysema) will tend to take slow and deep breaths and those with high elastic requirements
such as those with pulmonary fibrosis will preferentially take shallow quick breaths. In both cases the patient is
minimising the impedence cost and therefore the work of breathing. Each of these forms of impedence will be
discussed in greater detail below.

Compliance The slope of the pressure-volume curve, or the volume change per unit pressure change, is known as the compliance. For lungs in a normal patient the
compliance is 200ml.cmH2O . If the chest wall is equally compliant then it is possible to calculate the total compliance. This is because compliance is analogous to electrical
capatance. Addition of the reciprocals of lung and chest wall equals the reciprocal of total compliance. 1/200 + 1/200 = 1/100. Therefore TC = 100ml.chH2O
1
Total compliance

1
1
+
Lung compliance
Chest compliance

DYNAMIC COMPLIANCE
Is the slope of the volume/pressure curve (see above left)
500/3.3 = 150ml/cm.H2O

Inspiration

Pause

Expiration

Tidal
Volume

Airway Pressure

Inspiratory Flow

STATIC COMPLIANCE
Compliance is measured as the change in lung volume divided by the the corresponding change in appropriate
pressure gradient, there being no gas flow when the two measurements are made. For lung compliance the
appropriate pressure gradient is alveolar-intrapleural. For chest wall compliance the gradient is intrapleural-ambient
and for total compliance is alveolar-ambient. Dynamic compliance is measured during regular breathing at the end of
inspiration and expiration (when there is no flow). Static compliance is measured by interupting the breathing cycle at
different times, then waiting for stabilisation before plotting the change in pressure and volume. This stabilisation
period represents the tissue resistance and the airway resistance being removed from the calculation of compliance.
Generally it is total compliance which is measured as it is the comparison between the ambient and alveolar pressures
(pressure at the mouth equals alveolar pressure when there is no flow). It is possible however to measure lung
compliance by estimating the intrapleural pressures with an oesophageal balloon. Specific compliance is used to
compensate for the variation seen with different lung sizes and is the compliance per unit volume of the lung and is
usually calculated by compliance/FRC. It is almost constant for both sexes and all ages down to the neonate.

Pmax
P1
P2
Time

Elastic properties of the chest wall When air is introduced into the pleural space the lung collapses inwards and the chest wall springs outwards. The elastic forces
of the lung and the chest wall are in equilibrium; the tendency of the lung is to contract down, and the tendency of the chest wall is to expand resulting in negative
intrapleural pressure. At the end of normal expiration the two forces balance, the lung volume is at functional residual capacity (FRC). The transpulmonary pressure is the
difference between the alveolar and intrapleural pressures. Chest wall compliance may be reduced by obesity, by loss of skin elasticity (eg burns patients) or by skeletal
problems such as fusion of the costochondral joints. Posture is also very important in terms of chest wall compliance, compaired with the supine position, the seated
position results in an increase in thoracic cage compliance of 30%. Furthermore, total static compliance of respiratory system is dimished 60% in the prone position.

Pressures and flow during the breathing cycle At rest, the pressure in the alveoli of the lung is the same as at the mouth, ie zero with
respect to atmospheric pressure. The intrapleural pressure is -5cmH2O. The volume of gas within the lungs is the FRC, and there is no gas flow
into or out of the airways. During inspiration, intrapleural pressure falls because of the activity of the inspiratory muscles expanding the chest
wall. This is transmitted across the lung, and alveolar pressure falls towards -1cmH2O. Since this is subatmospheric air flows from the mouth to
the alveoli. At the end of inspiration the intrapleural pressure is -8 cmH2O, alveolar pressure is again atmospheric and gas flow to the lungs has
ceased, the result being 500ml of air has flowed into the lungs. Expiration commences when the activity of the inspiratory muscles stop. The
lung and the chest wall decrease in volume as the equilibrium between the expanding chest wall and the elascitcity of the lung move back
down to resting volume.
Regional differences in pleural pressure.

It has been shown that the intrapleural pressure is less negative at the bottom than the
top of the lung. The reason for this is the weight of the lung. The alveoli in the upper part of the lung have a larger volume than those in the
dependent part except at total lung capacity. The greater degree of expansion of of the alveoli in the upper part results in a greater transmural pressure gradient, which decreases steadily down the lung at about 1cmH2O per 3cm of vertical height. There are important
consequences of this regional differences in transmural pressure, in particular as it pertains to ventilation-perfusion relationships and the
airway closing capacity.

Ventilation consequences Now when we talk of regional differences in ventilation, we mean the change in volume per unit resting
volume. It is clear from that the base of the lung has both a larger change in volume and smaller resting volume than the apex. Thus, its
ventilation is greater. Note the paradox that although the base of the lung is relatively poorly expanded compared with the apex, it is better
ventilated. The same explanation can be given for the large ventilation of dependent lung in both the supine and lateral positions.

Interpleural Pressure
-10cm H2O

more inflated
less expansion

gravity

less inflated
more expansion

-2.5cm H2O
The airways and alveoli in the dependent parts of the lung are always smaller than those at the apex (except at TLC or
zero gravity when they are equal). As the lung volume is reduced towards residual volume, there is a point at which dependent airways begin to close, known as the closing
capacity (CC). An alternative term is the closing volume (CV) which equals the CC-RV. Closing capacity increases linearly with age and is less than FRC in young adults but
increases to become equal to FRC at the mean age of 44 in the supine position and 75 years in the upright position. The closing capacity seems to be independent of body
position but the FRC varies markedly with position. When the FRC is less than the CC some of the pulmonary blood flow will be distributed to alveoli with closed airways,
usually in dependent parts of the lungs. This will constitute a shunt. Measurement of closing capacity is made by inspiration of a tracer gas from RV when dependent airways
are closed, preferentially distributing it to the upper airways. The patient then slowly exhales from TLC. When the dependent airways close again the tracer gas will spike in
concentration, at this point is the closing capacity.

Closing capacity

Elastic Recoil of the Lung For many years it was thought that the elastic recoil of the lungs was solely due to the elastin fibres

present in the lung parenchyma. This notion was disproven by von Neergaard who showed a lung completely filled with saline had much
greater compliance. This is shown in the adjacent diagram. Also note that the pressure is greater during inspiration rather than expiration,
this is termed hysteresis and is a feature of all elastic bodies. Von Neergaard correctly concluded that this was due to the extensive surface
tension acting throughout the vast air/water interface in the lungs. Thus the elastic recoil of the lungs is dependent on both the elastic
fibres of the parenchyma and the surface tension of the alveoli. It is the later of these two which is considered more important.

Lung compliance may be reduced by an increase of fibrous tissue in the lung, due to alveolar oedema, if a part of the lung is
unventilated for a long period of time, and is somewhat reduced by increased pulmonary venous pressure and the lung becoming
engorged with blood. Lung compliance is also reduced at the extremes of inflation. Lung compliance is increased in patients with emphysema and there is conflicting
reports on the effects of age on compliance. By definition compliance is V/P, therefore larger lungs are likely to have a larger V and subsequent compliance,
hence the use of specific compliance to make conclusions about the intrinsic elastic properties of the lung tissue. The other main factor which influences lung
compliance, namely surface tension/surfactant.
WITHOUT SURFACTANT (T is constant)
2T
R
T

2T
r

FLOW
r

WITH SURFACTANT (T decreases with

decreased radius)
2T
R
T
t

FLOW
R

2t
r

Surface Tension develops at air-water interfaces where the forces of attraction between the water molecules are much greater than those
between the water and gas molecules. The result is that the liquid surface area becomes as small as possible as in a soap bubble where the
shape of a sphere is assumed and pressure (P) is produced inside the bubble because of the surface tension. The pressure inside the bubble is
determined by the radius of the bubble and the surface tension of the liquid. This was first characterised by Laplace. Pressure = 4(Surface
tension)/Radius. If the bubble is a sphere and therefore has only one surface the formula is P = 2T/R. There is a very important consequence
of this, if we assume that alveoli are spheres then smaller alveoli will have greater pressure and therefore will redistribute their contents to
larger bubbles. This is not what is observed and it is believed that this is due to the presence of surfactant.
Surfactant is formed from type II alveolar cells. It is mostly phospholipid with the principle component DPPC which equates to roughly
80% content. There are also four surfactant protiens SP A to D. These are believed to be important in the stabilisation of the surfactant, its
activation and release from alveolar cells. Surfactant forms a mono layer due to its structure with a hydrophilic head adjacent to the cell wall
and the hydrophobic tail facing inwards towards the air. Surfactant has a 15-30 hour half life and in addition to its primary role of reducing
surface tension also prevents transudation into in the the alveolus (less pressure inside alveolus) and has an immunological role. The exact
mechanism of how it reduces surface tension is unknown but the main hypothesis is that as it packs closer together when the alveolus
reduces in size the action is accentuated, causing a greater decrease in surface tension with decreases in radius.

Time constant and Fast and Slow Alveolus The concept of the time constant is used to describe the exponential filling and emptying of a lung unit. One time constant
is the time taken to achieve 63% of maximal inflation or deflation of the lung unit. After three time constants the lung unit will be 95% full. The time constant of the lung is a
product of the resistance and the compliance. The resistance for normal lung tissue is 2 cm.H2O/L pre second and the total compliance is 100ml/cmH2O (assuming lung
compliance and chest wall compliance of 200ml/cmH2O each), therefore the time constant for the whole lung is 0.2s. This is across the whole lung. We know however that the
resistance and compliance of alveolar units are not always equal throughout the lung, and therefore by definition there will be different time constants for different areas. An
alveolar unit with low resistance and low compliance will fill quickly - a so called fast alveolus and a unit with high resistance and high compliance will take a long time to fill,
resulting in a slow alveolus. This is not significant usually in non diseased lungs (as there is minimal differences in alveolar speed) but may make regional ventilation
dependent on the frequency of ventilation in disease states especially at high rates when the inspiratory time is decreased.

Respiratory system resistance unlike elastic resistance, respiratory system resistance, the non elastic components of impedence do not store potential energy, it is

dissapated as heat. There are three main types of resistance; tissues resistance, inertance and airway resistance. The later is the most important and is considered seperately
below. Tissue resistance originates from both lung and chest wall tissues, with a significant proportion originating from the chest wall. Tissue resistance can be measured in
anaesthetised patients using the end inspiratory interruption method similar to the measurement for static compliance adjacent. In this instance however, it is the decrease
from P1-P2 that represents tissue resistance. Inertance is analogous to electrical inductance. It represents the system resistance caused during the change in direction of gas
flow. Its contribution to total respiratory system resistance is likely to be negligable, however it may become a factor during high respiratory frequencies.

Physics of gas flow Gas flows from a region of high pressure to one of lower pressure. The rate at which it does so is a function of the pressure difference and the
resistance to gas flow thus being analogous to an electrical current. The precise relationship between pressure difference and flow rate depends on the nature of the flow
which may be laminar, turbulent or transitional.
Laminar flow; the gas flows along a straight unbranched tube of a minimum length as a series of cocentric cyclinders that slide over each other with the cental cyclinder
moving the fastest. This is particularly significant in high frequency ventilation, it means that some of the alveolar will be ventilated even when the tidal volume is less than
the anatomical dead space (by the high velocity central cylinder). With laminar flow the gas flow rate is directly proportional to the pressure gradient along the tube, and it is
the viscosity of the gas which influences flow rate according to the Poiseuille equation. Because it is to the fourth power, changes in radius have significant consequences.
resistance = P / flow rate

Poiseuille Equation

flow rate =

P X
X radius
8 X length X viscosity

Turbulent flow high flow rates, particularly through branched or irregular tubes results in the breakdown of orderly gas flow seen in laminar flow models. The result is
turbulent flow, which has a square front (rather than cone shaped). It means that no fresh gas can reach the end of the tube until the amount of gas entering the tube is
almost equal to the amount of gas in the tube, thus has important consequences with respect to anatomical dead space. Flow is no longer directly proportional to the
pressure drop but rather its square root. As the relationship is no longer linear, the resistance is not constant but varies with flow. Turbulent flow is not affected by gas
viscosity but is inversely proportional to the square root of density. This is why divers find it difficult to breath at depth, helium has a low density and is therefore easier to
breath at higher pressures if the flow is turbulent (larger airways). It has a similar viscosity to air and therefore at laminar flows it makes little difference.
Whether flow is turbulent or laminar is dependent on the Reynolds no. Re = 2(radius)(ave velocity)(density)/viscocity. The higher the number the more likely the flow is
turbulent (usually >2000). Due to the complex nature of the bronchial tree it is difficult to apply the above principles. It is unlikely that flow in the respiratory system is
laminar until the very small airways (probably the 11th generation) where the Reynolds numbers are low. In general, the driving pressure is determined by both the flow
2
rate and its square P=K(FR) + K(FR)

Airways Resistance the main site of airways resistance is the medium sized bronchi. This was determined experimentally. One consequence of this is that measurements
of airways resistance may not detect airways disease in the peripheries leading to a delay in diagnosis until the condition has progressed further. There are a range of factors
which determine airways resistance, and these relate to the physics of resistance. Anything that reduces the calibre of airways will lead to an increase in resistance, examples
of this are decreased lung volume, if the bronchi become narrowed due to bronchospasm, mucous oedema, mucus plugging, or epithelial desquamation. There are four
main pathways in controlling the muscle tone in bronchioles and bronchi. Neural pathways are primarily parasympathetic activation but also reduced levels of consciousness
there may be loss of pharyngeal reflexes and subsequent increase in resistance. Humoral pathways are adrenaline via the blood. Physcial and chemical effects include
laryngeal spasm or subglottic oedema due to anaesthetic procedures, inhalation of an irritant such as an aerosol of water or cold air. Local cellular effects include immunological activation and subsequent inflammation. Airways may become obstructed due to tumour, gastric contents or blood. In addition to changes in the calibre of the
airway (and length) the other important factor in airways resistance is the composition of the gas, which dense gases increasing resistance during turbulent flow and viscous
gases increasing resistance during laminar flow.
Airways resistance can be measured in anaesthetised patitents using end inspiratory interruption and is represented by Pmax-P1/flow rate. The other method involves using
a body plethysmograph and is based on boyles law to calculate the alveolar pressure accurately and therefore the using the pressure at the mouth the defference can be
calculated, divide by flow and the result is the airways resistance.

PULMONARY GAS VOLUMES AND VENTILATION

Pulmonary Volumes To the left in are listed four pulmonary lung volumes that, when added
together, equal the maximum volume to which the lungs can be expanded. The significance of each
of these volumes is the following: The tidal volume is the volume of air inspired or expired with each
normal breath; it amounts to about 500 milliliters in the adult male. The inspiratory reserve volume is
the extra volume of air that can be inspired over and above the normal tidal volume when the person
inspires with full force; it is usually equal to about 3000 milliliters. The expiratory reserve volume is
the maximum extra volume of air that can be expired by forceful expiration after the end of a normal
tidal expiration; this normally amounts to about 1200 milliliters. The residual volume is the volume of
air remaining in the lungs after the most forceful expiration; this volume averages about
1200 milliliters.
Pulmonary Capacities In describing events in the pulmonary cycle, it is sometimes desirable to

consider two or more of the volumes together. Such combinations are called pulmonary capacities.To
the right are listed the important pulmonary capacities, which can be described as follows: The vital
capacity equals the inspiratory reserve volume plus the tidal volume plus the expiratory reserve
volume. This is the maximum amount of air a person can expel from the lungs after first filling the
lungs to their maximum extent and then expiring to the maximum extent (about 4700 milliliters). The
inspiratory capacity equals the tidal volume plus the inspiratory reserve volume. This is the amount of
air (about 3500 milliliters) a person can breathe in, beginning at the normal expiratory level and
distending the lungs to the maximum amount. The functional residual capacity equals the expiratory
reserve volume plus the residual volume. This is the amount of air that remains in the lungs at the end of normal expiration (about 2400 milliliters). The total lung
capacity is the maximum volume to which the lungs can be expanded with the greatest possible effort (about 5900 milliliters); it is equal to the vital capacity plus the
residual volume.
As discussed in the previous page, the FRC has particular importance with realtion to the closing capacity. A range of different factors affect the FRC. These include sex;
for the same body height, females have a FRC that is 10% less than males. Age; FRC increases slightly with age increasing about 16ml per year. Body size; FRC is linearly
related to height. Obesity causes a marked reduction in FRC compared to lean subjects of the same height. These factors may be combined to calculate FRC for
example in white males aged 25-65 FRC = (5.95 X metre height) + (0.019 X age) - (0.086 X BMI) - 5.3. Other factors which influence the FRC are diaphragmatic muscle
tone and posture. The later is may result in differences of between 500-1000ml between the supine and upright positions. This is caused by the pressure of the
abdominal contents on the diaphram. Finally lung disease plays a major role in variation of FRC. Anything that increases the elastic recoil of the lungs, thoracic cage or
both will decrease FRC. Possible causes include lung fibrosis, pleural thickening, kyphoscoliosis, obesity and scarring of the thorax such as in a burns patient.
Conversely, if the elastic recoil of the lungs is diminished such as in emphysema and asthma the FRC is usually increased. This is beneficial as the airway resistance is
decreased as the lung volume increases.

Measurement of respiratory volumes Most of the volumes and capacities may be measured or inferred using normal spirometry. The residual volume
however in not able to be calculated by this method, and therefore also the functional residual capacity and total lung capacity. Three methods may be employed to
calculate these unknowns. The first employs nitrogen washout by breathing 100% oxygen. If the lungs are initially at 80% N2 (before the 100% O2) and 4 Litres is
collected following complete washout with O2, then the total lung capacity can be calculated as 5 Litres. The second method is a wash in of a tracer gas. If 50ml of
Helium is inhaled and the helium concentration is then found to be 1%, TLC is calculated as 5 Litres. The third method involves a body plethysmograph, the pressures
and volumes are measured and boyles law is applied.
Dead space It was realised in the 19th century that a component of each inspiration that does not
penetrate the regions of the lung in which gas exchage took place and therefore was exhaled unchanged.
This fraction of the tidal volume is known as the dead space whilst the efective component of the minute
volume of respiration is known as the alveolar ventilation.

APPARATUS DEAD SPACE

PHYSIOLOGICAL
DEAD SPACE

ANATOMICAL DEAD SPACE

ALVEOLAR DEAD SPACE

Alveolar Ventilation = Respiratory Frequency (tidal volume - dead space)

The first component to dead space is the apparatus dead space which is only a factor if there is external
breathing apparatus such as a ventilator.

Unperfused
alveolus

The next component is the anatomical dead space. This consists of the volume of all the conducting
airways where gas exchange does not take place. In normal physiological settings it is approximately 2ml/kg,
and often simplified to 150ml in adults (equivalent to a 75kg individual). Despite this simplification it is
important to be aware of the circumstances where it may be variable beyond the patient weight. In neonates
and infants the ADS is increased due to the disproportionate size of the head and neck, and a value of
3.3ml/kg is used up to the age of 6. Posture is important with a supine patient having approximately 30%
less ADS. The position of the neck and jaw is also significant with sniffing the roses producing higher
volumes and neck flexed and chin depressed decreasing the volume. Increasing FRC results in a larger ADS. Drugs which affect bronchiolar tone influence ADS. Finally
tracheal intubation, tracheostomy or LMAs bypass much of the extrathoracic ADS which is normal about 70ml.
The alveolar dead space is the part of the inspired gas that passes through the ADS but does not take part in gas exchange. The cause of the failure of gas exchange
is lack of effective perfusion of the spaces to which gas is distributed at the alveolar level. The alveolar dead space is too small to be measured with confidence in healthy
subjects but may be significant in two pathological states. Pulmonary embolism is a direct cause of alveolar dead space that may reach massive proportions. Low cardiac
output results in decreased pulmonary perfusion to the uppermost parts of the lung, and has appreciable influence on the alveolar dead space.

Physiological dead space is is the sum of all the parts of the tidal volume that do not take place in gas exchange. It is calculated by the Bohr equation and
represents the sum of the ADS and alveolar dead space.

Bohr equation Uses three parameter to estimate the physiological dead space and is based on the assumption that only perfectly perfused and ventilated alveoli take
place in exchange (and therefore the CO2 equalises vessel-alveolus) and the inspired CO2 is 0. The three parameters are Tidal Volume, End tidal CO2 and Arterial PCO2.
CO2 Output = PECO2
Tidal volume = TV
Arterial CO2 = PaCO2

PECO2 X TV = PaCO2 X (TV - PDS)

normally: TV =500
PECO2 = 28
PaCO2 = 40
28(500) = 40 (500-PDS)
therefore; PDS=150

Fowler method This orginially used a nitrogen washout technique, but has been subsequently modified to a CO2 washout technique. It is

based on a graphical method shown adjacent.

B
%CO2

CO2 Input = 0

A=B
A
0.15

0.30

Expired Volume (L)

CONTROL OF VENTILATION
CENTRAL CONTROLLER

SENSORS / FEEDBACK
Central Chemoceptors The most important receptors involved in the minute-byminute control of ventilation are those situated near the ventral surface of the medulla in
the vicinity of the exit of the 9th and 10th nerves. The central chemoreceptors are
surrounded by brain extracellular fluid and respond to changes in its H+ concentration. An
increase in H+ concentration stimulates ventilation, whereas a decrease inhibits it. CO2 is
able to cross the blood brain barrier but is normally impermiable to H+ and HCO3. CO2
therefore crosses the barrier and hydrates to carbonic acid, which ionises to give a pH
inversely proportional to the log of CO2. A hydrogen sensor is thus made to respond to
changes in CO2. The response in ventilation is (respiratory depth and rate) is linear over the
range that is usually studied. There is a compensatory shift in CSF bicarbonate concentrations when the patient has prolonged CO2 retention which happens over hours.

Suprapontine Cortex - Breathing can be voluntarily

interrupted and the pattern of respiratory movements altered

within the limits determined mainly be changes in arterial blood
gas tensions. The neurones involved in this cortical overide of
respiration may completely bypass the respiratory centres and
act driectly on LMNs. In addition to volitional changes in the
pattern of breathing suprapontine changes are important in
reflexes such as sneezing, mastication, swallowing and coughing
as well as coordination during speech. The Limbic and
hypothalamus may also affect breathing for example in
emotional states such as fear and rage.

Peripheral Chemoceptors are located in the carotid bodies at the bifurcation of the

Airway Reflexes

Nose: irritants may cause sneezing, or apnoea. Pharynx: mechanceptors that respond to pressure play a major role in activation of the pharyngeal dilator
muscles. Larynx: Three main groups, mechanoceptors respond to changes in transmural
pressure and act on the pharyngeal dilators, cold receptors are found on the vocal cords
and their activation generally depresses ventilation and irritant receptors cause cough,
laryngeal closure and bronchoconstriction. Cough Reflex may be elicited by chemical or
mechanical stimuli arising from the larynx, trachea, carina or main bronchi. It may be
voluntary and has three phases, inspiratory, compressive (expiration against a closed
glottis) and explusive.

Lung Reflexes Pulmonary stretch receptors are believed to lie within the airway
smooth muscle. main reflex effect of stimulating these receptors is a slowing of respiratory
frequency due to an increase in expiratory time. This is known as the Hering-Breuer
inflation reflex. The opposite response is also seen; that is, deflation of the lungs tends to
initiate inspiratory activity (deflation reflex). The reflexes are largely inactive in adult
humans unless the tidal volume exceeds 1 liter, as in exercise.

Pons Pontine neurones fire in synchonry with different

phases of respiration and are referred to as the pontine
respiratory group PRG. They influence the medullary
respiratory neurones via a multisynaptic pathway
contributing to fine control of the respiratory rhythm.

Medulla The medulla is accepted as the area of the brain

where the respiratory pattern is generated and where the
various demands on respiratory activity are coordinated.
Respiratory neurones in the medulla are mainly concentrated
in two anatomical areas, the ventral and dorsal respiratory
groups (VRG and DRG) which have numerous interconections.
The DRG is primarily concerned with the timing of respiration
and the inspiratory phase. The VRG comprises a column of
respiratory neurones. In influences both inspiratory and
expiratory phases and most inportantly has the pre Botzinger
complex which is believed to be the location of the central
pattern generator. Unlike the heart there is no single
pacemaker, but rather a group pacemaker hypothesis.
concentrated in the CPG. Groups of neurones influence the
three main phases of respiratory cycle. The inspiratory phase,
the pharyngeal dilators first contract then there is a ramp
increase in inspiratory neurone firing leading to inspiratory
muscle activation. The second phase (expiratory phase I) is a
passive let down of inspiratory muscles. The final phase
(expiratory phase II) involves active expiration if required, the
inspiratory neurones are now silent.

OVERRIDE

common carotid arteries, and in the aortic bodies above and below the aortic arch. The
carotid bodies are the most important in humans. The peripheral chemoreceptors respond
to decreases in arterial PO2 and pH, and increases in arterial PCO2. The carotid bodies have
a very high blood flow for their size, and therefore in spite of their high metabolic rate, the
arterial-venous O2 difference is small. The peripheral chemoreceptors are responsible for
all the increase of ventilation that occurs in humans in response to arterial hypoxemia. The
response of the peripheral chemoreceptors to arterial PCO2 is less important than that of
the central chemoreceptors. However, their response is more rapid, and they may be useful
in matching ventilation to abrupt changes in PCO2. In humans, the carotid but not the
aortic bodies respond to a fall in arterial pH. This occurs regardless of whether the cause is
respiratory or metabolic. Interaction of the various stimuli occurs. Thus, increases in
chemoreceptor activity in response to decreases in arterial PO2 are potentiated by
increases in PCO2 and, in the carotid bodies, by decreases in pH.

Baroreceptors An increase in arterial blood pressure can cause reflex hypoventilation or

apnea through stimulation of the aortic and carotid sinus baroreceptors. Conversely, a
decrease in blood pressure may result in hyperventilation.

Proprioceptors Impulses from moving limbs are believed to be part of the stimulus to
ventilation during exercise, especially in the early stages.

Pain and Temperature Stimulation of many afferent nerves can bring about changes
in ventilation. Pain often causes a period of apnea followed by hyperventilation. Heating of
the skin may result in hyperventilation.

Upper Motor Neurones

The intergration of respiratory

control which took place in the CPG continues to take place at
the junction of the UMN with the anterior horn cells supplying
the LMN. There are three groups of UMN from separate
anatomical locations integrated here. The involuntary rhythmic
control of inspiration and expiration group from the CPG, the
voluntary control of breathing group (speech etc) and in the
involuntary non rhythmic control of breathing group (cough,
sneezing, swallowing).

EFFECTORS
Muscles of Respiration These include the pharyngeal and
laryngeal muscles, in particular the pharyngeal dilator muscles,
including gleniglossus and tensor palati. The diaphram is the
most important effector of respiratory activity. The internal and
external intercostals and accessory muscles such as sternomastoids are also important but to a lesser extent. The abdominal
muscles are important in forced expiration.

Carbon Dioxide The most important control of ventilation under normal conditions is the PCO2 of the arterial blood. In the course of the day with periods of rest and
exercise the arterial Pco2 is probably held within a 3mmHg range. Following a rise in Pco2 the respiratory depth and rate increases until a steady state of hyperventilation is
achieved after a few minutes, this can be maintained in healthy subjects for up to 8 hours. The response is linear over the range usually studied. Most of the response comes
from the central chemoceptors but the peripheral chemoceptors also contribute and their response is faster. The response is enhanced if the PO2 is lowered.
Oxygen Because the PO2 can normally be reduced so far without evoking a ventilatory response, the role of this hypoxic stimulus in the day-to-day control of ventilation is
small. Only peripheral chemoceptors are involved. However, on ascent to high altitude, and in long term hypoxemia secondary to chronic lung disease, hypoxia drive can
become important.

pH A reduction in arterial blood pH stimulates ventilation. In practice it is often difficult to separate the ventilatory response to decreased pH and increased CO2. In normal
conditions peripheral chemoceptors are the only sensors, however in disease states it is possible that the BBB may leak resulting in central chemoceptor action.

Exercise

Increased ventilation in exercise remains largely unknown. Possible explanations have included, oscillation of arterial Pco2 and Po2, propriocetors in muscles and
joints, impulse from the motor cortex and increases in body temperature.

PULMONARY CIRCULATION
Physiological features of the pulmonary versus systemic circulation Blood flow to the pulmonary
circulation is roughly equal to that of the systemic circulation (6 litres at rest, up to 25 litres at full exercise). The pressure
however is greatly reduced and as a consequence resistance. (R=P/Blood Flow). As shown in the diagram adjacent
the mean pressure for the pulmonary circulation is 15 mmHg compared to 100mmHg for the systemic circulation. The
pressure decreases by roughly the same amount in the arterioles, capillaries and venules as opposed to the systemic
circulation where the majority of decrease is in the arterioles. A consequence of the reduced pressures is also a right
ventricle which has only half the muscle mass of the left ventricle. Whilst the high pressures and resistance of the
systemic circulation enable changes to perfusion of specific organs and regions, the control in the pulmonary system is
significantly reduced and subject to much greater variation with respect to gravity (discussed in detail below) resulting
in the under and over perfusion of parts of the lung. The benefit of this system however is that it is well designed to
perform its primary function of gas exchange, providing pressures which are just enough to perfuse the top of the
lungs (and therefore in disease states this may be the first impaired). The reduced pressures also reduce the likelyhood of transudation into the aveoli (pulmonary
oedema) which causes significant impairment of gas exchange. The pulmonary arterioles contain little smooth muscle (although vasoconstricition is still possible) and
the venules and veins are almost devoid of smooth muscle and are therefore very distensible. These features ensure that the pulmonary system is also able to act as a
blood reserve and increase its volume up to five times when systemic return is increased from 0.5-1.0 litres to 2.5-3.0 litres.
Pulmonary blood volume is influenced by both posture (changing from supine to erect decreases volume by a third
due to pooling in dependent regions of the sytemic circ) and systemic vascular tone (endogenous or exogenous pressors,
g-suits or diving).

VENOUS ADMIXTURE

Lungs

1 Intrapulmonary Shunt
VENOUS ADMIXTURE

Right
Heart

2 Congential Heart Disease

VENOUS ADMIXTURE

4 Bronchial
Circulation

Venous Return

Systemic
Circulation

Venous Admixture refers to the degree of mixed venous blood with pulmonary end capillary Po2 that would be

Left
Heart

3 Thesbian
Circulation

required to produce the observed difference in the endcap Po2 and the arterial Po2. Not all blood that passes through the
pulmonary circualtion is oxygenated. This consitutes the intrapulmonary shunt. There is also the bronchial circulation
which usually arises from the aorta or intercostal arteries. This supplies the pulmonary system down to the respiratory
bronchioles therefore a majority does not tke part in gas exchange. It returns via the pulmonary veins (unoxygenated to
the left heart) or the normal venous return (via the right heart therefore not shunted). This represents two of the four types
of venous admixture (the others are the Thebsian circulation which supplies the left heart and congenital heart defects).
This will be discussed in greater detail later in the respiratory section VQ mismatch.

Pulmonary vascular pressures As stated previously the pulmonary artery pressure is only about a sixth of the systemic system. There is only a small pressure drop in
the pulmonary arterioles and therefore unlike the systemic system the control is reduced. In order to correctly interpret the physiological parameters there are three
different pressures that are measured and used in clinical practice. The most common in the intravascular pressure. This is calculated by measuring the pressure in the
pulmonary system and comparing to atmospheric pressure. The same method is used in the systemic circulation. The second method is the transmural pressure, which is
the difference in the vessel compared to that in the tissue surrounding the vessel. It is measured by an oesophageal balloon (which equates to pleural pressures) and is
helpful when you need to exclude the effect of raised intrathoracic pressures (which may suggest a much higher intravascular pressure). The final pressure is the driving
pressure. This is the difference between one point in the system and another and is usually used for the calculation of system vascular resistance by comparing the
pressures in pulmonary artery and left atrium (P).

Pulmonary Vascular Resistance is an expression of the relationship between driving pressure (DP) and flow (often simplified to the cardiac output CO), as in the
case of resistance to gas flow. As previously stated it may be expressed as; PVR = DP/CO. It is important to note however that this relationship is non linear, which is
mainly due to passive changes in the pulmonary circulatory system although active changes may play some part.

Lung inflation is the second passive influence on pulmonary blood flow. At low lung volumes the dependent tissues are compressed

which increases the resistance overall due to compression of the extra-alveolar vessels (in the parenchyma). At high lung volumes the
vessels that are within alveolar become compressed which also contributes to a significant increase in resistance, and the extra alveolar
vessels become slightly distensed due to traction which slightly reduces resistance. Thus overall there is increased resistance at both low
and high volumes, with the least resistance around the point of FRC.

Pulmonary Vascular Resistance

Passive changes in pulmonary blood flow and resistance. Three main mechanisms contribute to passive changes in PBF/PVR. Recruitment and distension due
to increases in cardiac output, changes due to the opposing influences of different lung volumes have on intra and extra alveolar blood vessels and the effect of gravity and
the so called wests zones of perfusion. Each are considered seperately below.
The pulmonary circulation can adapt to large changes in cardiac output with only small increases in the pulmonary pressures. Therefore by using
the equation shown above there must be corresponding decrease in vascular resistance with inrcrease in CO (PVR x CO=DP). This is due to two
adaptations, recruitment of previously underperfused pulmonary vessels and the other is distension of the entire pulmonary vasculature.
Distension is the more important adaptation.
TOTAL
PVR

FRC

INTRA-ALEVOLAR
RESISTANCE

EXTRA ALVEOLAR
RESISTANCE

Lung Volume

Gravity and Wests Zones of the Lung The interplay between of alveolar pressure, flow rate and vascular resistance is best considered by dividing the lung field into

three zones. This was first described by West and colleages using a starling resistor model. It is best explained using a weir model. In zone 1 the alveolar pressure
exceeds the precapillary pressure therefore there is no flow. This does not occur normally although may
be present if the pulmonary artery pressure is decreased due to shock or iatrogenically due to PPV.
Zone 2 is a situation where the alveolar pressure is less than the precap but more then the post cap. In
this setting, the flow is determined by the pressure difference between the precap and the alveolar. In
the third zone the alveolar pressure is less than both the precap and post cap, therefore it is these two
parameters which determine flow. A Zone 4 is sometimes referred to where an increase in extralveolar
pressures due to gravity increase resistance and thus flow as described above. Therefore at the very
base there is actually a reduction in flow compared to zone 3.
Precap

Alveolar

Postcap

Precap

Alveolar

Postcap

Precap

Alveolar

Postcap

Active changes in pulmonary blood flow and resistance. In addition to the three mechanisms described above the pulmonary vasculatrue is able to control

resistance by both active vasoconstiction and vasodilation. It is believed that the lung is held in a state of active vasodilation. Cellular mechanisms which include
receptors and their associated second messengers do influence vascular tone but many of these are poorly understood. There is good evidence that the basal production
of NO occurs in normal lungs and contributes to maintenence of low pulmonary vascular resistance. There are three autonomic systems which influence active control of
vascular tone, adrenergic, cholinergic and non-adrenergic non-cholinergic (NANC). Adrenergic control is the most important, alpha 1 receptors mediate vasoconstriction
and predominate, beta 2 receptors will cause vasodilation to a lesser extent. Humoral control actioned by catecholamines, Eicosanoids (which may mediate the
development of sepsis associated PHTN) amines and peptides play a role. Drugs are also important, especially inhaled NO which causes localised vasodilation, prostacyclin, ACE inhibitors and calcium channel antagonists reduce pulomnary pressures. Phosphodiesterase inhibitors such as sildenafil have significant effects as do endothelin
receptor antagonists such as bosanten.

Hypoxic Pulmonary Vasoconstriction is the last active controller of vascular resistance considered here and is it is own section. It is influenced by both alveolar and
mixed venous oxygen tensions although the alveolar is most important. Regional vasocontriction to poorly ventilated alveoli is beneficial as a means of improving V/Q
matching. It is also critical in the neonatal period for establishing normal breathing. Long term however it leads to changes which result in PHTN. Both respiratory and
metabolic acidosis augment HPV and alkalosis of any cause results in pulmonary vasodilation and thus attenuates HPV.

VENTILATION - PERFUSION RELATIONSHIPS

RILEYS THREE
COMPARTMENT MODEL

V/Q RATIOS

DEAD SPACE

CONSEQUENCE

ALVEOLAR AIR

MEASUREMENT
Dead Space Bohr equation
PEco2(TV) = PaCO2(TV- Dead Space)

TREATMENT

Alveolar air approaches

inspired air concentrations
(no exchange wasted air)
P02 = 149 CO2 = 0

Decreased perfusion leads

wasted ventilation therefore
decreased minute alveolar ventilation
& primarily to increased blood CO2

Increased tidal volumes

will reduce the effect of
dead space (note that
Alveolar Vent = TV - PDS)

Alveolar air equals

concentration of postcap
blood due to ideal exchange
P02 = 104 CO2 = 40

V/Q scatter leads to decreased

PaO2 because a majority of
mismatch flow is at ratios < 1
and a small drop is acentuated
by the point on the Hb dissociation
curve

Increased FiO2 will improve

oxygenation unless the V/Q
ratio is 0 (true shunt). High
FiO2 will remove the V/Q
scatter effect.

Alveolar air approaches

mixed venous concentrations
(no exchange wasted blood)
P02 = 40 CO2 = 46

Shunt leads to both CO2 and

O2 but the decrease in PO2 is
more pronounced because it is on
the flat of the dissociation curve and
the CO2 dissociation is near linear

Improved recruitment may

work unless the shunt is extrapulmonary. FiO2 is decreasingly
effective in true shunts > 30%

3.3
IDEAL ALVEOLUS
1

V/Q Mismatch Using the multiple

inert gas elimination technique
(MIDGET) or nuclear med studies
Alveolar air equation

0.63

TRUE SHUNT

PAO2 = FiO2(Patm - PH2O) - PaCO2/RQ)

Shunt equation (Venous admixture)

0

QT(Art O2 cont) = QS(precap O2 cont)

+ (postcap 02 cont)(QT-QS)

Ventilation refresher

- the regional distribution of ventilation is dependent on two main processes and one minor. The first is the most important and is the effect of
gravity. As the lung has weight, the lower parts of the lung are generally more compressed and less inflated than the upper part of the lungs which leads to the more
dependent parts of the lung having greater compliance (compliance = volume/ pressure ) thus they generally receive greater ventilation. In the upright position,
with slow VC inspirations the uppermost slices of the lung have ventilation at around one third of the slices at the bases. When there is slow inspiration from FRC there is
a smaller but still significant gradient of 1.5 :1. In horizontal positions this gradient is significantly reduced. The second regional variation is due to the different time
constants of alveoli. The time constant is dependent on the compliance of the alveoli unit and the resistance of the tube supplying it. If the time constants for two units
is equal then they will fill and empty at the same rate. The ultimate volume will be dependent only on regional compliances. If however the constants are not equal some
units will fill and empty quicker, if inspiration is long enough then all units will eventually fill and again final volume will be dependent on compliance only. Therefore the
inspiratory duration (and thus RR) will cause regional variation of ventilation if it is not prolonged. In patients with the commoner forms of lung disease there is usually
different time constants and sequential filling and emptying of lung units leading to ventialtion variation. The last cause of regional variation in ventilation is the
anatomy of the conducting airways which have been observed to increase ventilation to central lung units.

Perfusion refresher -

because pulmonary circulation operates at low pressures, it is partcularly influenced by the force of gravity. This has previously covered in
reference to Wests zones of the lung and the waterfall analogy. A fourth zone is sometimes described where the weight of the lung reduces flow due to interstital forces
at the very based of the lung. The other factor which causes variation is due the the vascualar anatomy and the pattern of branching which mathematical models show
contribute significantly to the heterogeneity of flow.

Ventilation/Perfusion Ratio (V/Q) - Whilst the blood flow and ventilation to the lungs is roughly equal each usually between 4-5

PERFUSION (Q)

3.3
VENTILATION (V)

litres, in different parts of the lung they are not necessairly equally matched. The effect of gravity which is the most important factor for
both V and Q is more significant in terms of perfusion. This leads to a scatter of V/Q ratios which is exacerbated in older subjects even in
the absence of lung disease. V/Q ratios at the apex of the lungs (where ventilation is relatively greater than perfusion) has values of 3.3, at
the base (where perfusion dominates) is 0.6 in normal subjects. In pathologial states alveolus may recieve no perfusion and thus forms
part of the physiological dead space. Eamples of this include a pulmonary embolism, or a sudden decrease in cardiac output resulting in
decreased perfusion to the apicies. The V/Q ratio will approach infinity. If the alveolus receives no ventilation it represents a form of true
shunt and the V/Q ratio will be 0 . Compensatory mechanisms for V/Q scatter include hypoxic pulmonary vasoconstriction discussed
previously.

V/ Q R

1.0

ATIO

0.63
LUNG BASE

LUNG APEX

The shunt equation is based on the assumption that the total oxygen carried by the aterial blood may be calculated by adding the oxygen contents of the blood that
passes the lungs and the shunted blood. Assuming ideal gas exchange (to calculate Postcap O2 content) it is possible to create this in an equation as follows:
Lung flow = (T - S)

Cardiac Output X Aterial O2 Content = Lung Flow X Postcap O2 Content + Shunt Flow X Mixed Venous O2 Content
Postcapillary
O2 Content = Cco2
Cardiac input = T
Mixed Venous
= Cvo2
O2 Content

Left
Heart

Right
Heart

Cardiac Output = T
Aterial
= Cao2
O2 Content

Using the abbreviations shown in the diagram this becomes;

T X Cao2 = (S X Cvo2) + (T - S)Cco2

S
T

rearranged gives the shunt equation;

Cco2 - Cao2
Cco2 - Cvo2

Shunt flow = S

The Bohr equation is based on the assumption that CO2 exchange is ideal (alveolar and post capillary
values are equal) therefore any difference in the expired and arterial CO2 is due to dead space.
PECO2(VT) = PACO2(VT - VD)

it is commonly rearranged to

VD
VT

PEXPIRED CO2(Tidal Vol)

=

PECO2 - PACO2
PACO2

PARTERIAL CO2(Tidal Vol - Dead Space)

The alveolar equation calculates the ideal alveolar PAO2 . It can then be used to assess the Alveolar-arterial gradient of O2. It is never equal due to V/Q mismatching. The normal value in a 20 year old patient is around 7, but this increases gradually with age, an 70 year old patient having a normal A-a gradient of 17 (the formula is
2.5 + age x 0.21). The alveolar equation needs to account for water vapour and air pressure and is therefore represented by the following equation:
PAO2 = (FiO2 x [Patm - PH2O]) - (PaCO2 R)

R is usually 0.8
Patm is 760 at sea level
PH2O is 47 at body temp

the A-a gradient = PAO2 - PaO2

Measurement of V/Q mismatch is problematic. The shunt equation measures venous admixture which is the amount of venous blood that is needed to add
to the arterial blood to compensate for the difference between ideal and actual O2 content of the post capillary and arterial blood. In reality it consists of both V/Q
mismatching and true shunting. A three compartment model aggregates the mismatch compenent with the true shunt component. Response to increasing FiO2 can
tease out this difference. VQ Mismatch with correct however true shunt will not, especially if the shunt is >30% Accurate measurement of V/Q relationships is possible
using Multiple Inert Gas Elimination Techniques (MIGET) which uses six different gases with varialble solubilty to measure the V/Q ratios. This method is
very complicated which reduces its utility but it gives a much more accurate picture than the three compartment model.
Blood Flow
Ventilation

1
Normal 20 year old Patient

note the increased

mismatch due to
closing capacity at
low volumes

1
Normal 50 year old patient

The main issue is excess

ventilation without
perfusion. This pattern is
also present in the
destructive manifestation
of COPD (emphysema)
1
Patient with Pulmonary Emboli

The main issue is excess

perfusion without
ventilation. This pattern is
also present in the
obstructive manifestation
of COPD
1
Patient with Asthma

DIFFUSIVE TRANSFER OF RESPIRATORY GASES

The Oxygen Cascade
1. Inspired Gas
Barometric pressure (normally 760mm Hg)
Oxygen Concentration (21%)

160

2. Humidified Gas results in a decrease in oxygen of around 10mmHg

At body temperature, H2O = 47mmHg Therefore: ((760-47) 0.21)= 150

100

3
This step in the oxygen cascade is often the most important clinically. In
normal patients the decrease here is usually around 5mmHg usually due to V/Q mismatch, the
physiological shunt caused by the thebsian and bronchial venous systems. In disease states
however the drop may be more profound and is usually due to marked ventilation perfusion
inequality although pathological shunts such as congenital heart disease may also result in
significant O2 decreases. Rarely impaired diffusion may cause a drop in O2 as well.

6. Tissue O2. As oxygen is constantly required for aerobic metabolism, the partial pressure of
Oxygen in tissues is generally always lower than the capillary bed, therefore there is a diffusion
gradient is in place. The interstitual PO2 ranges normally from 40-5mmHg with an average of 23.
As mitocondria require an external gradient of only 2-3mmHg there is a good range of safety in
place. As the PO2 decreases oxygen is liberated from Hb according to the Hb-O2 Dissociation
curve. More O2 may be liberated without a change in PO2 by shifting the dissociation curve to
the right. This occurs due to increased H+ ions (pH drop), increased levels of DPG, increased CO2
and increased temperature. This makes sense because these factors are usually increased due to
increased O2 consumption. Because the curve is flat at the top of the dissociation curve the
decreased lung uptake of O2 with right shift has minimal effect on the saturations.

4
8
Ventilation (litres minute)

12
NORMAL

4. Arterial Blood

40

100

inute
ml m
800
on
pti
m
su
on

Alveolar PO2

150

3. Alveolar Air is influenced by the oxygen consumption (in that

higher consumtion leads to lower O2 levels) and the alveolar ventilation
which increases O2 levels up towards the humidified gas level. The
combination of these factors is shown below graphically. The cardiac
output and third gas effect are both transient although the later
important in off gassing from NO anaesthesia.

25
0m
l

40
0m
l

150

100
ml

PO2

5. Capillary Bed The amount of oxygen delivered to the capillary bed is

dependent on the cardiac output (or regional blood flow for a specific organ)
arterial oxygen saturation and the haemoglobin concentration. Impairment of any
of these leads to tissue hypoxia and chronically to compensation - eg
polycythemia in chronic anoxia, increased CO in anaemic patients. Since more
than 97% of oxygen is bound to Hb the O2 dissolved in blood is sometimes
ignored, although becomes significant in hyperbaric situations. Normal values in a
resting patient are CO = 5 litres, Saturation 97%, Hb 140 and the volume of O2
bound by a gram of Hb is 1.39 (1.34 if you correct for dysfunctional Hb - metHb
and COHb).
Delivery (O2 FLUX) = CO (Content)
= 5(Sats x Hb x 1.39 + dissolved)
= 960 ml/min (rounded to 1000ml)
5
Normal consumption is 250ml (25%) resulting in venous
sats of 75% or 40mmHg when assessed using the O2Haemaglobin dissociation curve.

The diffusion of oxygen and carbon dioxide across the blood gas barrier of the alveolar wall, interstitial fluid and pulmonary capillary endothelium is governed by
Ficks law of diffusion. This relates the flow of gas across a membrane to the characteristics of the membrane (area and thickness), the pressure gradient (difference in partial
pressures) and the characteristics of the gas (solubility and molecular weight).
Flow of Gas

Area
. Diffusion constant (P1 - P2)
Thickness

Diffusion constant is equal to the gas solubility/ square root of the molecular weight

The pressure gradient for oxygen is the alveolar PO2 to the mixed venous PO2 (105-40 = 65). This is much less than CO2 which has a gradient of (46-40=6). The surface area of
the lungs is estimated at around 70m2. The average thickness is about 0.6 micrometers. The square root of O2 and CO2 molecular weights are 4 and 5.29 respectively. Each
minute however 250ml of O2 and 200ml of CO2 disffuses. As can be seen from Ficks Law the reason CO2 is so effective must be due to its much higher solubilty, resulting in
an increased diffusion constant some 20 times greater than O2.
The diffusion process is rapid, equilibrium is established in 0.25 seconds. As the average capillary transit time is 0.75 seconds this usually ample time for diffusion to take
place. In extreme exercise the cardiac output is dramatically increased and the transit time may approach 0.25 seconds which, if there is some impairment of diffusion due to
diesase may result in a measurable fall in end capillary PO2.

Perfusion and diffusion limited transfer of gases. Whether or not substances passing from the alveoli to the capillary blood reach
equilibrium in the 0.75 s that blood takes to traverse the pulmonary capillaries at rest depends on their reaction with substances in the blood.
Thus, for example, the anesthetic gas nitrous oxide (N2O) does not react and reaches equilibrium in about 0.1 s. In this situation, the amount of
N2O taken up is not limited by diffusion but by the amount of blood flowing through the pulmonary capillaries; that is, it is perfusion-limited. On
the other hand, carbon monoxide (CO) is taken up by hemoglobin in the red blood cells at such a high rate that the partial pressure of CO in the
capillaries stays very low and equilibrium is not reached in the 0.75 s the blood is in the pulmonary capillaries. Therefore, the transfer of CO is not
limited by perfusion at rest and instead is diffusion-limited. O2 is intermediate between N2O and CO; it is taken up by hemoglobin, but much
less avidly than CO, and it reaches equilibrium with capillary blood in about 0.3 s. Thus, its uptake is perfusion-limited.

PERFUSION LIMITED

DIFFUSION LIMITED

Diffusing capacity The ability of the respiratory membrane to exchange a gas between the alveoli and the pulmonary blood is expressed in quantitative terms by the
respiratory membranes diffusing capacity, which is defined as the volume of a gas that will diffuse through the membrane each minute for a partial pressure difference of 1
mmHg. All the factors discussed above (area, thickness, solubility, molecular weight) that affect diffusion through the respiratory membrane can affect this diffusing
capacity.
Diffusing Capacity for Oxygen. In the average young man, the diffusing capacity for oxygen under resting conditions averages 21 ml/min/mm Hg. In functional
terms, what does this mean? The mean oxygen pressure difference across the respiratory membrane during normal, quiet breathing is about 11 mm Hg. Multiplication of
this pressure by the diffusing capacity (11 x 21) gives a total of about 230 milliliters of oxygen diffusing through the respiratory membrane each minute; this is equal to the
rate at which the resting body uses oxygen. The oxygen diffusing capacity can be calculated from measurements of (1) alveolar Po2, (2) Po2 in the pulmonary capillary
blood, and (3) the rate of oxygen uptake by the blood. However, measuring the Po2 in the pulmonary capillary blood is so difficult and so imprecise that it is not practical
to measure oxygen diffusing capacity directly.
Diffusing Capacity of Carbon Monoxide as a surrogate marker. To obviate the difficulties encountered in measuring oxygen diffusing capacity directly,

carbon monoxide diffusing capacity is measured instead and then oxygen diffusing capacity is calculated using the known diffusion coefficients. The principle of the
carbon monoxide method is the following: A small amount of carbon monoxide is breathed into the alveoli, and the partial pressure of the carbon monoxide in the alveoli
is measured from appropriate alveolar air samples. The carbon monoxide pressure in the blood is essentially zero, because hemoglobin combines with this gas so rapidly
that its pressure never has time to build up (it is diffusion limited). Therefore, the pressure difference of carbon monoxide across the respiratory membrane is equal to its
partial pressure in the alveolar air sample. Then, by measuring the volume of carbon monoxide absorbed in a short period and dividing this by the alveolar carbon
monoxide partial pressure, one can determine accurately the carbon monoxide diffusing capacity. To convert carbon monoxide diffusing capacity to oxygen diffusing
capacity, the value is multiplied by a factor of 1.23 because the diffusion coefficient for oxygen is 1.23 times that for carbon monoxide. Thus, the average diffusing capacity
for carbon monoxide in young men at rest is 17 ml/min/mm Hg, and the diffusing capacity for oxygen is 1.23 times this, or 21 ml/min/mm Hg.

Christopher Andersen 2012

GAS TRANSPORT IN THE BLOOD

Carriage of oxygen in the blood Oxygen is carried in the blood in two forms: dissolved and combined with

hemoglobin. Dissolved O2 obeys Henry's law, that is, the amount dissolved is proportional to the partial pressure. For
each mm Hg of PO2 there is 0.003 ml O2 per 100 ml of blood. Thus, normal arterial blood with a PO2 of 100 mm Hg
contains 0.3 ml O2 per 100 ml.
Haemoglobin is a tetramer of heme with four globin chains (two alpha and two beta). Each molecule is capable of
binding four molecules of O2 to heme. From this observation, and from the molecular weight of Hb (63 500 Da) it is
possible to calculate that at 100% Hb saturation (all sites occupied) 1.39ml of O2 will combine with 1g of Hb. The
measured value of 1.34 is slightly less due to some of the Hb occuring in the ferric form (metHb) and carboxyHb and
sulphHb which is unable to bind O2.
It is possible therefore to calulate the bound O2 by the formula
O2 bound

= [Hb] x SaO2 x 1.34

the normal value is 140 x 0.975 x 1.34 = 183 ml per litre (often quoted as 18-20 ml per 100ml)

O2 Delivery = Cardiac Output (O2 bound + O2 dissolved)

the normal value is 5(183 + 3)

= 930ml (often quoted as 1000ml per minute)

O2 Dissociation Curve Whilst the amount of O2 dissolved has a linear relationship with the PO2 (Henrys
Law) the amount of O2 bound to Hb does not. Haemoglobin exists in two conformational states the T or Tense
state which has a low affinity for O2 and the R or relaxed stated which has a high affinity for O2 binding. The
electrostatic binding of a single O2 to a deoxyhaemoglobin leads to a conformational change to the R state.
Additional O2 groups may be then added until full saturation, the dissociation constant of the last step Hb(O2)3
Hb(O2) 4 is much higher than the others which compensates for the reduced binding sites and the slowing
caused by the law of mass action. As a result of the complex kinetics of the chemical reaction between oxygen
and haemoglobin, the relationship between Po2 and percentage saturation is non linear, and the precise form of
the non linearity (a sigmoid curve) is of fundamental biological importance.
When assessing the influence of various factors on the O2-Hb dissociation curve the P50 (pressure at 50%
saturation) is often used as a reference point. An increased P50 results from a right shift and decrease in O2 affinity,
a decreased P50 indicates a left shift and increased O2 affinity. When O2 is unloaded the beta chains pull apart.
This allows the glycolytic metabolite 2,3 diphosphoglycerate (DPG) to slide between and bind, resulting in lower
affinity of haemoglobin. The importance of this step has been overstated in the past although it remains
important for transfused blood with minimal DPG. Several other factors lead to a propensity towards the T
conformation and a lower affinity. The Bohr effect has important effects within physiological ranges and results
from the transfer of CO2 and subsequent change in pH. This occurs along capillaries and although the actual change in CO2 and pH is small, it has been suggested that
up to 25% of the uploading of O2 to Hb in the pulmonary capillaries and offloading in the systemic circulation is due to the Bohr effect. Temperature has a large effect
on the dissociation curve with an increase causing a right shift and offloading of O2 (which occurs in warm exercising muscles) and a left shift in cold tissues.

Carbon dioxide is the end product of metabolism. Glucose is converted to CO2, H2O and energy according to the formula

C6H12O6 + 6O2 = 6CO2 + 6H2O + energy. The actual process is a three stage conversion of glucose via glycolysis into
lactate/pyuvate, conversion via the Krebs cycle and finally oxidative phosphorylation pathway within the mitochondria
creating a total of 38 units of ATP. Carbon dioxide is therefore at its highest concentration at the mitchondria and follows a
reverse path to oxygen down partial pressure gradients to the lungs (noting however that despite the lesser change in partial
pressures, the increased solubility makes the exchange similar to O2 250ml to 200ml per minute respectively).

Carbon dioxide carriage in blood occurs in three main forms; dissolved, in the bicarbonate ion and bound to Hb as

carbamino compounds. 1. Dissolved CO2, like O2, obeys Henry's law, but CO2 is about 20 times more soluble than O2, its
solubility being 0.067 ml per dL per mmHg. As a result, dissolved CO2 plays a significant role in its carriage in that about
5-10% of the gas that is evolved into the lung from the blood is in the dissolved form. The dissolved CO2 reacts with
water to form carbonic acid. This is usually a very slow reaction and does not occur to any significant effect in the
plasma. In the red blood cells however the presence of carbonic anhydrase catalyses the reaction leading to rapid
Dissolved
Carbamino
production of carbonic acid. This then dissociates rapidly to the bicarbonate ion and hydrogen ions. The Bicarbonate
compounds
ion then leaves the red blood cell, however the ionic H+ remains. To balance the charge of the RBC a phenomenon
known as chloride shift occurs with Cl moving into the RBC. Bicarbonate is the most important step accounting for
approximately 70-90% of CO2 carriage. In addition to reacting with H2O, CO2 also reacts with the exposed amine
Bicarbonate
groups of Hb to form carbaminocompounds. This occurs in a greater exent in RBCs but does also occur in the plasma.
Chloride Shift
Carbamino compounds contribute approximately 20-30% to CO2 carriage.

25
20

Several important features are noted from the CO2 dissociation curve. Firstly, within physiological ranges the curve is mostly linear. Secondly, whilst bicarbonate and dissolved CO2 increase in a linear fashion according to PCO2 levels
carbamino compounds vary mainly in respect to the oxygenation of the blood as evidenced by the seperate lines according to arterial and
venous blood. This is the component of the Haldane effect discussed above (the other relates to the improved buffering of deoxygenated
haemoglobin).

15

Carbon dioxide dissociation curve

Carbamino compounds
Venous
Arterial

Bicarbonate ion in
plasma and RBCs

Blood CO2 Content (m.mol.l-1)

The Hb characteristics discussed above relating to electrostatic bonds and conformational changes of Hb also have an
influence on CO2 carriage. This is known as the Haldane effect and results in improved CO2 carriage in the deoxygenated conformations rather than the oxygenated forms of Hb. This enables better uploading of CO2 from the tissue and
offloading at the lungs.

Oxygen and Carbon Dioxide stores The quantity of carbon dioxide and bicarbonate ion in the body is very large - about 120 litres,
Dissolved CO2
0
20
40
60
80
which is almost 100 times greater than the volume of oxygen. Therefore, when ventilation is altered out of accord with metabolic activity,
PCO2 (mmHg)
carbon dioxide levels change only slowly and new equilibrium levels are attained after about 20-30 minutes. In contrast corresponding
changes in oxygen are very rapid. In spite of great biological importance, oxygen is a very difficult gas to store in a biological system. Hb is the most efficient chemical carrier,
but total blood volume usually carries only 1000ml of O2. The concentration of O2 in blood far exceeds the concentration of any other body fluid. Even so, the quantity of O2
in the blood is barely sufficient to last three minutes metabolism at the resting state. Other stores include the lungs which have approximately 500ml (breathing 100% O2
increases this to 3000ml - hence pre-oxygenation in anaesthesia), dissolved in tissues around 50ml and in myoglobin 200ml. In comparison to the 120 litres of CO2, the stores
of O2 equate to only 1.75 litres.
Christopher Andersen 2012

APPLIED RESPIRATORY PHYSIOLOGY

Intermittant Positive Pressure Ventilation (IPPV) and Positive End Expiratory Pressure (PEEP). IPPV ventilation can be delivered in many different
techniques, often designed to correspond to patient initiated actions. During inspiration IPPV raises the pressure at the mouth above ambient levels and there is an inflow of
air into the lungs. If the inspiration is prolonged then the ventilation will be dependent on the regional compliance of the lungs, if it is short then different time constants may
result in preferential ventilation to regions of the lung with short time constants. During expiration two options exist. Firstly the pressure at the mouth drops to ambient
resulting in Zero End Expiratory Pressure (ZEEP). There is no change to FRC. The alternative is PEEP which is used to increase the functional residual capacity (FRC), reduce
airways resistance (wider calliber airways at higher FRC) and prevent or reverse lung collapse. Negative EEP is no longer used as a modality.
Physiological consequences of IPPV and PEEP. The physiological effects of IPPV with ZEEP or PEEP relate to the mean increase in intrathoracic pressure and as such

PEEP has a more significant effect. Respiratory effects: IPPV results in minor changes in the spatial distribution of ventilation which is only relevant in patients with acute
lung injury. PEEP increases lung volume, re-expands collapsed alveoli and therefore improves ventilation in these areas. Both delivery of IPPV and PEEP results in aparatus
deadspace which may or may not influence the overall deadspace (sometimes it is cancelled by a reduction in anatomical deadspace). There is a slight worsening of V/Q ratios
with IPPV but this is often not significant. As stated above PEEP increases FRC whilst IPPV with ZEEP does not. IPPV and PEEP do not change oxygenation in healthy patients
but may have significant benefits is diseased patients, for the afore mentioned reasons, increasing the FRC above closing capacity, reducing airways resistance and improving
recruitment and maintaining patency in alveolar units. The main deleterious effects of IPPV and especially PEEP is the cardiovascular effects. IPPV and PEEP cause a
reduction in cardiac output by reducing venous return to the right atrium because of increased
PRESSURE
introathoracic pressure. With normal inspiration there is negative intrathoracic pressure which
RESPIRATORY EFFECTS
IPPV + ZEEP or PEEP
both:
Changed Spatial Distribution
acts as a pump to draw blood into the chest from the major veins and this is abolished with
Changed aparatus/anatomical dead space
Widened V/Q Ratios
postive intrathoracic pressure. The reduction in RV filing leads to less LV filling, which is
PEEP only
Increased FRC
exacerbated in hypovolaemic states. Furthermore the increased airway pressures lead to
Decreased Resistance
Improved alveolar recruitment/retention
increased pulmonary vascular pressures and this increases RV strain. It is noted that whilst PEEP
may improve PaO2 the decrease in CO may actually lead to decreased O2 delivery to the
CARDIOVASCULAR EFFECTS due to increased intrathoracic
pressure (usually PEEP>IPPV+ZEEP)
tissues (remember that DO = CO(sats x Hb + dissolved O2)). There is some increase in
Reduced venous return
peripheral vascular resistance to counter the decreased CO but this is often inadequate.
Reduced Cardiac Output
Increased peripheral and pulmonary vasc resist
Interestingly, in heart failure patients the reduced RV filling may actually improve function by
RENAL EFFECTS
moving an overloaded RV to a more favourable position on the starling curve. Renal Effects:
Increased fluid retention (increased ADH and
decreased pressure gradient at the glomerulus)
Prolonged IPPV causes increases in oedema, this is beleived to be from a combination of
increased ADH and the reduced pressure gradient at the glomerulus caused by decreased
IMMUNOLOGICAL
Increased neutrophil retention (due to decreased
arterial pressures and increased CVP. Immunological effects occur from increased neutropulmonary vascular callibre)
phil retention in the pulmonary vasculature due to their reduced calibre with IPPV and PEEP.
PHYSIOLOGICAL CONSEQUENCES OF HYPERCAPNIA

Physiological effects of hypercapnia and hypocapnia. Hypocapnia is always due to increased

alveolar ventilation, and this may be due to hypoxaemia (which drives increased ventilation at altitude),
metabolic acidosis compensation and neurological disorders (such as head injuries) and emotional states such
as fear. Hypercapnia is due to four different causes; increased inspired concentration of CO2, increased CO2
production, hypoventilation and increased dead space. Carbon dioxide has at least five major effects on the
brain, it is the main factor governing cerebral blood flow, it influences ICP the through changes in blood flow, it
RESPIRATORY EFFECTS
is the main factor influencing the brain pH, it has inert narcotic effects like NO, and it influences the excitability
Tight control of ventilation
Increased pulmonary vascular resistance
of certain neurons especially those in the reticuloactivating system. It is the pH and to a lesser extent the inert
Hypoxia (CO2 occupying space in Alv)
gas narcotic effects which have the most clinical obvious influence which is on levels of consciousness. Raised
Displacement of Hb-O2 curve
ICP is also very significant in regards to clincial effects and deliberate hypocapnia was often an aim in head
CARDIOVASCULAR EFFECTS
injury although this is now out of vogue. In severe hypercapnia (<100 mmHg) increased catecholamines are
Decreased heart contractility and rate (usually
overridden by catecholamine release)
released especially adrenaline which leads to autonomic responses (organs may be less responsive however
AUTONOMIC EFFECTS
due to the low pH). From a respiratory perspective ventilation responses to a change in CO2 is very sensitive as
Adrenaline release during severe hypercapnia
previously discussed. When patients are hypercapnic there is noted pulmonary vasoconstriction which may
RENAL EFFECTS
cause V/Q changes, raised CO2 in the alveolar units displaces O2 and leads to hypoxia and there is a displaceArteriole constriction c severe hypercapnia (anuria)
ment of the O2-Hb curve to the right, improving O2 delivery at the tissues. Cardiovascular changes are
Renal bicarbonate compensation in respiartory
acidosis and alkalosis
complex, in isolation hypercapnia leads to decreased contractility and rate but increased catecholamines often
overwhelm this response. Renal blood flow in unchanged in normal ranges but during severe hypercapnia there is arteriole constriction and subsequent anuria. Prolonged
hypercapnia leads to increased HCO3 absorption and a compensatory metabolic alkalosis, in prolonged hypocapnia HCO3 is dumped leading to a metabolic acidosis
compensation. In addition to these electrolyte changes hypercapnia causes K to leak out of cells leading to an increase in plasma K levels.
NEUROLOGICAL EFFECTS

Increased cerebral blood flow

Increased intracranial pressure
Increased brain pH (and metabolic dysfunction)
Inert gas narcotic effects
Variable neurone excitability changes

Physiological consequences of Hypoxia

Hypoxia refers to inadequate tissue PO2 to ensure ongoing oxidative

phosphorylation. This is the PO2 at the end of the oxygen cascade which may equate to a gradient at the mitochondria
of as little as 2mmHg. There is no defined safe level however of arterial PO2 which will ensure adequate tissue PO2 due
to other variables such as perfusion, O2 consumption and Hb concentration. When tissue is hypoxic the body reverts to
anerobic pathways which result in energy production some 19 times less efficient that oxidative phosphorylation.
Furthermore the byproducts of anerobic energy production, H+ and lactate ions are transported away in the peripheral
tissues, but do not cross the BBB and therefore much of the damage in cerebral hypoxia is related to the damage caused
by intracellular acidosis rather than the depletion of energy stores. At a cellular level in addition to the production of
lactate and H+ ions, there is a leaking of K+ and an influx of Ca++, this leads to failure of the Na/K pump and eventual
cell death. On a systemic level hypoxia leads intially to hyperventilation (but only when the aterial PO2 is below 55),
hypoxic pulmonary vasoconstriction, increased organ perfusion, especially the brain, increased cardiac output,
decreased pH due to lactate production and right shift of the Hb-O2 curve due to DPG production. Long term hypoxia
leads to polycythemia as seen in chronic lung disease and aclimitisation.

TISSUE LEVEL
Impaired oxidative phosphorylation
+
Increased anerobic energy production lactate & H
Localised acidosis (worse in the brain due to the BBB)
+
++
+ +
K leakage Ca into cell Na /K pumps failure
rapid depolaristation cell death
SYSTEMICAL LEVEL
Hyperventilation when PaO2 is below 55 mmHg
Hypoxic pulmonary vasoconstriction
Increased cardiac output
Preferential organ perfusion (especially brain)
Acidosis and Hb-O2 curve right shift
LONG TERM
Increased haemaglobin levels

Carbon Monoxide Poisoning usually due to inhalation but may be due to ingestion of methylene chloride which is metabolised in the liver to CO. CO

binds to heme with an affinity 240 times that of O2. It causes an allosteric change in which greatly inhibits the three other heme binding sites from
offloading O2. The result is a shift of the O2 dissociation curve to the left. CO also inhibits oxidative phosphorylation like cyanide but to a less extent which
exacerbates the hypoxia. The mechanism of the delayed neurological sequelae is not well understood but may be related to toxic oxygen species generated
by xanthine oxidase. Treatment is via high flow O2 and HBOT may be indicated.

As patients age several changes occur in the respiratory system, most of which lead to a gradual worsening of function. Compliance bucks the trend and has no measurable difference as patients age. As patients age they have more variable patterns when sleeping with more apnoeic periods, variations in upper airways resistance and
episodes of transient hypoxaemia down as low as 75%. Anatomical dead space is increased in infants due to their large head and neck, with on average of 3.3ml/kg. This
reduces down to 2 ml/kg as a young adult and then gradually increases by roughly a ml per year. The diffusing capacity of the lung gradual worsens throughout life in a
linear fashion. Functional residual capacity gradual increases throughout life, and may increase markedly in disease states such as COPD. The closing capacity increases more
rapidly then FRC and as a result will equal FRC in a supine patient (gravity decreases FRC) at the age of 44 and an erect patient in their seventies. This leads to a worsening of
V/Q ratios with age as gas trapped by a CC>FRC constitutes a shunt. The end result is that arterial PO2 values gradually decline with age.

Effects of a change in posture on ventilatory function. Gravity has a major influence on the distribution of

ventilation and perfusion, therefore with the change to supine postion the posterior areas of the lung receive increased
perfusion and are more compressed. During normal breathing there is minimal change in V/Q ratios however in healthy
lungs because both ventilation and perfusion undergo similar changes . Change from erect to supine results in an
increase in pulmonary blood volume by almost a third due to return of blood from the periphery. Of particular
importance is the effect of the abdominal contents in the supine postion. These push the diaphram superiorly and
subsequently cause a reduction in the FRC. This is becomes important with respect to the closing capacity which
increases with age, closing capacity will exceed FRC at the age of 44 in average subjects. The tendency to airway closure
however may be counteracted by increased diaphram stretch capacity. Change in posture typically result in a decrease of
anatomical deadspace of one third. This results in a volume of VD/VT ratio change from 34% erect to 30% when supine
(improved ratio). Diffusing capacity is substantially improved when in the supine position despite decreased lung volume,
this is likely because of the increased pulmonary blood volume.

GRAVITY
Ventilation base posterior
Perfusion base posterior
V/Q ratio unchanged in healthy patients
Blood volume by a third
Improved diffusing capacity (because BV)
ABDOMINAL PRESSURE
Reduces FRC by compressing diaphram
ANATOMICAL DEADSPACE
Decreased by a third
Improves VD/VT from 34% to 30%

Humidification The upper airway normally warms, moistens and filters inspired gas. When these functions are impaired by disease,
or when the nasopharynx is bypassed by endotracheal intubation, artificial humidification of inspired gases must be provided.
Absolute humidity (AH) the total mass of water vapour in a given volume of gas at a given temperature (g/m3)
Relative humidity (RH) the actual mass of water vapour (per volume of gas) as a percentage of the mass of saturated
water vapour, at a given temperature.
Saturated water vapour exerts a saturated vapour pressure (SVP). As the SVP has an exponential relation with tempera
ture, addition of further water vapour to the gas can only occur with a rise in temperature (see adjacent table and note
that at 37 degrees the SVP is 47)
Latent heat of vapourisation is the energy absorbed per gram in the phase change from liquid to gas (LH2O = 540 cal.g )
Heating and humidification of dry gas are progressive down the airway, with an isothermic saturation boundary (i.e. 100% RH at 37 C or AH of 43 g/m3) just below the carina.
Under resting conditions, approximately 250 ml of water and 1.5 kJ (350 kcal) of energy is lost from the respiratory tract in a day. A proportion (1025%) is returned to the
mucosa during expiration due to condensation. The need for humidification during endotracheal intubation and tracheostomy is unquestioned. As the upper airway is
-1
bypassed, RH of inspired gas falls below 50% with adverse effects, including: 1. increased mucus viscosity 2. depressed ciliary function 3. cytological damage to the tracheobronchial epithelium, including mucosal ulceration, tracheal inflammation and necrotising tracheobronchitis 4. microatelectasis from obstruction of small airways, and
reduced surfactant leading to reduced lung compliance 5. airway obstruction due to tenacious or inspissated sputum with increased airway resistance
The cough reflex is a protective reflex which is initiated as a protective mechanism against chemical and
mechanical irritants. It derives primarily from airway receptors in the larynx, trachea and bronchi although
other locations have been identified. The information is fed back to the cough centre in the medulla via the
vagus nerve, where cortical input may modify or partial initiate the reflex. Information is then sent through
the effector nerves which consist of the spinal, phrenic and vagus. The muscles of the cough reflex then
coordinate in a three phase process. The first stage involves inspiration of a suficient amonut of air for the
expiratory activity. The compressive phase involves expiration against a closed glottis, cuasing a transient
increase in pressure of the thorax, arterial blood and the CSF of upn to 300mmHg. The final stage is the
expulsive stage in which the glottis opens allowing rapid expiratory flow through the respiratory tract.

HORMONAL CHANGES
PROGESTERONE - sensitises central chemoceptors
decreased PCO2 (30mmHg)
increased PO2 (103mmHg)
OESTROGEN - increased blood volume
greater oxygen delivery

MECHANICAL CHANGES
DIAPHRAM DISPLACED - decreased FRC
Less O2 reserve

During pregnancy there are significant changes to respiration which is a result of both the mechanical changes of
childbearing (which therefore are most significant in the third trimester) and hormonal changes which occur throughout the pregnancy. One of the most important changes in the sensitisation of chemoreceptors by progesterone which
increases six-fold during pregnancy. The sensitisation of chemoreceptors leads to three fold increase in the
CO2/ventilation response curve and a two-fold increase in the hypoxic response curve. Whilst RR is unchanged the tidal
volume increases up to 40% at full term. The consequence of this increased ventilation is resting PCO2 levels decrease
to around 30mmHg (35 normally), and PO2 levels increase to around 103 (95). Oestrogen increases the blood volume
and this leads to increased Oxygen delivery. In the final trimester the diaphram is displaced cephalad by the expansion
of the uterus and the abdominal contents and this is exacerbated in the supine position. The result of the diaphram
displacement is a substaintal reduction in FRC, this is particularly important as it removes an important store of O2 and
may be crucial in the setting of anaesthesia.

Non respiratory functions of the lung can be seperated into three main categories. The pulmonary circulation undertakes PULMONARY CIRCULATION
two important roles. Firstly the lungs can act as an important reservoir of blood through mainly distension but also recruitment of
Blood Reservoir
Blood Filter
vessels, increasing its volume without major increases in pulmonary pressures. The second role involves the extensive filtration of
the blood removing material in the blood stream which would have very deleterious effects in the arterial system such as thrombo- DEFENCE AGAINST INHALED SUBSTANCES
Mechanical - mucus, cillia
emboli reaching the brain. The lung also acts as an important defence against inhaled substances. This is achieved through
Chemical - antimicrobials, sufactant
mechanical means such as the action of the cilliated epithelium and the production of mucus, and chemical means through
Immune - IgA, Macrophages
METABOLIC FUNCTIONS
antimicrobial peptides in the airway lining fluid and surfactant. Lastly immune systems provide defences from a hummoral
Activation -angiotensin I, leukotrienes,
perspective with IgA and the cellular immunity of macrophages and immunologically active epithelial cells lining the airway. The
Inactivation -bradykinin, noradrenaline
third main category of non-respiratory functions of the lung is the processing of endogenous and exogenous compounds. This
includes the inactivation of amines such as noradrenaline, the activation of peptides such as angiotensin I and inactivation of bradykinin and the activation of arachidonic acid
derivatives into eicosanoids such as leukotrienes involved in bronchoconstriction. The lung also has an effect on exogenous drugs but usually through disposition (retention
in the lungs) rather than actual metabolism.
The respiratory effects of altitude. As a patient ascends from sea level the atmospheric pressure decreases. The partial pressure of O2 (21%) remains the same however
at around 5500m above sea level the atmosphere is halved (760 down to 380). The resultant decrease in PO2 is from 160 to 80. This is complicated at the alveolar by the SVP
of 47mmHg at body temp. The formula for Alveolar PO2 is (Barometric Pressure - 47)0.21, therefore as the BMP drops the SVP becomes an increasingly important component
and at 19200m the BMP = 47mmHg therefore the Alveolar PO2 is 0. Ascent to altitude presents three main challenges to the respiratory system. The first is the most
important and is the increasing hypoxia, the next is the decrease humidity and the third is extreme cold which occurs in outdoor environments. The bodies response to
hypoxia is marked by three phases, the first is the acute response which involves a rapid increase in ventilation due to carotid body feedback. This increases for about 5-10
minutes. The second phase is the hypoxic ventilatory decline which last 10-20 minutes until it reaches a plateau still above resting ventilation. The third phase is a gradual
increase in ventilation to a new increased minute ventiation baseline over eight hours if the patient remains at elevation. Whilst PCO2 decrease blunts this response there is a
reset of the central chemoceptors which leads to a lower baseline PCO2. There is an initial DPG driven right shift of the Hb-O2 curve to improve O2 offloading at the tissues.
Ongoing ascent eventually leads to central hypoxic depression of the respiratory centres and ultimately apnoea and death. Long term adaptation in addition to the increased
MV is polycythemia, left shift of the Hb-O2 curve to encourage O2 uptake and inceased vascularity to the heart and striated muscles. Less beneficial changes include hypoxic
pulmonary vasoconstriction and associated pulmonary hypertension, which in addition to the increased viscosity (polycythemia) leading to to right heart strain and RVH.
High pressure and diving At a depth of 10 metres the atmospheric pressure is doubled (2ATA), at 20 metres it is three times that of the surfance and so on. The

consequence of this in a significant increase in partial pressures of gases such that the SVP become less significant with regards to alveolar air. From a mechanical perspective
increased pressure leads to increased peripheral blood return adn therefore increased pulmonary blood volume, often leading to the ANP driven diuresis noted in divers. As
the pressure increases the denisty of gas also increases greatly increasing the work of breathing due to resistance to turbulent flow (this is the main benefit of helium). With
respect to oxygen there are several important consequences. Even at constant normobaric 100% O2 there is a risk in the long term of pulmonary toxicity which leads to
pulmonary absorption collapse and ulitmately may lead to acute lung injury. Oxygen levels above 2ATA (10ATA on air) may lead to oxygen convulsions (Paul Bert Effect) which
are poorly understood but believed to be related to GABA and NO. Nitrogen is a narcotic at increased pressures and may lead to narcosis, it is also very dense and increases
work of breathing, finally its solubility means that it is deposited in tissues and difusses out at a decreased rate leading to nitrogen bubbles in the blood stream and the risk of
decompression illness.

RESPIRATORY PHARMACOLOGY
Asthma is a syndrome characterised by airflow obstruction that varies markedly, both spontaneously and with treatment.
Asthmatics harbour a special type of inflammation in the airways that makes them more responsive than non asthmatics to a
wide range of triggers, leading to excessive narrowing with consequent reduced airflow and symptomatic wheezing and
dyspnoea. In allergic asthma, inhaled allergen initiates the inflammatory response by interacting with IgE bound to mast cells
and basophils. This leads to a cascade of events involving other immune cells and resulting in the release of numerous inflammatory mediators into the interstitial space, where they influence the growth and
DRUGS USED IN ASTHMA
function of cell types within the airway wall. The drugs available for the
BRONCHODILATORS
ANTI INFLAMMATORIES
treatment of asthma are targeted at inhibiting the inflammatory responses (of
Beta2 Agonists
Steroids
which steroids are the most important) and/or relaxing the bronchial smooth
Muscarinic antagonists IgE Antibodies
muscle (beta2 agonists).
Theophylline

Antileukotrienes (both)

DRUG CLASS & APPLICATION

Beta 2 Agonists

MODE OF ACTION

PHARMACOKINETICS

VARIABILITY / SIDE-EFFECTS

Beta2 Adrenergic receptors are found throughout

the airways and are involved in both smooth
muscle relaxation and reducing release of
inflammatory cytokines. Beta2 Agonists activate
the G-Protien - Adenyl cyclase - CAMP pathway to
cause reduced smooth muscle tone. Unlike the
smooth muscle effects, anti-inflammatory
response is quickly desensitised and therefore not
useful to control inflammation long term.

The mode of delivery is normally inhalation which

typically leads to <20% deposition in the lungs.
SABA have an onset of action within 1-5 minutes,
and are removed from the receptor environment
by aqueous diffusion. LABA have slower onset (30
mins) but have a prolonged action due to high
lipophilicity and reduced diffusion. Half life for
both is 3-5hrs. Hepatic metabolism via
hydroxlyation (salmeterol) or sulfation (salbutamol)

Skeletal muscle tremors is a common side effect.

The Beta2 selectivity is relative and therefore there
is often a degree of Beta1 response usually
manifested by tachycardia. There may be a minor
decrease in K levels due to increased skeletal
muscle takeup. Some studies show an increased
risk of asthma mortality with increased use
although this may represent worsening asthma
control. Lactic acidosis may occur with salbutamol.

Muscarinic antagonists

Muscarinic antagonists competitively block M3

muscarinic receptors in the airways and effectively
prevent the bronchoconstriction by vagal
discharge. They are less effective than Beta2
agonists because they only block the cholinergic
component of bronchoconstriction rather than all
bronchocontrictor mechanisms.

The mode of delivery is usually inhalation which

results in <20% deposition in the lungs.
Ipatropium has an onset of action of 15-30
minutes. Both drugs are minimally absorbed
systemically. There is very minor hepatic
metabolism but it is mostly excreted in the urine
and faeces (not absorbed). The half life of
tiotropium is 5-6 days whilst ipatropium is 2 hours.

The main issue with these drugs in their use for

asthmatics is that there is significant variability in
response. This is presumably due to the differences
in parasympathetic tone and in the degree to
which reflex activation of cholinergic pathways
participates in generating symptoms in individual
patients. Due to minimal systemic absorption there
are few side effects beyond a dry mouth. Elderly
patients may get urinary retention or glaucoma

Theophylline (Methylxanthines)

Methylxanthines are purine derivatives found in

beverages, theophylline (tea), caffiene, and
theobromine (cocoa). The mechanism of action is
inhibition of of Phosphodiesterases (PDE) which
results in increased CAMP and therefore
bronchodilation. The other mechanism is
competitive antagonism at adenosine receptors
which has a myriad of effects (possibly reducing
bronchoconstriction and inflammation).

Theophylline is delivered orally and is absorbed

rapidly and completely. It distributes poorly into
body fat and has a small volume of distribution.
Metabolism is hepatic via CYP450 into active
metabolites including caffiene and
3-methylxanthine. At higher doses follows zero
order kinetics. Exceretion via urine. The half life is
highly variable and dependent on age, liver and
cardiac function, lung disease, diet and smoking.

Due to the variable half life theophylline, it is not

uncommon for four-fold variations of plasma
levels. This necessitates monitoring of blood levels.
Common side effects include nausea, vomitting
and headaches are due to PDE inhibition. Diuresis
and palpitations may also occur and at higher
concentrations cardiac arrythmias, epileptic
seizures, and death may occur due to adenosine
receptor antagonism.

Corticosteriods

Corticosteriods move passively across the cell

membrane and act on the nucleus, switching off
transcription of multiple activated genes which
encode inflammatory protiens such as cytokines,
chemokines, adhesion molecules, and
inflammatory enzymes including arachidonic acid.
They also activate anti inflammatory genes, such as
mitogen activated protien (MAP) and increase
expression of Beta2-receptors.

CS are usually delivered in inhaled form to improve

deposition in the lung and reduce systemic effects.
They may also be given either as a short burst or
long term orally. Oral prednisone is converted to its
active metabolite prednisolone. Inhaled
budesonide systemic absorption is limited by first
pass metabolism. Hepatic metabolism for both
steriods takes place through CYP3A4, with a half
life around 3 hours., urine excretion.

Frequent aerosol administration of ICS may result

in a minor degree of adrenal supression, however
the main side-effects relate to localised candidiasis
and dsyphonia. Systemic corticosteroid use has
many well documented side-effects, although
short bursts during exacerbations limit these. SEs
include adrenal supression, trunkal obesity,
osteoporosis, diabetes, hypertension, gastric
ulceration, prox myopathy, and cataracts.

Antileukotrienes

Cysteinyl leukotrienes (CysLTs) include leukotriene

D4 (LTD4) and E4 (LTE4). All the CysLTs are potent
constrictors of bronchial smooth muscle, cause
microvascular leakage and eosinophillic and mast
cell mediated inflammation. Montelukast is a high
affinity competitive antagonist of LTD4 and LTE4.

Monteleukast is administered orally. It is absorbed

rapidly with 60-70% bioavailability. At therapeutic
concentrations it is highly protien bound (99%). It
is extensively metabolised hepatically by CYP3A4
and CYP2C9. The half life is around 3-6 hours.
Exceretion is primarily via faeces.

Some patients show an improved response to

antileukotrienes but this has not been genomically
linked to the leukotriene pathway. The are
relatively few side effects to inhibition of
leukotriene synthesis or function. This is likely due
to the fact that leukotriene production is limited
predominately to sites of inflammation.

Anti IgE Antibodies (Omalizumab)

Omalizumab is a recombinant humanised

monoclonal antibody of the IgG subclass, targeted
against IgE. IgE bound to omalizumab cannot bind
to IgE receptors on mast cells and basophils,
thereby preventing the allergic reaction at a very
early step in the process.

Omalizumab is delivered as a single subcutaneous

injection every 2-4 weeks. It has a bioavailabilty of
60% reaching peak serum levels after 7-8 days. The
serum half life is 26 days, with a clearance rate of
2.5ml/kg/day, which is somewhat faster than that
of free IgG. It is metabolised in the liver
reticuloendothelial system by the degradation of
IgG, some make be excereted in the bile
unchanged.

Omalizumab is generally well tolerated however

there was an increased incidence of various types
of malignancies during a large study into the drug
5 in 2236 versus 20 in 4127 which requires further
study.

Short acting (salbutamol) for treatment of

acute symptoms of bronchoconstriction
Long acting (salmeterol) for long term control
of bronchoconstriction.
Oral/IV preparation (salbutamol) occasionally in
children <5 unable to manage inhalers (PO), or
status epilepticus (IV)

Short acting (ipatropium bromide) is effective in

a subset of asthma patients and may give additive
effects to Beta2 agonists.
Long acting (tiotropium) is a structural
analogue of ipatropium which diffuses more slowly
away from the receptor.

Provides modest benefits and now rarely used

due to side-effects, narrow therapeutic window
and requirement for plasma level monitoring..
It may be used as an additional bronchodilator in
patients with severe asthma. At low doses may
provide additive anti inflammatory effects to ICS.
Its main application currently is in a slow release
preparation for supressing nocturnal asthma.

Along with Beta2 agonists these are the

mainstay of treatment and are used to suppress
the inflammatory response long term in patients
with moderate to severe asthma. They do not
directly relax smooth muscle and therefore have
little effect in direct bronchoconstriction.

Leukotriene receptor antagonists

(Montenlukast)
5-lipoxygenase (leukotriene precursor)
inhibitors (Zileuton)
Are not as effective as ICS in controlling asthma
and have less effect on airway inflammation but
may be useful as an add on therapy in some
patients with difficult asthma management.

Is used selectively in patients with severe

asthma not controlled by other modalities to
reduce the frequency of exacerbations. The cost of
this therapy is prohibitive.

Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries that is characterised by

vascular proliferation and remodelling. It results in a progressive increase in vascular resistance and, ultimately, right
ventricular failure and death. The abnormal elevation in pressure may be a result of left heart failure, pulmonary
parenchymal or vascular disease, thromboembolism or a combination of these
factors. In a percentage of patients no cause is found (idiopathic PAH). Cardiac
catheterisation is required to diagnose the condition and identify the
appropriate treatment strategy. This involves, firstly establishing the pressures
are elevated and then introducing either NO, adenosine or the prostacycline
epoprostenol and measuring the change in pressure. If the drop is significant
then Ca Channel blockers may be trialled as a first line therapy. Other recommended therapies once the diagnosis has been made include diuretic therapy
to reduce RV load and anticoagulation to reduce thromboembolic risk. Three
major pathways are implicated in the abnormal proliferation and contraction of smooth muscles in the pulmonary vasculature and
these provide the therapeutic targets. In addition to Ca Channel Blockers, the main therapies are Endothelin receptor antagonists
(Bosentan), Phosphodiesterase type 5 inhibitor (sildenafil) and Prostacyclin derivatives (incl illoprost and epoprostenol).

DRUG CLASS & APPLICATION

Endothelin Receptor Antagonists

MODE OF ACTION

PHARMACOKINETICS

VARIABILITY / SIDE-EFFECTS

In addition to exerting a direct vasoconstrictor

effect, endothelin-1 stimulates proliferation of
vascular smooth muscle cells, acts as a co-mitogen,
induces fibrosis and acts a proinflammatory
mediator by enhancing adhesion molecule
expression. Bosentan is a dual action ETA / ETB
endothelin receptor antagonist with a higher
affinity for ETA.

Bosentan is delievered orally and achieves

approximately 50% bioavailability. It has a volume
of distribution of 18 litres. Hepatic metabolism via
CYP3A4 and 2C9 into three metabolites, one with
10-20% pharmacological activity. The time to peak
plasma concentration is 3-5 hours and the half life
is 5 hours although this may be prolonged in heart
failure patients. Most of the metabolites are
excreted in the faeces.

The major issue with Bosentan is there is dose

dependent deranged liver function with
transaminitis of up to eight times the normal levels.
This necessitates monthly monitoring of LFTs in
patients on Bosentan. It strongly induces CYP3A4
and 2C9 and therefore may reduce the efficacy of
other drugs metabolised by this pathway.

Phosphodiesterase type 5
inhibitor

Like theophylline, Sildenafil is a phosphodiesterase

inhibitor, however sildenafil is selective for type 5
(PDE5) inhibition. This results in a reduction in
hydrolysis of cyclic GMP, and a subsequent increase
in pulmonary vasculature relaxation through
increased sensitivity to nitrous oxide actions. It
uses the same mechanism when used for erectile
dysfunction.

Sildenafil is taken orally and has an onset of action

within 60 minutes and duration of 2-4 hours. It is
absorbed rapidly with a bioavailability of 40%.
There is a large volume of distribution of 105 litres.
It undergoes hepatic metabolism via CYP3A4 and
forms an active metabolite. Half life is around four
hours and it is excreted 80% in the faeces and the
remainder in the urine.

Due to its action in sensitising the vasculature

response to NO, it is contraindicated in patients
taking nitrates as this may lead to a dramatic loss
in tone and subsequent profound hypotension.
The most common side effect with this treatment
is headaches which may occur in up to half of all
patients.

Prostacycline therapies

Prostacycline is the main product of arachidonic

acid in the vascular endothelium, induces
relaxation of vascular smooth muscle by
stimulating the production of cAMP and inhibits
the growth of smooth muscle cells. In addition it is
a powerful inhibitor of platelet aggregation.

Epoprostenol may only be delivered by IV infusion,

it has a very short half life of only 3-6 minutes, and
is often delivered via infusion pump through a
central line. It is rapidly metabolised by hydrolysis
and mostly exceted in the urine.
Iloprost is a chemically stable prostacycline
analogue delivered by inhaler. It has a short half
life of approximately 3o minutes therefore
requiring frequent dosing (q2hr).

Common side effects include jaw pain and cramps.

Sudden or abrupt withdrawal of the prostacyclines
may lead to rebound pulmonary hypertension.
Prostacyclines are inhibitors of platelet
aggregation and caution may be required in
patients with a bleeding diathesis.

Dual action - (Bosentan) is used for patients

who are New York Heart Association II-III.
Drugs selective for ETA (sitaxsentan) are not
currently in use.

Sildenafil is used for patients who are NYHA II-III

other PDE 5 inhibitors include vardenafil and
tadalafil

Prostaglandin I2 (prostacycline) is delivered in

several different forms and has the most beneficial
effect in patients with PAH even those which have
failed other therapies and is thus used in patients
with NYHA III-IV. Unfortunately the pharmacokinetics limits the use of this class of drugs.
IV Epoprostenol, IV or SC Treprostinil and
Inhaled Iloprost are the main drugs in this class.

Nitric Oxide therapy Nitric oxide is a powerful modulator of many aspects of bodily function. It is synthesised from L-arginine
and molecular O2 by NO synthase (NOS). There is usually an abundance of L-arginine so it is the NOS that limits the reaction. NOS
exists in three isoforms endothelial - eNOS (also found in platelets), inducible - iNOS (induced by macrophages and interferon
gamma) and neuronal - nNOS. The main action of nitric oxide is to activate soluble guanylyl cyclase, which in turn activates cGMP.
This leads to the main effects which include vasodilation, inhibition of platelet and monocyte adhesion and aggregation, as well as
inhibition of smooth muscle proliferation.
Inhaled Nitric Oxide

Is used as to test response in patients with

PHTN. It is also used in paediatric popluations to
improve oxygenation when paitents have
respiratory distress. There may be an indication in
patients with acute respiratory failure.

As stated above Nitric Oxide works by increasing

the expression of guanylate cyclase which inturn
increases production of cGMP. The result is
increased smooth muscle relaxation. Other effects
include decreased platelet aggregation and
angiogenesis.
When inhaled it preferentially dilates the vessels of
the well perfused alveoli which leads to an
improvement of V/Q matching.

Nitric oxide is rapidly inactivated by haemoglobin

in blood (hence its limited systemic effects). NO
forms methemoglobin and nitrate on reaction with
oxyhemoglobin. Almost 70% of inhaled NO is
excreted as nitrate in the urine within 48hrs. When
high conc O2 is combined with NO it forms the
toxic NO2, therefore delivering it with a high FiO2
is not recommended.

NOS
L-arginine + O2

NO + Citrulline

Activate Guanylate Cyclase

GTP

cGMP

Smooth muscle relaxation

The response of the patient to inhaled NO is

dependent on the degree of VQ mismatching is
contributing to decreased oxygenation. Doses
need to be titrated with worsened oxygenation at
both high and low doses. There is some concern
about environmental contamination to health care
professional although this is minimal in a well
ventilated room. Very high doses may lead to
significantly increased methemoglobin levels.

Pharmacology of oxygen oxygen may be regarded as a drug. It is a colourless, odourless and tasteless drug which is present in normal air at a approximately 21% of

the total pressure. The delivery of oxygen is determined primarily by a decrease down the oxygen cascade from a normal pO2 at sea level of 158 mmHg down to the
mitochondrial level where the partial pressure may be as low as 2-3 mmHg. Oxygen is primarily transported throughout the body bound to Hb but a small percentage is
dissolved in the blood. The dissolved component may be increased at supranormal pressures such as those observed in hyperbaric oxygenation. The main purpose of O2 in
the body is to participate in oxidative phosphorylation which produces the high levels of energy required for cellular function. Oxygen may delivered in a range of methods,
either via nasal prongs or a face mask where the inspired amount is variable on tidal volumes and rates, or in fixed amounts via closed circuits or fixed intake valves such as
venturi valves which entrain air at a set proportion. Oxygen has a range of therapeutic uses, by far the most common is treatment of hypoxia. Other less common
treatments are usually delivered at increased pressures and include treatment of air embolism, non healing diabetic foot ulcers, osteoradionecrosis of the jaw, and
infections such as myonecrosis. Delivered at high doses results in several physiological and potentially harmful changes. From a respiratory perspective there may be a
decrease in respiratory drive, which is usually only significant in patients with a desensitised hypercapnic drive such as those with CO2 retention. Breathing high doses of
oxygen also leads to the washout of nitrogen which may lead to absorption atelectasis and a subsequent shunt with a paradoxical decrease in oxygenation. Longer term
high dose may also lead to oxygen toxicity, which is characterised by parenchymal damage and diffuse lung injury and is likely due to increased reactive oxygen species
(Lorraine Smith Effect). Cardiovascular changes are minor and consist of a slight reduction in heart rate and cardiac output. CNS effects are noted at very high levels are
characterised by seizures (Paul Bert Effect) and visual changes.

Oxygen

Is used to primarily to treat hypoxia. Alternative

uses include treatment of CO posioning, diabetic
foot ulcers, infections such as clostridial
myonecrosis, air gas embolism, decompression
sickness and radiotherapy injury.

Oxygen diffuses passively throughout the body

down a concentration gradient. It reverses hypoxia
by increasing the partial pressure and improving
O2 delivery to mitochondria. It is believed to
improve chronic ulcers by creating a steep oxygen
gradient at wound margins similar to an acute
wound. In decompression illness is replaces
nitrogen bubbles with O2 bubbles which are
consumed.

Oxyen is inhaled by passive diffusion in the lungs

and is bound to Hb and dissolved in plasma.
Extracorporeal oxygenation is an alternative
delivery method. O2 is metabolised with gluclose
to form energy, CO2 and H2O. The precise
mechanism is a three step process of glycolysis, the
krebs cycle which are anaerobic (and produce 4
ATP) and finally oxidative phosphorylation in the
mitochondria which results in 34 ATP units.

Harmful effects of hyperoxia include include dry

mucous membranes, absorption ateletasis, acute
lung injury, depressed respiratory drive, and
seizures and visual changes at hyperbaric doses.
Delivery may be impaired in patients with reduced
haemaglobin capacity either due to anaemia, or
dysfunctional Hb such as the thalassaemias or
posioning due to CO, or damage to the oxidative
phophorylation process seen in cyanide posioning.

Pharmacology of Surfactant is formed from type II alveolar cells. It is mostly phospholipid with the principle component DPPC which equates to roughly 80%
content. There are also four surfactant protiens SP A to D. These are believed to be important in the stabilisation of the surfactant, its activation and release from alveolar
cells. Surfactant forms a mono layer due to its structure with a hydrophilic head adjacent to the cell wall and the hydrophobic tail facing inwards towards the air. Surfactant
has a 15-30 hour half life and in addition to its primary role of reducing surface tension also prevents transudation into in the the alveolus (less pressure inside alveolus) and
has an immunological role. The exact mechanism of how it reduces surface tension is unknown but the main hypothesis is that as it packs closer together when the
alveolus reduces in size the action is accentuated, causing a greater decrease in surface tension with decreases in radius.
Surfactant

Is currently only indicated in neonatal

resipartory distress syndrome and severe
meconium aspiration syndrome in newborns.
There is some research supporting its use in ARDS
although no benefit in outcome has yet been
proven.
Most surfactant in use are bovine or porcine
derived. Artifical surfactant also exists.

It is believed that surfactant acts by packing closer

together and causing a paradoxical decrease in
surface tension as the radius of the alveolus
decreases. It also has immunological role and
reduces exudation into the alveolus due to the
decrease intra alveolar pressure.

The half life of human surfactant is 15-30 hours.

Surfactant replacement therapy is currently
delivered via endotrachael tube although it is
possible to deliver in a aerosolised form. Upon
delivery much of the surfactant becomes lung
associated and not recoverable by BAL. It is
believed that exogenous delivered surfactant is
enters the normal recycling pathways and provides
substrate for endogenous production.

The main issues with surfactant administration are

the transient hypoxia, hypotension and
bradycardia and the risk of blockage of the ETT.
There is some association with pulmonary
haemorrhage.