Giles Kisby
GE Y1 Respiratory
Respiratory:
Spring Term:
LECTURES:
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Giles Kisby
GE Y1 Respiratory
Learning Outcomes – Year 1 (2013)
Autumn Term:
The main goal of this course is to help you develop a sound understanding of how the respiratory
system achieves the vital function of gas exchange, and how this is perturbed in disease. The primary
goal is to equip you with the knowledge base to apply basic respiratory science to clinical practice in
the later years of your course, recognising that the practice of respiratory medicine is integrally
related to the physiological processes you will cover over this term. We also hope to instill a finer
appreciation of the scientific intricacies of the respiratory system.
The course is structured in five overlapping themes: Theme one covers functional anatomy, and
embryology. In the second theme, the essentials of gas exchange are understood through
progression from mechanical considerations of gas transfer, delivery of blood to the alveolar
capillary unit, and ventilation perfusion matching. Theme three explores the regulation of breathing
both awake and asleep. In theme 4, we will focus on the consequences to normal physiology „when
things go wrong‟ in disease states. Finally, in theme 5, physiology in extreme normal circumstances
will be addressed as part of a review of the fundamentals covered within the course.
At the end of the course, you will be able to
the lung epithelium and the function of the cells contained within it.
Describe the main muscles used in breathing and how these are utilised to generate different lung
volumes. List the lung volumes that can be measured.
alveolar ventilation
the control of breathing and how this changes during sleep
dyspnoea, chest pain.
nd how they influence
breathing.
hypersensitivity, specifically asthma.
physiological consequences of infection in healthy lungs
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LECTURES
Lecture 1: Respiratory System I (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
This lecture should allow you .....
uscles that enable expiration and inspiration
tilising concepts
of surface tension, the Law of Laplace, and pulmonary surfactant.
e difference between obstructive and restrictive airways disease
Lecture 2: Respiratory System II (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able
provide three mechanisms that increase the rate of diffusion
ace
d the principle of haemoglobin and oxygen carriage
Lecture3: Mechanisms of Breathing (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able to
• Recall the principal muscles associated with inspiration and expiration
• Recall the anatomical basis of breathing, describing the two phases of respiration and the role of
the thoracic cage and diaphragm and changes in the capacity of the thoracic cavity during these
events.
• Recall how contraction of inspiratory muscles causes the chest wall to expand and the lungs to
enlarge
• Recall how the chest wall contracts and lungs reduce in size
• Explain what is meant by elastic recoil
• Define compliance
• Explain how pulmonary versus chest wall compliances can vary in various respiratory diseases
• Explain the concept of surface tension and the Law of Laplace
• Explain how pulmonary surfactant affects lung volume and airway patency
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GE Y1 Respiratory
• Recall the relationship between alveolar and atmospheric gas pressures, airway resistance and
airflow
• Recall the factors that affect airway resistance centrally and peripherally
• List the two major components that contribute to the work of breathing and explain how each may
be altered in disease states
• Recall the relationship between mechanical work and oxygen cost of breathing in normal
individuals and patients with respiratory insufficiency
• Recognise that respiratory muscles control air movement during other behaviours including,
speech, laughter, coughing, sneezing and vomiting.
Lecture 4: Respiratory Muscles (Dr. Kevin Murphy (kevin.murphy@imperial.ac.uk)
At the end of this lecture you should be able to:
additional non-respiratory actions of these muscles.
to enlarge.
lungs
to reduce in size.
Specifically: identify which will be active during quiet breathing, and which will be active when
ventilatory demand is increased such as during exercise or during lung disease.
will control air movement during other behaviours including, speech, laughter, coughing, sneezing
and vomiting.
Lecture 5: Lung Development (Dr Matthew Hind, m.hind@imperial.ac.uk)
At the end of this lecture you should be able to understand and describe.....
ital defects arise
development
al period
Lecture 6: Pulmonary Circulation I. (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able to:
structure of the two ventricles of the heart.
standing human.
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GE Y1 Respiratory
recruitment and hypoxic vasoconstriction.
disadvantage of this response in an adult suffering from chronic lung disease
capillaries to lymphatics
Lecture 7: Pulmonary Circulation II. (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able to:
may lead to this state.
o the right side of the heart and the pulmonary circulation,
o the viability of the lung tissue and
o the implications for gas exchange.
differences between normal, shunting, and
dead space. Give one example of each.
The last three concepts will be emphasized in a quiz.
Lecture 8: Blood Gases (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able to:
following acid-base disturbances:
o Acute respiratory acidosis
o Acute respiratory alkalosis
following renal compensation.
rterial blood pH. PCO2 and Base Excess in the following acidbase disturbances:
o Metabolic acidosis with respiratory compensation
o Metabolic alkalosis with respiratory compensation
-base status lead to alteration in
ventilation and hence respiratory compensation.
(i) Type I respiratory failure (ii) Type II respiratory failure, in each case after full renal compensation.
Lectures 9 and 10: Regulation of Breathing (Professor Mary Morrell, m.morrell@imperial.ac.uk)
metabolic homeostasis) and the behavioural controller (other needs such as speech) .Give five
examples of respiratory or non-respiratory functions achieved by control of respiratory muscle
activity
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breathing, and structures in higher brain areas (suprapontine) that drive behavioural (nonautomatic) control of breathing. Describe how they can act independently or interact for control of
the respiratory pump.
tory control system (central and peripheral
chemoreceptors, lungs, airways and chest wall) and describe the common motor outputs.
, consider its role in breathing control and its clinical impact
(also considered in lecture 11).
and „congenital central hypoventilation syndrome‟ („ondines curse‟)
in chemosensitivity and the apnoeic threshold led to central sleep
apnoea.
sleep apnoea.
erbated by the sleep-related
changes in the control of breathing; briefly explain why sleep is detrimental to these patients
Lecture 11: Sensory Aspects of Respiratory Disease (Professor Fan Chung, f.chung@imperial.ac.uk)
At the end of this lecture, in the indicated settings, you should be able to
General
research
thophysiological basis of the respiratory symptoms cough, chest
pain (and dyspnoea, covered elsewhere):
Cough
glottis. Briefly explain how this manouevre serves to i) protect the lungs from inhaled noxious
materials and ii) clear excessive secretions from the lower respiratory tract
stimulated to give rise to cough. Identify the neural pathways which transmit this afferent (sensory)
information to the brain
-ordinated neural activity
that results in a cough. Identify the efferent (motor) neural pathways and the main muscle groups
which produce cough.
Chest pain
receptors within the thoracic cavity that when stimulated
give rise to chest pain. Identify the neural pathways that transmit this afferent neural information to
the brain.
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pain
Dyspnoea
and its measurement
Lecture 12: Hypoxia (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able to:
and SaO2
(i.e. the O2 and CO2 dissociation curves), and factors affecting these curves with particular reference
to oxygen uptake in the lung and the downloading of oxygen in the tissues.
oxygen consumption; and the development of tissue hypoxia when delivery fails to meet demand
with onset of anaerobic metabolism (lactic acid production)
There is an accompanying computer aided learning quiz which you can run through with Dr Shovlin
which will assist your understanding of:
the „hyperpnoea‟ of
exercise.
-pulmonary capillary PO2 and PCO2.
Explain the consequences of this for systemic arterial PO2 and PCO2.
naemia) affects PaO2, PaCO2 and
oxygen content.
-enriched gas mixture in correcting any
abnormalities associated with anaemia.
g the effectiveness (or lack
of it) of breathing an oxygen-enriched gas mixture in correcting any abnormalities associated with
hypoventilation.
NB:
covered in Pulmonary Circulation II lecture
Lecture 13: Diving (Dr Peter Wilmshurst) At the end of this lecture you should be able to
-respiratory physiological principles are reinforced and modified by
hyperbaric conditions
Lecture 14: Lung function testing (Helium dilution and transfer factor)
H Tighe (h.tighe@imperial.nhs.uk)
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GE Y1 Respiratory
At the end of this lecture you should be able to
e of measurement for lung volumes/capacities that can‟t be measure by
simple spirometry
trapping in COPD)
gas diffusion across the alveolar membrane
Lecture 15: Exercise Physiology. (Dr Luke Howard l.howard@imperial.ac.uk)
At the end of this lecture you will appreciate and understand
Lecture 16: Lung Cancer. (Dr Claire Shovlin c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able .....
susceptibility of the lung to particular carcinogens
Lectures 17 and 18: Respiratory Failure I and II.
Dr Umeer Waheed, Umeer.Waheed@imperial.nhs.uk, Dr Richard
Stumpfl,Richard.Stumpfle@imperial.nhs.uk
At the end of these lectures you should be able to
-a gradient in Type 1 and 2 Respiratory Failure
Lecture 19: Altitude and Air Travel. (Dr Robina Coker Robina.Coker@imperial.nhs.uk)
This lecture will be delivered on line. At the end, you should be able to understand and describe....
poxic challenge tests
Lectures 20 and 21: Airways Disease. (Dr Philip Ind p.ind@imperial.ac.uk)
At the end of these lectures you should be able to understand and describe.....
–distinction from restriction
pirometry, peak flow, other measurements
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-responsivenesss
-COPD overlap
d introduction to Guidelines for asthma and COPD
PRACTICAL SESSION OBJECTIVES
Practical 1: Lung volumes and spirometry
Hannah Tighe (h.tighe@imperial.nhs.uk)
values for lung volumes in a young healthy adult.
predict these values.
how these volumes may change during exercise.
chronic restrictive lung disorder (2) severe chronic obstructive pulmonary disorder, and be able to
give reasons for these changes.
Practical 2: Airways resistance
Hannah Tighe (h.tighe@imperial.nhs.uk)
lung disease.
females, increase with subject‟s
height and decrease with age peaking at 20 years.
Practical 3: Integrated exercise practical
Dr. Luke Howard ( l.howard@imperial.ac.uk)
Dr. Kevin Murphy (Kevin.murphy@imperial.ac.uk);
techniques used to obtain the following cardio-pulmonary
measurements taken during exercise : Ventilation, Heart rate, Blood Pressure, O2 consumption and
CO2 production. SpO2.
-respiratory response to an incremental work rate exercise test to
exhaustion.
disease , (iv) training.
(eg field exercise) may be limited by breathlessness.
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GE Y1 Respiratory
LECTURES:
07/11/13: Respiratory system I: Dr Shovlin
Los (from booklet):
Lecture 1: Respiratory System I (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
This lecture should allow you .....
 To gain an overview of the respiratory system
 To list the main functions of the respiratory system
 To describe the respiratory pump
 To review the bones and muscles that enable expiration and inspiration
 To understand the passive properties of the respiratory system
 To explain what is meant by elastic recoil and compliance.
 To explain the factors that keep the non cartilagenous airways and alveoli open, utilising
concepts of surface tension, the Law of Laplace, and pulmonary surfactant.
 To describe the relationship between airway resistance and airflow.
 To describe the factors that affect airway resistance centrally and peripherally.
 To understand the difference between obstructive and restrictive airways disease
Notes:
-
-
-
Aerobic respiration more efficient than anaerobic and therefore lungs needed for gas
exchange (both O2 in and CO2 out)
Lung functions:
o O2 for tissue delivery
o CO2 removal to regulate pH
o Filtration (prob to catch emboli before reach brain) [nb filtration of particles in the
air also occurs: big particles at nose/mouth; small particles at cilia of conducting
zone (and resp bronchioles); small particles at alveolar macrophages of alveoli]
Requirements for airflow:
o Patent airways
o Open alveoli
o Elastic and compliant lung parenchyma
o Sealed pleural space
o Functional muscles & bones at chest walls
Requirements for gas exchange:
o High concentration gradient:
 Airflow (see above)
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

o
o
o
-
Pulmonary circulation; bloodflow maintained
partial pressure difference is the driving force for O2 across the
alveolar/pulmonary capillary barrier
High surface area
 Greater in adult than newborn (even proportionally speaking)
 23 divisions of the airways; total SA increases at each level to 130m2 at
alveoli in adult
 Capillaries form dense network over the alveoli; give 115m2 total endothelial
surface area
Thin distance to traverse
 <0.5µm distance between air and blood (endothelium, epithelium and
interstitial space)
 To achieve this the capillary width falls to barely above RBC width
[Exchange is also improved by “matched blood flow and air delivery”]
 Eg if pneumonia affecting one part of the lung would want airflow to be
diverted; and intrinsic (non-nervous, non-hormonal) system achieves this;
see later (is the same as how before birth the blood is diverted to the
placenta)
Fick’s Law:
o The diffusion coefficient of a gas (D) is a combination of the usual diffusion
coefficient, which depends on molecular weight (see Chapter 1), and the solubility of
the gas. The diffusion coefficient of the gas has enormous implications for its
diffusion rate, as illustrated by differences in the diffusion rates of CO2 and O2. The
diffusion coefficient for CO2 is approximately 20 times higher than the diffusion
coefficient for O2; as a result, for a given arterial pressure difference, CO2 diffuses
approximately 20 times faster than O2
o Several of the terms in the previous equation for diffusion can be combined into a
single term called the lung diffusing capacity (DL). DL combines the diffusion
coefficient of the gas and the thickness of the membrane (Dx). DL also takes into
account the time required for the gas to combine with proteins in pulmonary
capillary blood (e.g., binding of O2 to hemoglobin in red cells).
 In emphysema, for example, DL decreases because destruction of alveoli
results in a decreased surface area for gas exchange.
 In fibrosis or pulmonary edema, DL decreases because the diffusion distance
(membrane thickness or interstitial volume) increases.
 In anemia, DL decreases because the amount of haemoglobin in red blood
cells is reduced (recall that DL includes the protein-binding component of O2
exchange).
 During exercise, DL increases because additional capillaries are perfused
with blood, which increases the surface area for gas exchange.
o Emphysema (from smoking): SA loss due to burst alveoli
o Pneumonia, fibrosis: increased distance for diffusion (thickened walls – “alveolarcapillary block”
o Pneumonia:
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

-
-
-
caused by infection with viruses or bacteria
The lungs quickly fill with fluid and become stiff.
 Stiffness gives restrictive problems with breathing
 Fluid gives “alveolar-capillary block” and can trigger
vasoconstriction; a problem if the pneumonia is widespread
The conducting zone:
o Includes the nose, nasopharynx, larynx, trachea, bronchi, bronchioles, and terminal
bronchioles. These structures function to bring air into and out of the respiratory
zone for as exchange and to warm, humidify [important: prob to help maintain a
moist surfactant layer], and filter the air before it reaches the critical gas exchange
region.
The respiratory zone:
o Includes the structures that are lined with alveoli and, therefore, participate in gas
exchange: the respiratory bronchioles, the alveolar ducts, and the alveolar sacs
Compliance:
o Describes change in volume for a given change in pressure
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o V. Low for pulmonary fibrosis
o V. High for emphysema
Airway defences by epithelial cells ‘pseudostratified columnar epithelium’:
o 80% of conducting airway cells: ciliated bronchial epithelial cells:
 At conducting airway cells and respiratory bronchioles: ciliated cells
dominantly occupy that of the trachea-bronchus (while Clara cells are
dominantly distributed at the epithelium of the bronchioles; see diagram)
 Beat to reduce entry to lower airways; function lost in smoking / infections
o 20% of conducting airways: goblet cells;
 They are found inside the trachea, bronchus, and larger bronchioles in
respiratory tract
 Secrete mucus:
 Adhesive for incoming particles
 Antimicrobial
 Antioxidant
o Also: clara cells:
 Metabolise chemicals coming through; involved in metabolism of inhaled
foreign compounds
 Clara cells are dominantly distributed at the epithelium of the bronchioles
(while ciliated cells dominantly occupy that of the trachea-bronchus; see
diagram)
o Alveolar Type II pneumocytes:
 At alveoli
 Produce surfactant which has immune properties and used to prevent
alveolar collapse (see later)
o Phagocytic cells:
 Immune system function
 Eg. Alveolar macrophages [at alveoli], polymorphonuclear neutrophils
-
Types of cell in the lung:
o
o
o
Trachea:
 Basal Cells
 Ciliated Cells Glands
 Goblet Cells
 Neuroendocrine
Airway:
 Ciliated Cells (80% number)
 Clara Cells
 Neuroendocrine
 Goblet Cells (20% number)
Alveolus:
 Type 1 Cells: 90% of SA, equal number as type 2, thin for gas exchange
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[ie Alveolar Type I pneumocytes]
Simple squamous epithelium

Type 2 Cells: 10% of SA, equal number as type 1, produce surfactant
[ie Alveolar Type II pneumocytes]
Cuboidal epithelium



-
Lipofibroblasts
Myofibroblasts
[also prob phagocytes]
Airway structure:
o See diagram below:
o Nb only in areas of the lung with smooth muscle present can sympathetics and
parasymapathetics give dilation/constriction [ie not at alveolar sacs; most plentiful
in conducting zone]
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07/11/13: Respiratory system II: gasses, Pressure and
Volumes: Dr Shovlin
Los (from booklet):
Lecture 2: Respiratory System II (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able



’s Gas Law and apply at sea level and Everest




nderstand the principle that PaCO2 is the primary driver of ventilation



Notes:
-
Gas Laws:
o Dalton’s Law: Total pressure = sum of the partial pressures
o Air total composition (at any altitude): 21% oxygen, 78% nitrogen, 1% other
o p(O2) will always be 21% of the total pressure of dry air at that altitude (but its
pressure contribution in kPa/mmHg will vary with altitude)
o Total pressure at sea level = 101kPa so p(O2) = 21.2 kPa (159mmHg)
o Note that pressures may be given in kPa, mmHg, cmH2O, atm
o To factor in the influence of humidity:
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FRC = Functional residual capacity;
RV = residual volume
- Tidal and reserves:
o Tidal volume usually 0.5L but all other values show large variation between people
o Note that not all intrathoracic air is available for gas exchange; exchange can only
occur in functional alveoli:
 Anatomical /anatomic deadspace volume is volume of intra-thoracic air in a
tidal volume minus intr-alveolar air
 The anatomic dead space is the volume of the conducting airways,
including the nose (and/or mouth), trachea, bronchi, and
bronchioles. It does not include the respiratory bronchioles and
alveoli.
 The volume of the conducting airways is approximately 150 mL: is
the first air expired [important to consider if sampling breath etc]
 At the end of expiration the conducting airways are filled with
alveolar air; that is, they are filled with air that has already been in
the alveoli and exchanged gases with pulmonary capillary blood.
With the inspiration of the next tidal volume, this alveolar air is first
to enter the alveoli, although it will not undergo further gas
exchange. The next air to enter the alveoli is fresh air from the
inspired tidal volume (350 mL) which will undergo gas exchange
 Physiological /physiologic deadspace volume is is volume of intra-thoracic
air in a tidal volume minus intr-alveolar air of functional alveoli only
 Ie includes the anatomic dead space of the conducting airways plus
a functional dead space in the alveoli [ventilated alveoli that do not
participate in gas exchange].
 In normal persons, the physiologic dead space is nearly equal to the
anatomic dead space [due to good regional V/Q matching]
 Volume of the physiologic dead space is estimated with the
following method: If physiologic dead space is zero, then PECO2 will
be equal to alveolar PCO2 (PACO2). However, if a physiologic dead
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space is present, then PECO2 will be “diluted” by dead space air and
PECO2 will be less than PACO2 by a dilution factor. [nb PaCO2 =
PACO2]
o
The Minute ventilation (= minute volume = total ventilation = pulmonary ventilation)
is the mlmin-1 at rest.
 Ie volume of gas inhaled (inhaled minute volume) or exhaled (exhaled
minute volume) from a person's lungs per minute
 Around 12 breaths per min at rest so is 12*500 = 6000mlmin-1
o
The alveolar ventilation is the volume of air moving into or out of the functioning
alveoli per min at rest (usually in mlmin-1):
 Ie Is 12 * (500 – anatomical deadspace volume – alveolar deadspace
volume) = 12 * (500 – physiological deadspace)
o
Key values: [from sea level atm 100KPa = 760mmHg downward]
 inhaled dry air p(O2) = 21.2 kPa = 160mmHg
 inhaled dry air p(CO2) = negligible
 Humidified tracheal air on inspiration p(O2) = 20 kPa = 150mmHg
 Humidified tracheal air on inspiration p(CO2) = negligible
 It is assumed that the air becomes fully saturated with water
vapour. At 37°C, PH2O is 47 mm Hg (=6.3kPa)
 Values can be calculated from the dry values using the relevant
equation
 Alveolar p(O2) = 13.3 kPa =100 mmHg
 arterial p(O2) = 13.3 / 13kPa = 98/100 mmHg [slight decrease due to
physiologic shunts]
 Reason for low p(O2): due to dilution with high CO2 levels (ie prior
to gas exchange) and due to the gas exchange events themselves (ie
loss of O2: equilibrates with blood in healthy person; and further
CO2 dilution)
 Alveolar p(CO2) = 5.3kPa = 40mmHg
 arterial p(CO2) = 5.3kPa = 40mmHg [slight increase due to physiologic
shunts]
 venous p(O2) = 5.3kPa = 40mmHg
 venous p(CO2) = 6.1kPa = 46mmHg
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GE Y1 Respiratory
o
o
o
Shunts:
 Physiologic shunt. About 2% of the cardiac output normally bypasses the
alveoli—there is a physiologic right-to-left shunt. Part of the physiologic
shunt is the bronchial blood flow, which serves the metabolic functions of
the bronchi. The other component of the shunt is the small amount of
coronary blood flow that drains directly into the left ventricle through the
thebesian veins and never perfuses the lungs. Small physiologic shunts are
always present, and PaO2 will always be slightly less than PAO2 (V. small Aa
difference). Shunt V/Q defects add to the magnitude of physiologic shunt
and increases Aa difference.
 Right-to-left shunts. Shunting of blood from the right heart to the left heart
can occur if there is a defect in the wall between the right and left ventricles.
In a right-to-left shunt, hypoxemia always occurs. Cannot be corrected by
having the person breathe a high O2 gas (e.g., 100% O2)
“Aa gradient” [ie A=alveolar, a = arterial]
 Increases with:
 V/Q defect [inc Diffusion defects (e.g., fibrosis, pneumonia) and
Right-to-left shunt]
 Age
o Due to lower arterial blood O2 levels caused by poorer gas
exchange primarily due to less elastic lungs
 Normal in:
 High altitude (dec PIO2)
 Hypoventilation (dec PAO2)
pa(CO2) [ie p(CO2) of the arteries] leaving the lungs is the main driver of ventilation
via pH changes:
 looked at in detail in later lecs
 chemoreceptors at carotid body and aortic arch respond to pH, pa(CO2) and
pa(O2) of blood (relevance mainly to pa(O2) but relatively insensitive to
pa(O2) as can drop greatly without ill effect due to being at the flat part of
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o
oxygen dissociation curve; before this occurs usually CO2 signals: quickly
accumulates and signals to raise ventilation so this acts as the main driver
for increased ventilation)
 If arterial PO2 is less than 60 mm Hg, the breathing rate increases in
a very steep and linear fashion. In this range of PO2,
chemoreceptors are exquisitely sensitive to O2
o Such hyperventilation can occur at altitude; at first gives inc
in pH due to breathing off extra CO2 than what is necessary
(to try to gain sufficient O2 which may only be at 60mmHg)
– this inc pH gives ventilation dec via dec pH ventilation
signalling but then within a few days the alkylosis is
compensated for via HCO3- excretion from body so
hyperventilation resumes
o The initial phase of ascent to high altitude is associated with
a constellation of complaints, including headache, fatigue,
dizziness, nausea, palpitations, and insomnia. The symptoms
are attributable to the initial hypoxia and respiratory
alkalosis, which abate when the adaptive responses are
established.
 Detection of changes in PCO2 by the peripheral chemoreceptors is
less important than detection of changes in PCO2 by the central
chemoreceptors.
 chemoreceptors of medulla respond to pH and p(CO2) of CSF
 blood-brain barrier is relatively impermeable to H+ and HCO3 CO2 passes through BBB and brain-CSF barrier
 In the CSF, CO2 is converted to H+ and HCO3- and is detected by the
chemoreceptors
 pa(CO2) = ~5.3kPa is normal [important to know] (45mmHg)
 Acceptable: 4.7-6 kPa
 2kPa  dizziness (due to high RR)
 12kPa  drowsiness, life threatening
 If the patient's arterial partial pressure of carbon dioxide (PaCO2) is
greater than 6 kPa: - refer them urgently to a specialist respiratory
service (to be seen within 1 week)
 Other receptors:
 Lung stretch receptors
 Joint and muscle ergoreceptors [pre-emptive response]
 Irritant receptors
 J receptors
pa(O2) governs O2 delivery to tissues:
 Henry’s law: rate gas dissolves in an inert liquid is proportional to its partial
pressure
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

At normal pa(O2) only 0.3mls O2 /100mls [ie PaO2 x solubility in
ml/100ml/pressure unit] of blood dissolves [2% of the total O2 content of
blood] – this is not enough; haemoglobin is used to aid O2 capacity of blood
– carries 20mls / 100mls [ie 1.34ml/g x 15g/100ml – see pukka notes] of
blood [98% of the total O2 content of blood]
 Ie total O2 in blood = O2 dissolved + O2 on haemoglobin
 Haemoglobin: amount of O2 bound vs p(O2) is a sigmoidal curve due
to cooperativity of O2 binding
 Haemoglobin leaving lungs is usually ~100% saturated
 At rest, normal conditions, in the tissues saturatin is approximately
40 mm Hg: hemoglobin is only 75% saturated and the affinity for O2
is decreased
 Haemoglobin: not 100% O2 delivered to tissues but large amount is
due to shift of sigmoidal curve due to CO2 presence, etc
 P50; 23DPG; temp; CO2; pH; Bohr; Haldane; CO [left shift (Those
heme groups not bound to CO have an increased affinity for O2) and
change shape (decreases the number of O2-binding sites available
on hemoglobin); carboxyhaemoglobin; carbaminohaemoglobin
 Methemoglobin [Fe3+ doesn’t bind O2; nitrates, sulphonamides;
methaemoglobin reductase]; Fetal hemoglobin (hemoglobin F);
Hemoglobin S (sickle cell disease)
Delivery to tissues:

o
Anemia, trauma, low HR gives reduced O2 delivery to tissues
Disease:
 Types of breathing problem:
i. Airflow obstruction: is only concerned with airway issues; eg asthma
ii. Airflow restriction: concerned with:
 Patent airways
 Open alveoli
 Elastic and compliant lung parenchyma
 Sealed pleural space
 Functional muscles & bones at chest walls
iii. Bloodflow obstruction: emboli
iv. Nervous: Polio can cause phrenic nerve damage and therefore breathing
difficulties
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08/11/13: Mechanisms of breathing: Dr Shovlin
Los (from booklet):
Lecture3: Mechanisms of Breathing (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able to
 Recall the principal muscles associated with inspiration and expiration
 Recall the anatomical basis of breathing, describing the two phases of respiration and the
role of the thoracic cage and diaphragm and changes in the capacity of the thoracic cavity
during these events.
 Recall how contraction of inspiratory muscles causes the chest wall to expand and the lungs
to enlarge
 Recall how the chest wall contracts and lungs reduce in size
 Explain what is meant by elastic recoil
 Define compliance
 Explain how pulmonary versus chest wall compliances can vary in various respiratory
diseases
 Explain the concept of surface tension and the Law of Laplace
 Explain how pulmonary surfactant affects lung volume and airway patency
 Recall the relationship between alveolar and atmospheric gas pressures, airway resistance
and airflow
 Recall the factors that affect airway resistance centrally and peripherally
List the two major components that contribute to the work of breathing and explain how
each may be altered in disease states
 Recall the relationship between mechanical work and oxygen cost of breathing in normal
individuals and patients with respiratory insufficiency
 Recognise that respiratory muscles control air movement during other behaviours including,
speech, laughter, coughing, sneezing and vomiting.
Notes:
-
-
Posteriorly the oblique fissure starts at T4
Inspiration is louder than expiration
Pneumonia gives “bronchial breathing” with expiration as loud as inspiration
At the Functional residual capacity (FRC) the outward force of the chest wall trying to
expand to its more favourable, larger state is exactly balanced by the tension of the lungs
trying to contract to their more favourable, smaller state.
o Inspiratory and expiratory muscles give deviations from this volume
o If thorax opened, chest would expand by 600-1000mL
Zones of apposition: lateral zones of the diaphragm that are directly against the inner
surface of the rib cage
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Note that decent of diaphragm, as well as expanding the intrathoracic volume directly, also
exerts an outward force on the lower abdominal wall (presumably due to resistance of
abdominal organs) to cause rib elevation and expansion and further expand the
intrathoracic volume
Oesophageal pressure changes follow pleural pressure changes
Boyle’s law states that P x V is constant at a given temperature
o P1V1 = P2V2
Transmural pressure is calculated as alveolar pressure minus intrapleural pressure. If
transmural pressure is positive, it is an expanding pressure on the lung, and the arrow points
outward.
If transmural pressure is negative, it is a collapsing pressure on the lung, and the arrow
points inward (does not ever occur in healthy state)
During inspiration, intrapleural pressure becomes more negative than at rest:
o As lung volume increases, the elastic recoil of the lungs also increases and pulls
more forcefully against the intrapleural space, and
o airway and alveolar pressures become negative.
Tidal breathing gives smooth sine waves:
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Compliance = Δvolume/ΔPressure
o High in healthy lungs (but not extremely high as for emphysema)
o The external force required to deform the structure (ie refers to inspiration)
o Compliance Increases with age
Elasticity = ΔPressure/Δvolume = 1/compliance
o High in healthy lungs
o Property of matter that causes it to return to its resting shape after deformation (ie
refers to expiration)
o Determines the volume left in the lungs after a normal tidal exhalation (ie the FRC)
o Elasticity decreases with age so FRC rises and potentially more input from expiratory
muscles instead of relying on passive exhale
-
The thin rubber band has the smaller amount of elastic “tissue”—it is easily stretched, and is
very distensible and compliant. The thick rubber band has the larger amount of elastic
“tissue”—it is difficult to stretch and is less distensible and compliant. Furthermore, when
stretched, the thick rubber band, with its greater elastance, “snaps back” with more vigor
than the thin rubber band does.
-
Floppy balloon/emphysema = high compliance, low elastic resistance/recoil (expiratory
muscles have to work harder – passive insufficient to expel air [these will also have to work
harder for asthma too (but this is for reasons of airflow obstruction not airflow restriction)]
[will also have to work harder with age])
Stiff balloon/pulmonary fibrosis = low compliance, high elastic resistance/recoil (inspiratory
muscles have to work harder)
[ie regardless of which type of disease will give larger overall energy cost of expiration]
-
-
Below diagram shows volume changes with changing transmural (= transpulmonary)
pressure (difference in pressure across the alveolar wall); the dotted lines just indicate the
favourability of the position at that pressure of the chest wall/lung
o Ptp = Palv - Pip. Where Ptp is transpulmonary pressure, Palv is alveolar pressure, and
Pip is intrapleural pressure
o If 'transpulmonary pressure' = 0 (alveolar pressure = intrapleural pressure), such as
when the lungs are removed from the chest cavity or air enters the intrapleural
space (a pneumothorax)
o Under normal physiological conditions (ie tidal breathing) the transpulmonary
pressure is always positive; intrapleural pressure is always negative and relatively
large, while alveolar pressure moves from slightly positive to slightly negative as a
person breathes.
o Eg. At FRC the chest wall lines are equidistant from the combined line indicating
balance of the forces; collapsing force equal to the expanding force
 [ie muscle actions are not present on the plot but this is the only position at
which they are not active – elsewhere are required to overcome the
collapsing/ expanding forces]
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
o
o
o
eg above FRC the muscles are overcoming the net collapsing force due to
lung collapse > chest wall expansion force or at higher pressures them both
exerting collapsing florce.
 Similarly below FRC there is a net expansion effect due to chest expansion >
lung collapse but the muscles are overcoming this to hold the lungs in this
position
 in fact on the 2nd graph an applied pos/neg pressure is used to hold the
positions
NB her diagram prob bad as shouldn’t be getting negative transmural pressures
(would indicate a collapsing effect)
The slopes of the relationships for inspiration and expiration are different, a
phenomenon called hysteresis. Usually, compliance is measured on the expiration
limb.
 On the inspiration limb, one begins at low lung volume where the liquid
molecules are closest together and intermolecular forces are highest; to
inflate the lung, one must first break up these intermolecular forces.
 On the expiration limb, one begins at high lung volume, where
intermolecular forces between liquid molecules are low; one needn’t break
up intermolecular forces to deflate the lung.
Gradient is proportional to compliance: The compliance of the chest wall alone is
approximately equal to the compliance of the lungs. However, the compliance of the
combined lung and chest-wall system is less than that of either structure alone (like
a balloon in a balloon) [nb the combined compliance curve changes with diseases]
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Emphysema (increased lung compliance).
o Emphysema is associated with loss of elastic fibers in the lungs.
o Reduced collapsing force at a given volume
o Thus, the combined lung and chest-wall system seeks a new higher FRC, where the
two opposing forces can be balanced
o breathe at higher lung volumes (in recognition of the higher FRC) and will have a
barrel-shaped chest.
Fibrosis (decreased lung compliance)
o stiffening of lung tissues
o Increased collapsing force at a given volume
o Thus, the combined lung and chest-wall system seeks a new lower FRC, where the
two opposing forces can be balanced
o breathe at lower lung volumes
Keeping the alveoli open during inspiration:
o the alveolar pressure is negative during this period so would think they would want
to collapse
o Alveoli can be considered as gas bubbles in a liquid so can use the Law of Laplace
 Law of Laplace states that P = 2T/R for such a bubble to be stable and to
stop collapsing, where P = pressure at which the bubble is stable (want it to
be low), T=tension (ie low allows for lower pressure) and R=radius (ie high
allows for lower pressure)
 Hence smaller alveoli require larger pressures to remain open and should be
the first to collapse
 This problem is avoided by using a higher surfactant concentration at
smaller alveoli; the surfactant (produced by type II pneumocytes) lowers
surface tension to allow alveoli stability at reduced pressures and by using
higher surfactant concentrations at smaller alveoli further reductions in
surface tension are offered to compensate for their greater propensity to
collapse.
 For a given drop in pressure, as alveoli start to shrink (reducing R, radius) the
tension (T, surface tension) falls faster, therefore will quickly reach a new set
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o
-
of R&T values that via the equation match the required P value which was
previously too high.
Surfactant info:
 Is dipalmatoylphosphatidyl choline mainly
 Has the lowest surface tension of any biological substance
 Intermolecular forces between the DPPC molecules break up the attracting
forces between liquid molecules lining the alveoli
 Prevents collapse
 Increases compliance
 Form relatively late in gestation; premature babies without it have breathing
difficulties: “(neonatal) respiratory distress syndrome”; glucocorticoids can
be given to mother to encourage type II pneumocyte cells of child to
produce surfactant
Airflow resistance [must be overcome in active inspiration, passive expiration, active
expiration]:
o Components:
 Elastic resistance of lungs (ie dependant on how elastic/compliant the lungs
are)
 Flow Resistance in upper airways and tracheobronchial tree to airflow
(turbulent / laminar flow is relevant) (Poiseuille’s equation is relevant)
(airway patency is relevant)
 Frictional resistance of tissues in lung parenchyma and chest wall sliding
over each other
o Effect of flow type:
 ΔP α airflow for laminar flow
 ΔP α airflow2 for turbulent flow [ie greater pressure required for given flow]
 Reynolds number = (2 * Radius * Density of gas * velocity of gas) / gas
viscosity
 The number is used to predict which type of flow will occur
 High numbers indicate turbulent flow, low numbers indicate laminar
flow
 Ie wide airways, branch points (inc radius) and high velocities are
associated with turbulent flow
 Helium can be used to extend life a small amount by reducing
density but not viscosity of the air
o Poiseuille’s equation:
 Airflow = ΔP / R
 R = (8Ln)/(πr4)
 Therefore: Airflow = (ΔP πr4)/8Ln
 Consequence is that while smaller airways individually have higher airflow
resistance, many in parallel give a low overall resistance
 Quiet breathing:
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o

o
Airflow resistance is greatest in the upper airways and low
in the small peripheral airways [specifically the (mediumsized)bronchi are the sites of highest airway resistance]
However, towards the end of forced expiration:
o As lung volume decreases, airways narrow, esp peripherally
and the main contribution to airflow resistance moves
peripherally
Airway patency:
 Central airways:
 Held open by cartilage
 Factors affecting resistance:
o Symp/para action on smooth muscle modulates width
(bronchioconstriction/dilation)
o Breathing: will give some changes to width via width
changes
o Foreign bodies
o Mucus hypersecretion
 Peripheral airways:
 Are connected to the alveolar network and therefore held open by
the same forces holding open the alveoli (as described by Law of
Laplace
 Factors affecting resistance:
o Symp/para action on smooth muscle modulates width
(bronchioconstriction/dilation)
o Breathing: will give some changes to width via width
changes
o Emphysema: reduced “radial traction” – parenchyma fails to
hold the airways open: choke points are more likely to occur
(see later) [ie despite the usually beneficial effect of high
lung volumes on radial traction]
o Inflammatory fluid / edema [inc stiffness and displaces air]
 Some key determinants of Airway Resistance:
 Autonomic nervous system: sympa and para
 Lung volume. Changes in lung volume alter airway resistance
because the surrounding lung tissue exerts radial traction on the
airways. High lung volumes are associated with greater traction,
which decreases airway resistance.
 Viscosity of inspired air
 Leukotrienes: from arachidonic acid metabolism; airway constriction
[are metabolised at lung to lower level]
 Disease states
 NB O2, Thromboxane A2, prostacyclin (prostaglandin I2) are
vasoactive so not relavant here
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o
Investigation by following airflow rates: [see graphs below]
 Moving clockwise from extreme right side of the graph patient is initially at
the end of a forced exhale.
 Note that the Y-axis is flow rate; all inspiration is effort dependant (ie can
be affected by patient thoughts); flow rate falls to 0 at end of inhale
 Patient asked to breath out as fast as possible; early part is effort dependant
and is utilising the forced expiration muscles
 However because the exhalation was so fast the passive exhalation has yet
to occur (ordinarily would happen first!); this is passive and so effort
independent (can’t be falsified by patient)
 In healthy person this last section is a continuation of the parabola
into a straight line (as below): ie airway compression continues to be
the limiting factor giving smooth change in flow rate
 If airway obstruction there will be a “sagging” of the line first
(cannot passively maintain that airflow ejection rate due to block –
block as well as airway compression is influencing the flow rate
change) then a lower gradient loss of airflow
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o
o
Bronchial movements and choke points:
 Note: at start of inspiration negative intrapleural pressure gives some
bronchial expansion
 Note: during forced expiration, positive intrapleural pressure gives partial
bronchial collapse between cartilages
 Choke points can develop in disease states; during forced exhalation
the positive pressure magnitude reduces from the alveoli to the
mouth but the pleural pressure is constant throughout
 Result is regions where the pleural pressure exceeds the pressure in
the airways; the choke point forms at the point furthest to the
alveoli where this condition is true; ie transmural pressure is
negative here
 Air trapping behind the blockade occurs; blockade typically at 2nd /
3rd generation airways
 By lip pursing during their forced exhalation the patient is able to
move the EPP (equal pressure point) (choke point) into the mouth as
it gives raised airway pressures ‘upstream’
Pressure-flow relationships: [ie here are looking at flow vs pressure graphs which
are different to the flow vs volume graphs so results give diff info]
 At high lung volume & expiration:
 Flow increases with increasing effort
 FEV1/VC should be more than 80% (ie for fastest possible exhale:
forced expiratory volume in one second divided by vital capacity)
o if not then obstruction likely to be present
o ie would indicate a problem with the airways
 At low lung volume & expiration:
 Flow does not increase with increasing effort once a maximum is
reached; thought to be because of airway compression in a healthy
individual (note that this cannot be compared to the airflow vs
volume graphs because is not for a cycle – is just the results at set
applied transpulmonary pressures)
[this graph is for the flow changes of a normal individual at three levels of
lung inflation; high, mid, low lung inflation]
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in a normal person, FEV1/FVC is approximately 0.8, meaning that 80% of the vital capacity
can be expired in the first second of forced expiration (see Fig. 5-6A).
o In a patient with an obstructive lung disease such as asthma, both FVC and FEV1 are
decreased, but FEV1 is decreased more than FVC is. Thus, FEV1/FVC is also
decreased, which is typical of airway obstruction with increased resistance to
expiratory airflow (see Fig. 5-6B).
o In a patient with a restrictive lung disease such as fibrosis, both FVC and FEV1 are
decreased, but FEV1 is decreased less than FVC is (or indeed may increase). Thus, in
fibrosis, FEV1/ FVC is same or actually increased
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08/11/13: Respiratory Muscles: Dr. Kevin Murphy
Los (from booklet):
Lecture 4: Respiratory Muscles (Dr. Kevin Murphy (kevin.murphy@imperial.ac.uk)
At the end of this lecture you should be able to:
 Identify the principal muscles associated with inspiration and expiration.
 Understand the additional non-respiratory actions of these muscles.
 Understand how contraction of inspiratory muscles causes the chest wall to expand and the
lungs to enlarge.
 Understand how contraction of expiratory muscles causes the chest wall to contract and the
lungs to reduce in size.
 Recognise that these muscles will be differentially activated during different breathing
states. Specifically: identify which will be active during quiet breathing, and which will be
active when ventilatory demand is increased such as during exercise or during lung disease.
 In addition to their primary role in maintaining alveolar ventilation, know that respiratory
muscles will control air movement during other behaviours including, speech, laughter,
coughing, sneezing and vomiting.
Notes:
-
Inspiratory muscles:
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Inspiration
Quiet
Augmented
Expiration
Quiet
Augmented
Resisted
(eg in speech
after large
inhalation)
Diaphragm
mainly
(others to
a small
degree)
Diaphragm
No muscles (passive:
elastic recoil gives
return to FRC)
External
oblique
Sternocleidoma
stoid
Internal
oblique
Scalene
Transversalis
External
intercostals
Rectus
abdominis
Parasternal
muscles
Internal
intercostals
Diaphragm (to
retard flow)
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08/11/13: Lung Development: Dr Matthew Hind
Los (from slides):
-
Understand that lung development is a continuous process [continues well after birth]
Describe the stages of lung development
Think about the plasticity of lungs
Disorders during lung development can lead to lung diseases
Can learn about lung development by looking at flies
Many of the underlying mechanisms remain unknown
Dramatic changes occur at birth
Notes:
-
Gas exchange passive, dependant on Sa (achieved by high lung network complexity),
thinness, conc grad
-
Types of cell in the lung:
o
o
o
Trachea:
 Basal Cells
 Ciliated Cells Glands
 Goblet Cells
 Neuroendocrine
Airway:
 Ciliated Cells (80% number)
 Clara Cells
 Neuroendocrine
 Goblet Cells (20% number)
Alveolus:
 Type 1 Cells: 90% of SA, equal number as type 2, thin for gas exchange
[ie Alveolar Type I pneumocytes]




-
Type 2 Cells: 10% of SA, equal number as type 2, produce surfactant
[ie Alveolar Type II pneumocytes]
Lipofibroblasts
Myofibroblasts
[also prob phagocytes]
5 morphological stages of lung development: [need to know about each stage – see
below]
[6162636 weeks]
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NB The foregut is the anterior part of the alimentary canal, from the mouth to the
duodenum at the entrance of the bile duct.
•
•
Embryonic - (day 22- 6 weeks) including lung bud formation
• Occurs at day 22 human, mouse E9
• early in dev gastrulation occurs to give a tube (effectively mouth to
anus)
• Foregut endoderm invades splanchnic mesoderm (ie the lung is derived
from the foregut (as is pancreas, etc))
• Lateral plate mesoderm is a type of mesoderm that is found at
the periphery of the embryo. It will split into two layers, the
somatic layer/mesoderm and the splanchnic layer/mesoderm:
• The somatopleuric layer forms the future body wall.
• The splanchnopleuric layer (splanchnic mesoderm)
forms the circulatory system and future gut wall.
• Larngotracheal groove moves in caudocranial direction (ie upwards)
[The laryngotracheal groove is a precursor for the larynx and trachea]
• Day 26-29 lung tube bifurcates into left and right bronchial buds
• By 4.5 weeks the lung forms 5 saccules, the secondary bronchial buds: 3
right 2 left (ie become the lobes of the lung in the adult)
• By continuous dichotomous branching upto the end of the 6th week the
tertiary bronchial buds form – the bronchopulomonary segments of the
mature lung
• Branching morphogenesis and patterning occurs
• Epithelial/mesenchymal signalling – factors released from mesenchyme
act as cues for the developing lung bud
• endoderm patterned by the mesenchyme – [Proof: remove the
mesenchyme, tube dies; foreign mesenchyme eg somatic or mesonehric
keeps tube alive but no branching; tip mesenchyme can induce
branching in proximal endoderm]
• FGF10 induces branching (ie factors from the mesenchyme are
important in triggering lung branching) but not exclusively; chicken FGF
is the same as mouse FGF but induces a different pattern of branching
so other factors must be important
Pseudoglandular (6 –16 weeks)
• 7 weeks lung looks like a primitive gland; airways lined by columnar
epithelium separated by thick undifferentiated mesenchyme
• 65-75% of bronchial branching occurs between 10 and 14 weeks
• Branching of airways is complete at the end of this phase
• Epithelial cells are loaded with glycogen
• Cilliated cells and goblet cells appear
• Surfactant proteins first appear
• Mesenchyme differentiates into cartilage and smooth muscle
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•
•
•
Cannalicular (16-26 weeks) [only after 22-24 weeks when this is nearly complete
is breathing possible = min survival requirement]
• Characterised by appearance of acini [cluster of cells that resembles a
many-lobed "berry"] consisting of airway stem and a spray of tubules
arranged as a cluster surrounded by loose mesenchyme – ie will become
the alveoli eventually
• Mesenchyme becomes riddled with capillaries becoming canalised
• Differentiation of type II and type I cells.
• Type II cells accumulate lamellar bodies (surfactant)
• Proximal bronchiolar (Clara) cells accumulate CCSP
• 26-28 weeks, human lung can support some gas-exchange especially if
supported by surfactant (exogenous surfactant can be sprayed in)
• Antenatal steroids given to mum induce surfactant synthesis and induce
mesenchymal thinning and prevent RDS (BPD)
Saccular (26/36 weeks)
• Distal airspaces form terminal clusters of widened airspaces called
saccules (will become the alveoli eventually) and there is expansion of
airspace volume
• Terminal sacs give rise to three generations of alveolar duct [Alveolar
ducts are tiny ducts that connect the respiratory bronchioles to alveolar
sacs] and one generation of alveolar sacs
• As a result of the expansion of airspace volume the interstitum is
compressed and its volume falls.
• The capillaries become close together and the walls of the airspaces
contain a double capillary network
Alveolar (36 weeks -??? [ie evidence that further alveolar development can
occur into puberty])
• Alveolar stage species dependant (ie varies between species when it
occurs)
• Elastin is involved in contracting to pinch sections into alveoli
• Depends on oxygen requirements at birth
• Guinea pigs, sheep and deer septate in utero
• Rats mice and human largely postnatal
• Humans 26 weeks – 18 months
• Mice P4 – P14
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[Pharmacology: The effects of ACh are relatively weak on nicotinic receptors so
anticholinesterases have more potent effects at muscarinic receptors because raising ACh conc
at nicotinics will proportionally give far less of a response than at muscarinic receptors]
-
-
-
Comparative biology:
o genes that control fly respiratory development also control lung development in
mouse and human
o Mice have a highly manipulated genome and lots of molecular biology reagents
that we can use to ask specific questions about developmental processes
o Other models include rat, sheep, pig and baboon - different advantages
Is lung disease lung development gone wrong?
o Increasing evidence that early life events alter susceptibility to disease
o Low birthweight associated with low FEV1
o Maternal smoking and asthma
o Gene environment interactions and epigenetics
o Genome, transcriptome, proteome and metabolomics
o Stem cells as a causes of disease eg lung cancer or fibrosis
o Impaired alveologenesis resulting in fewer alveoli, a reduced Sa and
susceptibility to age related lung decline/emphysema
Can we exploit developmental cues as novel therapy?
o Retinoic acid has been demonstrated to restore SA in animal models of
emphysema possibly by inducing regeneration (systemic retinoic acid has shown
alveoli-regenerative action in models; steroids/elastase used to cause damage
with RA giving regeneration; could equate to regeneration of emphysema
damage in humans where alveoli lost)
o HGF demonstrated to induce lung regeneration
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o
o
o
o
Stem cells potentially could restore a lacking progenitor population with the
correct microenvironment differentiate into functional lung tissue
Understanding how airway remodelling occurs might reveal blocking strategies
for airway conditions such as asthma
Lung fibrosis seems to be driven by abnormal developmental signals can we
switch them off?
Ex-vivo lung perfusion systems with human donor lungs and artificial blood and
air pumps can be used in such research to aid investigation.
QUIZ important facts:
[well worth doing again during revision – also, any quizlet exercises?]
- Diffusion of gases across the alveolo-capillary membrane is very efficient. As a result the
PO2 and PCO2 of the blood leaving a pulmonary capillary will be almost identical to that
in the adjacent alveoli.
- Although it is a bit of an oversimplification, you won't go far wrong if you assume that
the appropriate level of ventilation is that which results in an arterial PCO2 of 5.3 kPa.
o partial pressure of oxygen vs amount of oxygen in the blood:
- The partial pressure of oxygen in systemic arterial blood (ie here are considering the
amount dissolved – so Hb not relevant) in a healthy individual is determined by alveolar
PO2 (in accordance with Henry’s Law) - but the amount of oxygen in the blood (the
oxygen content) depends both on the PO2 (which affects amount dissolved and amount
added to Hg) and on the haemoglobin concentration.
- In adult males, the normal haemoglobin levels are 13.8 - 17.2 g/dl – note the units
involve decilitres (men prob at the higher end, women prob at the lower end; prob dec
with age). Decilitre = 100ml
- the oxygen content of arterial blood in a healthy person with a Hb concentration of 15
g/dl is around 9mmol/L
- If you breathe an oxygen enriched mixture, alveolar PO2 may rise to (say) 55 kPa (4 x
higher than normal) the arterial PO2 will scarcely rise at all, since at 13 kPa the Hb is
already virtually fully saturated anyway (are at the flat top section of the sigmoidal
curve)
- Anaemia: alveolar and arterial PCO2 will be pretty normal (unless the anaemia is
extremely severe) because it is the pa(CO2) that regulates ventilation and this is not
affected by a drop in Hb levels
- If the inspired gas was 100% oxygen, all the nitrogen normally present in alveolar air will
gradually be replaced by oxygen and, in consequence, alveolar PO2 will increase
enormously and eventually rise above 80 kPa but this will not (a) significantly improve
and/or (b) correct oxygen delivery to the tissues in an anaemic subject because
regardless of Hb conc, saturation has already almost been reached at a p(O2) of 13kPa
(the small rise in anaemia and non-anaemia is similar in both cases) (main help is in
reducing the ventilation rate required to sustain a p(O2) of 13+kPa – however note that
no help will be given in aiding CO2 removal by using high conc O2 to breath; must hope
that the ventilation rate stimulated by the pa(CO2) levels will be sufficient)
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Must know normal values for pA(O2) [13.3kPa], pa(O2) [13kPa] and pa(CO2) [5.3kPa] as
is expected knowledge in helping pick a correct answer
Alveolar PCO2 in a child aged six is roughly the same as it is in an adult.
Haemoglobin is abbreviated Hb or Hgb (not Hg)
Hb dissociation curves: The shape of the curve does depend on the PCO2 (as this alters
the affinity of Hb for oxygen) but it is independent of the Hb concentration. However, if
the actual AMOUNT of oxygen is plotted on the y axis instead of the percentage
saturation of Hb, there is a marked change with inc Hb.
Must consider what is 'normal' for someone of that AGE and SEX – these factors
influence what is a normal result. Having said this, as an approximation, 15g/dl can be
taken as a typical value for the Hb concentration in the blood of a healthy adult.
The rate of oxygen consumption of the tissue concerned AND its rate of blood flow
affects how much O2 is removed from the blood: O2 consumption = O2 delivered – O2
returned Which is …
o VO2 = (Q x Ca O2) – (Q x CvO2)
o VO2 = Q (CaO2 - CvO2)
o VO2/Q = CaO2 –CvO2
o Where Q= rate of blood flow [not same as CO for all tissues but CO used when
considering all tissues as a whole], VO2 = O2 consumption, CaO2 = oxygen
concentration in arterial blood, CvO2 = oxygen concentration in venous blood.
o This is the Fick principle
breathing an oxygen enriched mixture where alveolar PO2 is 55 kPa (4 x higher than
normal):
If the PO2 in alveolar air is 55 kPa and that in the blood is 13 kPa, then there is a
concentration gradient across the alveolo-capillary membrane and O2 WILL diffuse into
the blood thus raising the concentration of free' O2(i.e. NOT bound to Hb) (ie the P(O2)).
N.B. The best way of regarding the PO2 of the blood is as a measure of the amount of
'free' O2. This is not readily saturated -so the PO2 can definitely rise above 13 kPa.
HOWEVER the amount of oxygen bound to Hb will scarcely rise at all as the binding sites
on the Hb are almost all already 'full' when the PO2 is 13 kPa. Although the amount of
'free' O2 goes up fourfold as the PO2 rises from 13 kPa to 55 kPa, the effect on the
overall O2 content of the blood is small - because O2 is poorly soluble.
what do you think will happen to arterial PO2 in a moderately anaemic subject at rest:
The PO2 of mixed alveolar air depends on (i) the alveolar ventilation (ii) the rate of
oxygen consumption and (iii) the composition of inspired gas. None of these will be
changed in anaemia.
The same ventilation that results in an alveolar PCO2 of 5.3 kPa also results in a PO2 of
roughly 13 kPa in a healthy subject. [ie The best way of regarding the PO2 of the blood
is as a measure of the amount of 'free' O2 – the Hb is not relevant]. In anaemic subjects
alveolar and therefore arterial PO2 will NOT be lower than normal
Breathing an oxygen-enriched gas mixture is not very effective at increasing O2 delivery
to the tissues in anaemia.
although the amount of ‘dissolved O2' will be substantially increased, breathing 100%
oxygen (in someone with normal lungs) has little or no effect on the amount of oxygen
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bound to Hb. Consequently, there will only be a comparatively small increase in the
overall O2 content.
Breathing an oxygen-enriched gas mixture will NOT improve the raised PCO2 resulting
from hypoventilation. Basically the only factors that determine alveolar PCO2 are (a) the
ventilation and (b) CO2 production. There is no obvious reason why either of these will
change much when breathing O2 and if they don't, PACO2 will stay unchanged.
However, in some patients with Chronic obstructive airways disease (i.e. COPD) who
hypoventilate the arterial PO2 may be so low that it helps to drive breathing (ie oxygen
level can signal for breathing rate change but normally are at flat part of sigmoidal curve
so a lowered RR will usually give a CO2 inc before a O2 dec so CO2 tends to signal first
before O2 gets a chance – these patients develop a resistance to high blood CO2). If so
then if you improve the PO2 by giving oxygen, this drive to breathe will be removed and
the ventilation may fall to even lower levels - which in turn will result in a further
(potentially dangerous) RISE in PCO2 and FALL in pH.
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14/11/13: Respiratory practicals 1&2:
1. Los (from sheet):
1. Describe spirometry procedures to measure lung volumes and capacities.
2. State approximate values for lung volumes in a young healthy adult.
3. Appreciate how body height, weight, age and gender influence lung volumes, and can be used
to predict these values.
4. List lung volumes/capacities that can be measured by simple spirometry.
5. Be aware of how these volumes may change during exercise.
6. Identify lung volumes/capacities (including: RV, FRC, VC, TLC) that are affected by: (1) severe
chronic restrictive lung disorder (2) severe chronic obstructive pulmonary disorder, and be able
to give reasons for these changes.
Notes:
-
The volumes of air present in the lungs/airways are described in terms of “Volumes” and
“Capacities” (a capacity is made up of 2 or more volumes):
-
The standard lung volumes are:
o Tidal Volume (VT or TV). The volume of air inspired (or expired) in a single
“spontaneous” breath.
o Inspiratory Reserve Volume (IRV). The additional volume (i.e. in reserve) of air
that could be inspired at the end of a VT inspiration.
o Expiratory Reserve Volume (ERV). The additional volume (i.e. in reserve) of air
that could be expired at the end of a VT expiration.
o Vital Capacity (VC). The maximum volume of air that it is possible to exhale from
the lungs following a maximal inspiration. (VC = IRV + VT + ERV).
o Inspiratory Capacity (IC) The volume of air that it is possible to inspire at the end
of a normal quiet expiration. (IC = VT + IRV).
o Residual Volume (RV). The volume of air remaining within the lungs/airways at
the end of a maximal expiration. (Maximum Expiratory Level in diagram)
o Functional Residual Capacity (FRC). The volume of air contained within the
lungs/airways at the end of a quiet VT expiration (Resting Expiratory Level in
diagram). This is the equilibrium volume at which the elastic recoil forces of the
lungs pulling inwards exactly balance the forces pulling the chest wall structures
outwards. (FRC = RV + ERV)
o Total Lung Capacity (TLC). The volume of air contained within the lungs/airways
at the end of a maximal inspiration. (Maximum Inspiratory Level in diagram).
(TLC = RV+ERV+VT+IRV).
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[Note: Normal values for lung volumes depend on gender (lower for female), age
(decrease with age) and body size (lower if small)]
o Equations factoring in these variables can be used to gain predicted volume
values for that person
Normal values in young healthy adults (20-30 years):
o Costanzo figures: IR=3L, TV=0.5ml, ER = 1.2L, RV = 1.2L, VC = 4.7L, TLC = 5.9L, FRC
= 2.4L, IC = 3.5L
o Female:
 Vital capacity: 3.7L
 Residual volume: 1L
o Male:
 Vital capacity: 4.6L
 Residual volume: 1.2L
Measurement of lung volumes with simple spirometry:
o The lung volumes measured are made without having to breathe out as fast as
possible; the respiratory movements can be carried out slowly.
o While seated comfortably and wearing a nose-clip, breathe from the spirometer
for 5 normal breaths, (VT) followed by a maximum inspiration, hold for 1-2
seconds; then a slow maximum expiration, hold for few seconds; then breathe
normally again for 2 normal breaths.
o Results from the machine are: VT (litres), IRV (litres), ERV (litres), VC (litres), IC
(litres) [ie everything but FRV] but the volumes measured from a spirometer
trace are in ATPS (i.e. for the air at atmospheric temperature & pressure &
saturated) and so underestimate the volume actually occupied by that amount
of gas – have to use a constant to change to BTPS (body temperature & pressure
& saturated)
Restrictive lung disorders
o VC: Restrictive lung disorders are characterised by an abnormally low thoracic
“compliance”. In consequence, the ability of the patient to expand the lungs is
“restricted”. An example of such a disorder is interstitial pulmonary fibrosis, in
which (as its name implies) there is a substantial increase in the amount of
collagen contained within the pulmonary interstitium. Ie reduced VC due to
reduced IRV
Obstructive lung disorders
o RESISTANCE: In obstructive lung disorders, some or all of the airways are
“obstructed” i.e. narrowed. The most common lung diseases including asthma
and chronic obstructive pulmonary disease (= chronic obstructive airways
disease + bronchitis + emphysema) have a large obstructive component
(inflammation, airway trapping, hypersecretion of mucus, etc). In considering
this increase in resistance, FEV1 / VC is prob a good measure of this; should be
>80%.
o VC: VC is often reduced in patients suffering from chronic obstructive pulmonary
disorder: this is largely due to loss of elastic fibres for preventing overinflation of
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alveoli and for aiding alveoli contraction in exhale  therefore lungs are more
sensitive to the process of airway trapping (collapse of bronchioles at specific
positions) and less able to evacuate airways so giving reduced VC via reduced
ERV. [also, airway trapping occurs and may contribute to reduced ERV] Ie
reduced VC due to reduced ERV
2. Los (from sheet):
1. Briefly describe two indirect methods to evaluate airways resistance.
2. Define FVC, FEV1, and PEFR
3. Explain why FEV1 is reduced in obstructive and in restrictive lung disease.
4. Explain the significance of the ratio FEV1/FVC and state its normal value.
5. Explain why the Wright Peak Flow meter is particularly useful for patients with asthma or
COPD.
6. State that values for FVC, FEV1, and PEFR are generally lower in females, increase with
subject’s height and decrease with age peaking at 20 years.
Notes:
-
-
-
-
Many (obstructive) respiratory disorders result in a reduction of the diameter of the
airway lumen and hence an increase in the resistance to flow making breathing more
difficult.
Indicators of airways resistance can provide useful information on the severity and
progression of respiratory disease and on the efficacy of any treatment.
Airways resistance is the pressure difference between alveoli and mouth divided by the
rate of air flow. (ie from the “Flow = ΔP / R” equation)
Measurement of this pressure difference is technically tricky and this is not routinely
done for testing a patient’s respiratory function. However, if the airways are narrowed
by disease, then flow rates during forced expiration will be lower than expected. Ie ΔP
exerted prob constant but with obstructive disease will achieve lower flow (FEV1 / VC is
prob a good measure of this; should be >80%)
The values obtained will depend upon the age, size and gender of the subject, but if
expressed as a % of the predicted value for that individual they provide a simpler,
indirect indication of airways resistance.
The following forced expiratory measurements can be made:
o Forced expiratory volume in 1 second (FEV1): This is the total amount of air in
litres that you can forcibly blow out in one second after full inspiration.
 Measured by a vitalograph
o Forced vital capacity (FVC): This is the total amount of air in litres that you can
forcibly blow out after full inspiration.
 Measured by a vitalograph
 [Vital capacity can be measured as forced vital capacity (FVC), slow vital
capacity (SVC; prob the same as above but slow), and inspiratory vital
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capacity (IVC; prob means working from full expiration to full inspiration
as the measure). Note it is well known that the latter two are generally
greater]
o Peak expiratory flow rate (PEFR): This is the highest speed at which the air
moves out of your lungs at the beginning of the forced expiration, measured in
litres per second.
 Measured by a Wright peak flow meter
Using a vitalograph:
o Adopt an upright position – standing erect.
o Ensure vitalograph is primed and reset to the starting position
o First inspire maximally, and then seal your lips around mouthpiece
o Blow as hard and fast and as far as possible into vitalograph
o Try not to come off to breathe in again until vitalograph reaches the end
o FEV1 and FVC are read off the trace (trace already calibrated to give readings in
BTPS)
Using a Wright peak flow meter:
o Adopt an upright position – standing erect.
o Ensure meter is zeroed
o Seal your lips around mouthpiece with neck slightly extended
o Blow as hard and fast as possible applying maximal effort.
o PEFR is determined
What can FVC, FEV1 and FEV1/FVC tell us about lung pathology?
o 1) An individual with an obstructive respiratory disorder (such as asthma or
COPD) will have impaired ability to exhale quickly because of obstruction to air
flow. A reduced airway caliber can occur due to:
 bronchial oedema
 excess mucus secretion
 smooth muscle hypertrophy
 bronchospasm (constriction of the muscles in the walls of the
bronchioles: think asthma)
 inflammation (think bronchitis)
 floppy airways (think emphysema)
 airflow trapping (think emphysema)
o A low FEV1 (due to the above obstructions) and a low FVC (due to some
complete airway trapping) is the norm in these obstructive pathologies. The
severity of obstruction is determined by the FEV1/FVC ratio:
 An FEV1/FVC ratio < 75% = indicates mild air flow limitation
 An FEV1/FVC ratio < 60% = indicates moderate air flow limitation
 An FEV1/FVC ratio < 40% = indicates severe air flow limitation
o
2) An individual with a restrictive respiratory disorder (pulmonary fibrosis or a
neuromuscular condition preventing “normal” lung inflation) will normally have
low FVC (due to low ERV). Unless there is a second pathology limiting airflow,
FEV1 will be proportionately normal (ie both FEV1 & FVC reduced): “FEV1 is
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o
o
reduced in both obstructive and restrictive lung disease”]. So in restrictive
disease, although the FVC is low,
 The FEV1/FVC ratio will be ≥ 75%
In certain restrictive respiratory disorders, the FEV1, and FEV1/FVC ratio may be
higher than normal. The reason for this relates to how the expiratory flow is
generated. In normal compliant lungs, expiration depends on elastic recoil of
the alveoli producing a measured expiratory flow. In restrictive disorders due to
pulmonary fibrosis, collagen fibres replace elastic fibres, the alveoli and
bronchioles become stiffer than normal, and normal elastic recoil is lost. Loss of
elastic recoil tends to produce alveoli that aggressively recoil on expiration
producing a high FEV1. Thus expiration may occur even faster than normal.
 In any condition in which FEV1 is preserved or enhanced and where FVC
is simultaneously lower than normal, the resultant FEV1/FVC will always
be higher than normal i.e. > 75%.
Overall, you can think of restrictive conditions as being disorders in which lung
expansion is impaired, but the ability of the lung to empty is preserved (or
enhanced).
-
Vitalograph traces: Left one is for restrictive lung disease and right graph is for
obstructive lung disease:
-
How is measurement of PEFR used clinically?
o A measure of the highest flow rate achieved during a forced expiration after a
full inspiration indicates the ease with which expiration occurs. The chief
limitation of this test is that it only reflects resistance to airflow in larger, more
central airways. Clinically, the peak expiratory flow meter has 2 main uses; to
help confirm or refute a possible diagnosis, and to provide a convenient way to
monitor a patient’s progress, deterioration or response to therapy.
-
Peak expiratory flow rate (PEFR) data:
o An adult male (20-50 years) without lung pathology should score between 540
and 670 l.min-1. (see graph)
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o
o
o
o
o
-
An adult female (20-50 years) without lung pathology should score between 400
and 470 l.min-1. (see graph)
Since the test is effort dependent, results will vary, depending on the effort one
puts in.
To make an individual score meaningful it is common practice to refer to
normative data categorised according to gender age and build etc.
An adult with obstructive disease will score significantly lower than an individual
with healthy lungs.
With patients it is important to note intra-subject variability (should always
repeat)
How might you classify the following conditions? Restrictive or obstructive? Remember
to ask yourself if the condition; a) limits the ability of the lung to fill, b) limits the ability
of the lung to empty:
-
-
Asthma: obstructive
COPD [Chronic obstructive pulmonary disease (COPD) is the name for a collection of
lung diseases including chronic bronchitis, emphysema and chronic obstructive
airways disease]: obstructive
Bronchiectasis: obstructive [Involved bronchi are dilated, inflamed, and easily
collapsible, resulting in airway obstruction and impaired clearance of secretions]
cystic fibrosis: obstructive [It is characterized by abnormal transport
of chloride and sodium across an epithelium, leading to thick, viscous secretions]
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pulmonary fibrosis: Restrictive
non-productive pneumonia: restrictive (ie if was producing fluid further up the
airways then could have an obstructive component too)
Pneumothorax: restrictive
Kyphoscoliosis: restrictive (curvature of the spine)
Neurological and neuromuscular disorders resulting in difficulties activating
respiratory muscles [like Guillain–Barre, motor neurone disease, multiple sclerosis,
polio, or myasthenia gravis]: restrictive
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19/11/13: Regulation of Breathing (Awake & Asleep)
Los (from slides):
•
•
•
•
•
•
•
•
•
•
•
•
•
[says we must understand blood gases (and know their normal values) and be able to
interpret lung function (ie as well as the below)]
Distinguish the primary purpose of the automatic reflex and the behavioural controller
Define neuronal groups in the brainstem that make up the automatic reflex controller
for breathing, and structures in higher brain areas (suprapontine) that drive behavioural
(non-automatic) control of breathing.
Explain how they can act independently or interact for control of the respiratory pump.
Recall the sources of sensory input to the respiratory control system and the common
motor outputs (also see Lecture 11)
Explain the ventilatory response to increased arterial PCO2, decreased arterial PO2
Recognise breathlessness (“dyspnoea”) and start to consider its role in breathing control
(lectures 12,13&15).
Recognise the effects on respiratory control of the neurological conditions; ‘locked in’
syndrome and ‘congenital central hypoventilation syndrome’
Explain the effect sleep on breathing and blood gases in healthy people
Summarise the changes in chemosensitvity that occur during sleep and define the
apnoeic threshold
Explain how the changes in chemosensitivity and the apnoeic threshold led to central
sleep apnoea
Explain the influences of sleep on the upper airway which lead to obstructive sleep
apnoea
Recall one major cardiac, one major respiratory disease that is exacerbated by the sleeprelated changes in the control of breathing
Notes:
-
Key aspects of breathing control:
o To regulate gas exchange
 1. for homeostasis: Acid base balance
 2. for metabolism:
 At rest O2 consumption ~ 250 ml.min-1;
 At rest alveolar ventilation ~ 5 l.min-1.
 Exercising O2 consumption can increase by 20 fold; alveolar
ventilation must increase to match this demand.
o To execute behavioural acts
 communication
 speech, singing, playing wind instruments
 emotion
 laughter, crying, anxiety
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
o
-
non respiratory functions
 swallowing
 defecation, micturation, parturition (giving birth), vomiting
To maintain airways and lung function
 Coughing, sneezing, yawning, sighing
 Control the pharynx and larynx to maintain upper airways patency (note
that there is no cartilage in the uppermost area of the airways)
[Pharyngeal muscle activity decrease during sleep contributes to
obstructive sleep apnoea]
 Control the pump muscles for inspiration and for expiration
Inputs to respiratory muscle control:
o Voluntary/behavioural
 Ie are able to voluntarily change our blood gases up to a point
 Motor cortex (from the part of the cortex between the “shoulder” and
“trunk” regions (ie makes sense for it to be there)
 Outflow of signals is via the corticospinal pathway to the cervical chord
before distribution to the diaphragm
o Emotional
 Limbic system
 Poorly understood but is known to exist due to studies on patients with
locked in syndrome showing changes to breathing rhythm in response to
emotion (locked in patients have a lesion above the bulbospinal tract
and so while autonomic breathing is unaffected and all sensory inputs
are present there is no voluntary muscle control (except for eyes))
o Reflex/autonomic
 Brainstem (mainly the medulla but the pons has some role too)
 Pacemaker for respiratory rhythm generation is thought to be present in
the Pre-Bötzinger Complex (preBötC) of the medulla
[the pacemaker is understood to be the result of interconnections of the
different respiratory neurones (early inspiratory neurones + late
inspiratory neurones + expiratory neurones) which interact by
reciprocally inhibiting each other (to result in the observed rhythm)]
 Outflow of signals:
 Outflow of signals to the pump muscles (Diaphragm, Intercostal
Muscles, Abdominal muscles) is via the bulbospinal pathway /
tract to the cervical chord before distribution to the “pump
muscles”:
o Diaphragm
 phrenic nerve; cervical plexus (C3 - C5)
o Intercostal Muscles
 T1 - T12
o Abdominal muscles
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
 T12, L1
 Outflow of signals to the upper airway muscles is predominantly
via cranial nerves
o glossopharyngeal (IX)
o vagus (X)
o spinal accessory (XI)
o hypoglossal (XII)
Autonomic regulation of breathing takes its input from changes to
ppCO2, pH and ppO2 (though will also take inputs from respiratory
muscles and lung inflation so is “aware” of what results it is producing –
see below diagram)
 Sensory inputs for exercise: cortical, ergoreceptors,
cardiodynamic (as well as all of the below)
 Sensory inputs: [nb J-receptors, irritant, stretch, muscles/joints]
o Nose
 Trigeminal (V)
o Pharynx
 Glossopharyngeal (IX) Vagus (X)
o Larynx
 Vagus (X)
o Lungs
 Vagus (X)
o Chest wall
 spinal nerves

[Chemoreceptor – type sensory inputs]:
o Peripheral chemoreceptors
 carotid bodies, aortic arch
 hypoxia (ie mainly involved in O2 sensing), (also
some pH, PCO2 sensing but this is mainly done
by the central chemoreceptors)
o Central chemoreceptors [presumably these are the
ones important in regulating ventilation as they are key
in CO2 detection]

located on the surface of the medulla and

detect changes in CSF
PCO2 , pH (ie NO O2 SENSING)
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[note: only autonomic and voluntary pathways are annotated as little known about mechanism
of emotion input]
-
Disorders of breathing during Sleep:
o Central sleep apnoea:
 Gives Cheyne–Stokes respiration / Cheyne–Stokes breathing. This is a
type of breathing in which ribcage/thoracic effort and abdominal effort
(as plotted as displacement of that structure anterior / posterior) shows
a period of baseline / zero effort followed by crescendodecrescendo
effort before the cycle repeats
 In effect is repeated over and under breathing in an attempt to
find an optimum and is associated with falling asleep with an
abnormally low blood CO2 concentration
 Can occur if woken up and then fall back to sleep (while asleep a
high blood CO2 conc is tolerated but upon waking this needs to
be lowered and high respiratory rate is stimulated; this can
overcompensate to give abnormally low blood CO2
concentration and therefore if then fall asleep will give a
starting point for the repeated over and under breathing in an
attempt to find an optimum
 Is also associated with heart failure patients because they will
likely suffer from pulmonary congestion so tend to overbreathe
in response (ie in fact therefore tend to have lower than usual
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o
blood CO2 concentration) so if fall asleep the conditions for
encouraging Cheyne–Stokes breathing are met
 A final group at risk are babies with Ondine's curse = CCHS
(congenital central hypoventilation syndrome): a congenital or
trauma induced brain problem
 Treatment is artificial ventilation during night
Obstructive sleep Apnoea
 Involves collapse of the pharyngeal region of the airway; no cartilage at
this region so in obese patients with big necks collapse can occur during
inspiration when the negative pressure adds to the weight of the fat to
overcome the patency. [normally maintained by neural tone of this part
of the airway but Pharyngeal muscle activity decreases during sleep]
 Obstruction causes paradoxical breathing (as mimicked by closing
mouth and pinching nose) which is where inspiration gives posterior
movement of abdomen and anterior movement of thorax and visa versa
for expiration (occurs to far less a degree when airways patent)
 Gives cycles (see below) like central sleep apnoea but this is just because
patient keeps waking up and immediately falling back to sleep (prob
won’t realise they have woken up)
 Treated with a mask to blow air in during inspiration
 [see below as the restriction at back of tongue which will seal during
sleep inspiration]:
***Importantly central sleep apnoea is no airflow and no effort whereas obstructive sleep
apnoea has no airflow but effort occurs
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-
Ventilatory sensitivity slopes:
o Refers to the first of the two graphs below; is investigating sensitivity of
ventilation rate to an increasing concentration of inhaled CO2 (subject
effectively breathes into bag so CO2 conc increases)
o Varies between subjects, some people naturally more sensitive than others; for
all subjects though the sensitivity drops during sleep (ie reduced gradient) as
tolerance to elevated CO2 levels increases (a higher benchmark for CO2 conc
becomes established)
o The second graph is just to show that ventilation remains constant for a wide
range of PAO2 values (horiz flat line region) and so is not having an input into
ventilation redulation (except possibly at very very extreme O2 levels)
-
During sleep only autonomic control of breathing is occurring (not voluntary /
emotional)
During waking state an EEG shows low amplitude, high frequency signals, During sleep
EEG shows High amplitude, Low frequency signals – except for REM sleep which shows
trace similar/same to waking state (breathing is still different though because during
sleep only autonomic control of breathing is occurring)
Sleep cycle is ~90mins with 1x REM per cycle and length of REM in cycle lengthens with
each cycle
Antidepressants supress REM
During sleep the respiratory volume falls (but the frequency actually doesn’t change) so
the minute ventilation and alveolar ventilation fall by ~10%:
o CO2 levels in blood will therefore rise but due to increased tolerance of blood
CO2 (less sensitive chemoreceptors) a new baseline will be reached (consistent
with the respiratory volume fall).
o In turn the pa(O2) of blood will fall but this is not a problem in most people
because we are at the flat part of the oxygen dissociation curve therefore the O2
saturation of tissues will not be affected (see graph below)
o However if the patient has lung disease (eg COPD) then due to their exchange
problems they will already be near the edge of the flat part and so there will be
a fall into the more vertical region of the plot and problems relating to
-
-
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saturation will arise (tissues not getting enough blood) [nb their CO2 sensitivity
will also likely be lower already (due to disease induced bradypnoea, loss of
alveoli, and obstruction including hypoxic vasoconstriction) and breathing may
be partially O2 driven so inc inc in CO2 and fall of HB sats may not be as big as
otherwise]
Excel monster notes extras:
-
Resting position of chest wall 70-80% of TLC
Resting position of lung ~0% TLC
capnic (CO2 driven)
Normal resting figures [APPROXIMATION – is variable]: O2 consumption = 200-300
ml/min, CO2 production = 200-250 ml/min
Amount of oxygen bound to haemoglobin is 20mls/100mls of blood so 1g haemoglobin
binds up to 1.34mls of O2 for Hb normal at 15g/dl (ie 100ml = 1dl)
Also: the oxygen content of arterial blood in a healthy person with a Hb concentration of
15 g/dl is around 9mmol/L
During inspiration the chest wall is expanded and the intrapleural pressure falls. This
increases the pressure gradient between the intrapleural space and the alveolar
pressure, stretching the lungs. The alveoli expand and and alveolar pressure falls
creating a pressure gradient between the mouth and alveoli causing air to flow into the
lung. The airflow profile closely follows that of alveolar pressure. During expiration both
intrapleural pressure and alveolar pressure rise. In quite breathing, intrapleural
pressure remains negative for the whole of the respiratory cycle, whereas alveolar
pressure is negative during inspiration and positive during expiration. Alveolar pressure
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is always higher than intrapleural pressure, because of recoil of lung it is zero at the end
of both inspiration and expiration and airflow ceases momentarily. When ventilation is
increase the changes of intrapleural and alveolar pressure are greater than and in
expiration intrapleural pressure may rise above atmospheric. In forced expiration,
coughing or sneezing, intrapleural pressure may rise to +8kPa or more.
Oxygen dissociation haemoglobin curve
o to the left:
 increase pH, decrease oCO2, decrease temperature
 decrease 2,3,DPG [2,3-diphosphoglycerate; metabolic product present
in respiring tissues]
o To the right:
 decrease pH increase co2 increase temperature
 increase 2,3 DPG
Half of airway resistance lies in the nose, pharynx and larynx (prob is referring to start of
exhale)
Anatomical dead space 30% of tidal volume
During REM patients with COPD cannot use accessory muscles for breathing (if are
essential then will start to suffocate and will wake up)
Efficiency of gas exchange = Pulmonary venous PO2/ alveolar P02 [usually is very high]
Vascular resistance = (arterial pressure - venous pressure) / cardiac output
The alveolar partial pressure of oxygen PAO2 can be calculated from the following
equation: PAO2 = PIO2 – (PaCO2/R)
o R is the respiratory quotient, which represents the amount of carbon dioxide
excreted for the amount of oxygen utilized, and this in turn depends on the
carbon content of food (carbohydrates high, fat low)
o PIO2: the partial pressure of inspired oxygen
1 kPa = 7.5 mmHg (for converting purposes)
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[Exact normal figures depend on age, height, weight and gender but these figures (from the
notebank) match closely with the excel notes so are good general estimates (prob are really for
male; bit lower for female) and worth learning]
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21/11/13: Sensory Aspects of Respiratory Disease:
Los (from slides): Prof. Fan Chung
•
•
•
•
General
• Understand how respiratory symptoms are generated and perceived
• Discuss the importance of measuring respiratory symptoms in clinical medicine and clinical
research
• Outline the clinical causes and pathophysiological basis of the respiratory symptoms cough,
chest pain (and dyspnoea, covered elsewhere):
Cough
• Describe the mechanics of a cough with reference to inspiration, expiration and closure of the
glottis. Briefly explain how this manouevre serves to i) protect the lungs from inhaled noxious
materials and ii) clear excessive secretions from the lower respiratory tract
• Identify the type and location of sensory receptor within the airways indicating how these are
stimulated to give rise to cough. Identify the neural pathways which transmit this afferent
(sensory) information to the brain
• Describe which regions of the brain are involving in generating the co-ordinated neural activity
that results in a cough. Identify the efferent (motor) neural pathways and the main muscle
groups which produce cough.
• Explain the concept of the sensitised cough reflex in disease as a basis for chronic cough.
• Discuss ways of controlling unnecessary cough
Chest pain
• Identify the type and location of sensory receptors within the thoracic cavity that when
stimulated give rise to chest pain. Identify the neural pathways that transmit this afferent neural
information to the brain.
• Describe in outline which regions of the brain are involved in the perception of pain
• Discuss the concept of referred pain in the chest
• Describe typical patterns of chest pain that can help in diagnosing the cause of pain
Dyspnoea
• Review the terms used by patients to describe the troublesome symptom of shortness of
breath and its measurement
• Discuss the main important causes of shortness of breath and approach to management
Notes:
-
Recommended textbook: Murray & Nadel’s Textbook of Respiratory Medicine 5th
Edition 2010 Volume 1
o Chapter 28. Dyspnea
o Chapter 29. Cough
o Chapter 30. Chest pain
-
Prevalence/importance of respiratory symptoms
o Cough
 Third most common complaint heard by GP
o Chest pain
 Most common pain for which patient seeks medical attention
o Shortness of breath (SOB, dyspnea)
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 3% of visits to A&E
Pathway of physiologic or pathological stimulus leading to conscious sensation:
1. Sensory stimulus
2. Transduction of the signal to the nerve by receptors
3. Excitation of Sensory nerve
4. Integration of signals at CNS
5. Sensory impression
6. Perception
7. Evoked sensation
Cough:
o A crucial defence mechanism protecting the lower respiratory tract from:
 inhaled foreign material
 excessive mucous secretion
o Usually secondary to mucociliary clearance (cilia move debris to the larger
airways and then either completes removal to esophagus or cough occurs)
 but important in lung disease when mucociliary function is impaired and
mucous production is increased (ie here cough becomes more
important)
o Expulsive phase of cough
 generates a high velocity of airflow
 facilitated by bronchoconstriction and mucous secretion.
o Localisation of cough receptors
 Rapidly adapting irritant receptors which are located within airway
epithelium.
 Most numerous on posterior wall of trachea,
 Also: at main carina, and branching points of large airways, less
numerous in more distal airways.
 Absent beyond the respiratory bronchioles [ie beyond the first main
bronchi]
 Also in the pharynx.
 Possibly also in the external auditory meatus, eardrums, paranasal
sinuses, pharynx, diaphragm, pleura, pericardium, and stomach.
 Stimuli: laryngeal and tracheobronchial receptors respond to chemical
and mechanical stimuli.
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o
Sensory receptors in the lung and airways
 Slowly adapting stretch receptors [Fibers that respond to movement
and also static indentation are termed slowly adapting
mechanoreceptors; respond to stretch but also produce sustained
responses to static stimulation]
 Rapidly adapting stretch receptors [Fibers that respond only to
movement are termed rapidly adapting mechanoreceptors. Underlies
the perception of flutter and slip. Produce transient responses to the
onset and offset of stimulation]
 Come under the category of “A fibres”
 Location: Naso-pharynx, larynx, trachea, bronchi
 Small, myelinated nerve fibres
 Because of their higher conduction velocity (compared to C
fibres), Aδ fibers are responsible for the sensation of a quick
shallow pain that is specific on one area, termed as first pain.
They respond to a weaker intensity of stimulus
 Stimuli: Mechanical, chemical irritant stimuli, inflammatory
mediators
 C – fibre receptors
 Location: Larynx, trachea, bronchi, lungs
 Small, unmyelinated fibres [C fibers are unmyelinated unlike
most other fibers in the nervous system]
 C fibers respond to stimuli which have stronger intensities and
are the ones to account for the slow, but deeper and spread
out over an unspecific area, second pain
 “free” nerve endings: [C fibers and the majority of Aδ fibers end
as free nerve endings - an unspecialized, afferent nerve ending,
meaning it brings information from the body's periphery toward
the brain]
 Stimuli: Chemical irritant stimuli, inflammatory mediators
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
o
Release neuropeptide inflammatory mediators Substance P,
Neurokinin A, Calcitonin Gene Related peptide
 In addition other cough receptors are thought to be present as
determined from staining studies, etc and are not covered in the above
categories
Afferent neural pathways for cough;
 Stimulation may be mechanical
 (e.g. dust, mucous, food/drink)
 Stimulation may be chemical
 (e.g. noxious, intrinsic inflammatory agents)
 From the positions of the sensory receptors the signals are transmitted
via the vagus (or by the superior laryngeal nerve (a branch of the vagus)
in the case of receptors in the pharynx which then join the vagus)

Vagus takes signals to the
“cough center” at the
medulla; some signalling is also passed on to the cerebral cortex (ie
o
some voluntary control of coughing can occur eg in suppression of
coughing)
Efferent neural pathways for cough
 Signal flow out from the “cough center” at the medulla; and some
signalling occurs from the cerebral cortex (ie some voluntary control of
coughing can occur eg in suppression of coughing)
 Signals flow to a complete range of the muscles involved in breathing;
both inspiratory and expiratory because cough involves first a intake of
breath before it is then expelled
 The Glottis is also the recipient of signals and during the cough will
remain closed allowing the subglottic pressure to rise before then
allowing the forceful release of air; this should clear the airways and is
responsible for the first, loud, cough sound
 Following this there is a second, quieter, cough sound generated due to
the vibration of the glottis fold as the pressures are re-established
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Sensitising of the afferent pathways is possible and is thought to be underlying many
diseases: they often involve cough reflexes to stimuli that would not cause stimulation
in a healthy subject [Cough is typically difficult to control (ie is not throat clearing)]
o Excitability of afferent nerves is increased by chemical mediators eg
prostaglandin E2
o Increase in receptor numbers seen
o Neurotransmitter increase eg neurokinins in brain stem
Causes of cough:
o Acute infections
o Chronic infections
o Airway diseases
 Asthma
 Chronic bronchitis
o Parenchymal disease
 Interstitial fibrosis
 Emphysema
o Tumours
o Foreign body
o Cardiovascular
 Left ventricular failure
 Pulmonary infarction
 Aortic aneurysm
o Reflux oesophagitis
o Drugs
 Angiotensin converting enzyme
o Acute cough is <3 wks
o Chronic cough is >3 wks
 Asthma and eosinophilic-associated (25%)
 Gastro-oesophageal reflux (25%)
 Rhinosinusitis (postnasal drip) (20%)
 Chronic bronchitis (‘smoker’s cough) (8%)
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o
o
 Bronchiectasis (5%)
 Drugs eg Angiotensin converting enzyme inhibitor (1%)
 Post-viral (3%)
 ‘Idiopathic’ (10%)
 Other causes (3%)
Complications of cough:
 Pneumothorax with subcutaneous emphysema
 Loss of conciousness (cough syncope)
 Cardiac dysrythmias
 Headaches
 Intercostal muscle pain
 Rupture of rectus abdominis juscle
 Social embarrasment
 Depression
 Urinary incontinence
 Wound dehiscence
Cough treatments:
-
Antitussive: Capable of relieving or suppressing coughing.
o Eg opiates
-
Chest pain:
o Sensory input from lungs, airways and chest wall:
 Nose
 Trigeminal (V)
 Pharynx
 Glossopharyngeal (IX) Vagus (X)
 Larynx
 Vagus (X)
 Lungs
 Vagus (X
 Chest wall
 spinal nerves
o Touch sensation vs pain sensation:
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

Different receptors: touch = A, A; pain = A, C-fibres
Differ at level that the fibres change to the contralateral side (pain
crosses at the same level that access to the spine occurs whereas touch
fibres cross higher up in the lower brain region)

Ultimately both travel to the thalamus
and some onto the
cortex
o
o
o
o
o
o
[output will be perception in brain and any relevant outflow signalling to respond]
Different types of pain: somatic vs visceral
 Visceral pain (from visceral organs eg heart, gi tract, bronchial wall) is
not the same as somatic pain (from skin).
 Visceral pain is difficult to localise, diffuse in character and is referred to
somatic structures.
 Number of visceral afferents is less than number of somatic afferents
 Pain arising from various viscera in the thoracic cavity and from the
chest wall is often qualitatively similar and exhibits overlapping patterns
of referral, localisation and quality, leading to difficulties in diagnosis.
Chest pain from respiratory system:
 Pleuropulmonary disorders:
 Pleural inflammation eg infection, pulmonary embolism,
Pneumothorax, malignancy eg mesothelioma
 Tracheobronchitis:
 Infections, inhalation of irritants
 Inflammation or trauma to chest wall:
 Rib fracture, Muscle injury, Malignancy, Herpes zoster
(intercostal Nerve pain)
 Referred pain:
 shoulder-tip pain of diaphragmatic irritation
Chest pain from‘non-respiratory’ disorders:
 Cardiovascular disorders
 Myocardial ischaemia/infarction
 Pericarditis
 Dissecting aneurysm
 Aortic valve disease
 Gastrointestinal disorders
 Oesophageal rupture
 Gastrooesophageal reflux
 Cholecystitis
 Pancreatitis
 ‘Psychiatric disorders’
 panic disorder
 Self-inflicted
PET is an important tool in pain studies; active areas show up on scan
Many different brain areas are activated during pain:
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o
-
 Somatosensory processing:
 Motor processing
 Affective processing:
 Attentional processing:
 Autonomic function;
Treatment of chest pain:
 Treat the cause
 Chronic pain is more difficult to manage
 Analgesia may reduce symptoms
 Pain can be severe & refractory
 Such cases best dealt with at specialist “pain clinics”
Dyspnoea:
o General:
 Troublesome shortness of breath reported by a patient
 Occurs at inappropriately low levels of exertion, and limits exercise
tolerance
 Can be associated with feelings of impending suffocation. Unpleasant
and frightening experience. [same brain areas that are associated with
pain are associated with cough therefore explaining the unpleasantness]
 Poor perception of respiratory symptoms and dyspnea may be lifethreatening
 A scale of severity is used
 Exercise testing can be performed
o disorders presenting with chronic SOB (dyspnea):
 Impaired pulmonary function
 Airflow obstruction eg Asthma, COPD, tracheal stenosis
 Restriction of lung mechanics eg idiopathic pulmonary fibrosis
 Extrathoracic pulmonary restriction eg Kyphoscoliosis, pleural
effusion
 Neuromuscular weakness eg Phrenic nerve paralysis
 Gas exchange abnormalities eg Right to left shunts
 Impaired cardiovascular function
 Myocardial disease leading to heart failure
 Valvular disease
 Pericardial disease
 Pulmonary vascular disease
 Congenital vascular disease
 Altered central ventilatory drive or perception
 Systemic or metabolic disease / Metabolic acidosis
 Anaemia
o Treatment of dyspnoea:
 Treat the cause (eg lung or cardiac)
 Treatment of dyspnea itself is difficult
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




Therapeutic options:
Add bronchodilators eg anticholinergics or b-adrenergic agonists
Drugs affecting brain eg morphine, diazepam
Lung resection (eg lung volume reduction surgery)
Pulmonary rehabilitation (improve general fitness, general health,
psychological well-being)
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22/11/13: Blood Gases: (someone stood in for Dr Shovlin)
Los (from booklet):
• Understand what blood gases are, and how they are measured or calculated [this LO is not
present on the slide LOs]
• Describe the qualitative changes in arterial blood pH, PCO2 bicarbonate and Base Excess in the
following acid-base disturbances:
o Acute respiratory acidosis
o Acute respiratory alkalosis
• For (i) and (ii) above, describe the qualitative changes in arterial blood pH, PCO2 and Base
Excess following renal compensation.
• Describe the qualitative changes in arterial blood pH. PCO2 and Base Excess in the following
acid-base disturbances:
o Metabolic acidosis with respiratory compensation
o Metabolic alkalosis with respiratory compensation
• Comment on the mechanism whereby metabolic changes in acid-base status lead to alteration
in ventilation and hence respiratory compensation.
• Describe the qualitative changes in arterial blood pH. PCO2, Base Excess and PO2 in a patient
with (i) Type I respiratory failure (ii) Type II respiratory failure, in each case after full renal
compensation.
Notes:
-
Arterial blood gases:
o Gives info on:
 Oxygenation level
 Acid / base status
o Obtained by:
 Two fingers on radial artery inch apart
 Ensure pulse on other side of wrist too otherwise hand goes ischaemic
 Warfarinised needle & syringe takes sample
 Pressure then used to stop the bleeding (is pulsatile)
 Sample processed by blood gas analyser
o 3x electrodes:
 “pO2 electrode”: Ag (oxidised) and Pt (reduced) electrodes are involved
 Careful control of pressure essential as this also affects the
current so would give different pO2 reading
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
o
o
“pCO2 electrode”: [really is referring to a pair of electrodes for pCO2
measurement]
 Involves measuring the change in pH to a buffer as the CO2
diffuses into it across a permeable membrane
 “pH electrode”:
 Involves measuring change in voltage/PD across a membrane
(sample one side, buffer the other); will vary depending on the
amount of H+ (ie the pH) of the sample
Normal values: [these stats should override any from elsewhere]
 paO2: >10.7kPa [>80mmHg]
 hypoxic / hypoxia / hypoxaemnia
 paCO2: 4.7 – 6kPa [35-45 mmHg]
 Hypercapnia / hypocapnia
 Hypocapnic / hypercapnic
 pH: 7.37-7.45 [ie little variation in normal subjects]
 acidotic / academia / acidosis
 alkylotic / alkalemia / alkalosis
 [Hb: 13.3 – 17.7 g/dl]
 13.3-17.7 g/dL in adult males and 11.5-16.5 g/dL in adult, nonpregnant females
Respiratory influence of pH:
 Is via a shift in the equilibrium of the below equation:
 Ie respiratory influence is via paCO2 changes; nb deviations
from normal of paCO2 are only from ventilation and respiration
influences (though kidney can contribute to resetting CO2 level
– see below)
 In fact there is an intermediate compound that exists: carbonic
acid (H2CO3); the full reaction is shown on a diagram lower
down


Additionally the CO2 can give a decrease in pH by reacting with Hb
(haemoglobin) [ie instead of H2O] to form H+:
 Involves forming a carbamino-CO2 group on the Hb
 The reverse reaction occurs at the lungs to release the CO2
 However, Hb also acts as a buffer by accepting H+ thereby dampening
any drop in pH from any cause
 Ie Hb- +H+  HHb
 Diagram summarising the reactions:
Circulating hydrogen ions and bicarbonate are shifted through the carbonic
acid (H2CO3) intermediate to make more CO2 via the enzyme carbonic
anhydrase according to the following reaction:

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o
Metabolic influence of pH:
 Kidney can help regulate pH by regulated excretion of bicarbonate; ie
bicarbonate levels will affect the equilibrium of the below reaction:

o
Kidney regenerates its supply of bicarbonate ions in conjunction
with the excretion of H+ ions
 Metabolic acids can be generated:
 Eg lactic acid from anaerobic respiration
 Eg Ketoacids (ketoacidosis) [ketones are formed by the
breakdown of fatty acids and the deamination of amino acids;
ketoacidosis occurs when the liver breaks down fat and proteins
in response to a perceived need for respiratory substrate]
o Diabetic ketoacidosis: Insulin stops the use of fat as an
energy source by inhibiting the release of glucagon so
ketoacids are high in cases of insulin deficiency; also if
insulin is low then uptake of glucose to tissues is poor so
fats used as fuel instead
 Eg Sulphuric acid (from the metabolism of proteins; ie Cys has
sulphur atoms)
Compensation:
 May be “partial” or “complete” compensation
 Compensation is always by the opposing system (resp/metabolic) to the
one giving the initial deviation
 Respiratory compensation is quick whereas renal compensation takes
longer (therefore can distinguish acute and chronic respiratory
acid/alkylosis)
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o
Bicarbonate reading;
 Is derived from the 3x electrode readings using the Henderson
Hasselbach equation:
 0.23 is the solubility coefficient of CO2 (when the pCO2 is in kPa)
[ie the coefficient / constant for pCO2 conversion to H2CO3]
 pKa of HCO3- is 6.1
 Normal range is 22-26 mEq
o
-
Base excess:
 Gives an indication as to the proportional contribution of metabolic factors
to the overall acid/base disturbance
 Theoretical HCO3- level based on paCO2 is calculated (assuming no renal
or metabolic disturbance);
 Then the difference between this value and the actual HCO3- value is
determined
 a positive value means a base (ie HCO3-) excess (see below for causes)
 Base excess normal range = -2  +2 mmol/L
Base excess beyond the reference range indicates
o metabolic alkalosis if too high (more than +2 mEq/L)
o metabolic acidosis if too low (less than −2 mEq/L)
 NOT ALWAYS: IS TRUE THAT MEANS THAT THE HCO3
FORMED FROM THE LEVEL OF CO2 IS BEING GREATLY LOST
BUT THIS MAY BE PHYSIOLOGICAL EG INSTEAD COULD JUST
BE RENAL COMPENSATION FOR A RESP ALKYLOSIS AS
BELOW:
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A high base excess, thus metabolic alkalosis, usually involves an excess of bicarbonate. It can
be caused by
o Compensation for primary respiratory acidosis
o Excessive loss of HCl in gastric juice by vomiting [so more H+ secretion to stomach
which is coupled to HCO3- excretion to blood]
o Renal overproduction of bicarbonate, in either contraction alkalosis or
Cushing's/Conn’s disease
A base deficit (a below-normal base excess), thus metabolic acidosis, usually involves either
excretion of bicarbonate or neutralization of bicarbonate by excess organic acids. Common
causes include
o Compensation for primary respiratory alkalosis
o Diabetic ketoacidosis, in which high levels of acidic ketone bodies are produced
o Lactic acidosis, due to anaerobic metabolism during heavy exercise or hypoxia
o Chronic renal failure, preventing excretion of acid and resorption and production of
bicarbonate
o Diarrhea, in which large amounts of bicarbonate are excreted
o Ingestion of poisons such as methanol, ethylene glycol, or excessive aspirin
o
Metabolic alkalosis:
 Subject may be vomiting up stomach contents
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o
 Antacids given for indigestion may cause this state
Hyperventilation: [ ~ acute respiratory alkalosis]:
[get subject to breath into paper bag to break the cycle]
o Acute respiratory acidosis:
 Patients with COPD etc build up resistance to having a high paCO2 so
that it no longer acts as the driver for increased ventilation – instead low
paO2 becomes the driver (= hypoxic drive); Therefore if patient is given
oxygen their RR will fall considerably giving acute respiratory acidosis
 Heroin is another cause of low RR which then would lead to respiratory
acidosis [naloxone is an opioid antagonist drug used to counter heroin
effects]
Examples:
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[ie low RR is due to having COPD etc but being put on oxygen: see explanation above]
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-
Pulse oximetry:
o Measures SaO2 from surface
o Measured by absorption spectra (spec of Hb and deoxyHb differ); reading
comparison with pulse variations in absorbance allow exclusion of absorbances
by other tissues that would otherwise contribute to the reading
o If <95% then need a fitness to fly test (cabin pressure equates to being at 8000ft
so less oxygen (lower partial pressure because lower OVR pressure)
o <90%: home O2 prescribed
o <87%: emergency
-
Types of resp failure: [covered properly later; this is from wiki]
o Type 1:
 Type 1 respiratory failure is defined as hypoxia without hypercapnia,
and indeed the PaCO2 may be normal or low. It is typically caused by a
ventilation/perfusion (V/Q) mismatch; the volume of air flowing in and
out of the lungs is not matched with the flow of blood to the lungs.
 Eg alveoli filling with debris etc but CO2 is relatively easy to remove
from the blood so normal levels (or low levels if patient is reacting to
low O2 with high RR)
 Eg.
 Parenchymal disease (V/Q mismatch)
 Diseases of vasculature and shunts:
o right-to-left shunt [presumably unlikely to be severe enough
to rise CO2 significantly],
o pulmonary embolism
 Interstitial lung diseases: ARDS, [pneumonia].
o Type 2:
 Hypoxia with Hypercapnia
 Type 2 respiratory failure is caused by inadequate ventilation; both
oxygen and carbon dioxide are affected. Defined as the build-up of
carbon dioxide levels (PaCO2) that has been generated by the body.
 The underlying causes include:
 Increased airways resistance (chronic obstructive pulmonary
disease, asthma, suffocation)
 Reduced breathing effort (drug effects, brain stem lesion,
extreme obesity)
 A decrease in the area of the lung available for gas exchange
(such as in chronic bronchitis).
 Neuromuscular problems (GB syndrome.,[1] myasthenia gravis,
motor neurone disease)
 Deformed (kyphoscoliosis), rigid (ankylosing spondylitis), or flail
chest
MISC UNRELATED UNEXAMINABLE: [NAVY mnemonic]:
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Misc from internet:
•
TLCO = transfer factor for the lung for carbon monoxide i.e. Total diffusing capacity for
the lung
–
Same as DLCO
•
KCO = transfer coefficent i.e. Diffusing capacity of the lung per unit volume,
standardised for alveolar volume (VA)
•
VA = Lung volume in which carbon monoxide diffuses into during a single breath-hold
technique
•
Low TLC: Low TLCO and low/normal KCO = intrapulmonary restrictive defect
•
–
Interstitial lung diseases e.g. Idiopathic pulmonary fibrosis, sarcoidosis, CTD,
HP
–
Cardiac e.g. Pulmonary oedema
–
Pulmonary vascular disease e.g. Pulmonary hypertension (may have normal
TLCO)
High TLC: Low TLCO + KCO
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–
emphysema (in the context of obstruction)
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26/11/13: Respiratory physiology and diving: Dr
Peter Wilmshurst
Los from booklet:
-respiratory physiological principles are reinforced and modified by
hyperbaric conditions
Notes:
-
Hydrostatic effects of diving: Immersion in warm water:
o Increases venous return and central blood volume by 500ml and reduces lung
volumes (due to the weight of the water compressing tissues and blood)
 Increases Right atrium and Pulmonary artery pressures by 15-20mm Hg
 Increases stroke volume and cardiac output by 20% (because of the frankstarling law)
 The cold (if the water is cold) will supplement these effects via
sympathetic nervous signalling
 Can lead to pulmonary edema (the commonest cause of death in
divers but can be misinterpreted as having drowned at post
mortem)
o Causes natriuresis [process of excretion of sodium in the urine; lowers the
concentration of sodium in the blood and also tends to lower blood volume
because osmotic forces make water follow sodium out of the body's blood
circulation and into the urine] and diuresis [increased urine production]
o [has been used in the past to help ease symptoms of peripheral edema]
o Sudden lifting out water vertically after long period will give pooling of blood in
legs (as body has been trying to vasodilate); this loss of blood from brain can
cause death
-
Effects to lung volume and partial pressure of gases (nitrogen and oxygen) in the lungs:
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o
o
Lung volume is divided by the number of “Bar” exerted:
 Ie VC, FRC, etc reduced
 Will become negatively buoyant as lungs are less full (minor
supplementary contributor: the gases in them are at a raised pressure)
 Compression of gas spaces can cause barotrauma (lung squeeze, middle
ear, sinuses)
 Expansion of gas can cause barotrauma on ascent
Partial pressure of a given gas at a given initial value is multiplied by the number
of bar exerted:
 Means that breathing takes more work as are moving gases of higher
pressures
 [Denser gas increases work of breathing for ambient pressure
divers; nb Boyle’s law: pressure exerted by a given mass of gas is
inversely proportional to its volume]
 This is one reason for mixing the O2 with helium instead of N2
(to maintain lower pressure of the gas)
 The higher partial pressure of N2 in the lungs means that far more N2
becomes dissolved in the blood (ie the P(N2) is the key determinant of
amount that will be transferred to blood)
 N2 is fat soluble and not inert at high partial pressures:
o 30m on air – mild euphoria
o 40-50m on air – impaired responses, mathematical
errors
o 50m on air - max for commercial air dives
o 50-70m on air – confusion, drowsiness
o 70-90m on air – hallucinations, loss of consciousness
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

-
This N2 in the blood can then be liberated from solution at
tissues/blood upon ascent as bubbles [like releasing pressure
when opening a fizzy drink]; gas bubbles are usually tolerated
well by the body and absorbed readily at tissues and at the lungs
but tissues are likely supersaturated with N2 upon diving so
bubbles can persist; the bubbles can give gas embolism [or in
eye can give bubbles between contact lens and cornea giving
temporary cornea damage]
In contrast, the amount of O2 in blood does NOT change significantly
due to depth because its presence in blood is determined by carrier
molecules (Hb) and these are usually already fully saturated; does
however mean that the tanks can be filled with a far lower
concentration of O2 than would be required for breathing at the surface
 NB O2 at partial pressure of >1.6 bar can have toxic effects
[presumably due to some increase in dissolved O2 in blood]:
o air at 70m: can cause convulsions
“Decompression illness”: [ie disease from decompression due to the above phenomena]
o Causes of decompression illness
 Unsafe dive profile – rapid ascent or missed decompression stops
[pneumothorax, etc could result]
 Shunt-mediated with paradoxical gas embolism – venous bubbles pass
to the systemic circulation – slightly delayed onset
 Ie PFO (patent foramen ovale) lets the bubbles into the systemic
arterial circulation (if had just gone to lungs would have just
been absorbed out of the blood there); ~25% of people have
PFO but for arterial bubbles will need a right to left shunt too –
present in ~2.5% of people (then gas embolism); the bubbles are
formed on the venous side as during ascent the arterial blood
has just come from lungs so contains a suitable amount of N2
for that ambient pressure – the venous blood has come from
the tissues and so reflects suitable N2 content for some time
ago (this delay means that upon ascent veins have too much N2
for that depth; therefore decompression stops are essential)
 Lung disease causing pulmonary barotrauma – very rapid onset [eg a
slight pneumothorax / any gas trapping could lead to barotrauma upon
ascent]
o Types of decompression illness
 Neurological – most frequent in amateur divers
 Cardiovascular – uncommon but most frequently fatal
 Joint pains – most common in caisson workers [underwater tunnel
building: have to work in pressure chambers to avoid water inflow to
work area]
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
-
Cutaneous
Breath-hold diving
o Hypercapnia
 Is the normal reason for breaking the breath-hold (CO2 level regulates
breathing)
o Hyperventilation
 Does nothing/little to help O2 saturation (already maximal) but pushes
down CO2 levels so takes longer to get the urge to breathe
 However, upon ascent after hyperventilation when O2 needed most and
is already low in lungs, the P(O2) in lungs will plummet as ambient
pressure drops  blood O2 levels drop further  unconsiousness
o Compression of gas spaces in middle ear giving pain limits record attempts but
214m free-dive is the record
o Negative buoyancy experienced due to loss in lung volume / in in gas pressure
upon descent (so difficult to swim back up)
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27/11/13: Helium Dilution and Other Lung Function
Measurements: Hannah Tighe
Los from booklet:
be measured by simple spirometry
can’t be measure by
simple spirometry
trapping in COPD)
Notes:
-
Volumes and capacities:
-
Lung Function:
o Primary function of Lung is gas exchange
o Interaction of 3 processes:
 Ventilation
 Diffusion
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o
-
 Perfusion
Lung Function Tests used to aid diagnosis; assist with prognosis and monitor
progression of disease and response to interventions
Lung Disease
o Obstructive
o Restrictive
o Mixed
o
Differentiate between these disease types using the following investigations:
-
Spirometry:
o Useful tool for monitoring disease progression in chronic conditions
o VC gives us a useful indication of the ability of the lung to expand
o For judging overall lung volume is not good enough on its own (there may be a
big/small RV?; reading may be inaccurate for many patients due to onset of
coughing towards end of breath (esp for airflow obstruction patients giving
underestimates) [for these reasons must measure TLC and RV (can’t be obtained
by spirometry) for important additional info as to what is occurring in the lungs]
-
Variations in compliance: [nb elastin is involved in expansion and recoil]
o Compliance varies through inhaled volume: decreases towards end of inspiration
so takes more energy per unit volume inhaled as an increasing change in pressure
is required for each additional unit volume
 In a normal lung breathing typically occurs in the lower 70% of the curve (ie
where breathing takes relatively little energy) [Little change in pressure is
needed to expand lung at normal tidal levels]
o
Compliance varies with diseases: High in emphysema [elastic properties of alveoli
are lost and lungs become large and floppy], low in fibrosis [lungs stiffen and are
harder to inflate]:
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-
How do we measure TLC and RV?
o Gas dilution
o Plethysmography
o Gas washout
-
Gas dilution
o Principle:
1. Gas mixture with known concentration of a tracer gas breathed in over time
[eg 3.5L of 10% He]
 NB Patient is connected to the system at FRC, not RV. This is so that
the patient can breathe comfortably at that volume (important for
mixing); ie value found will be FRC which then has ERV subtracted
(from simple spirometry results) to give the RV
2. Helium (He) is used:
 Not found in room air
 Inert
 Will not diffuse out of the lung
3. Mixes with air in lungs [patient breathes freely to allow mixing]
4. Once equilibrated, expired gas concentration measured [Final [He]
measured]
5. Volume of gas in lungs calculated from dilution effect
 Calculated using mass balance [OVR mass of He remains constant;
Mass = Concentration x Volume]
 Eg. Mass of He before mixing: [mass in lung] + [mass in spirometer]:
(0*RV) + (10*3.5) [ie conc * vol = mass (if conc in mass per vol)]
 Mass of He after mixing: [mass in lung] + [mass in spirometer]:
(5*RV) + (5*3.5) or 5*(RV+3.5)
 No He is lost, so RV = 3.5L [nb as above the calculations in reality
will be working out FRC which then has ERV subtracted (from simple
spirometry) to give the RV]
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-
Interpreting lung volumes (TLC and RV)
o Low TLC and RV
 Restriction [ie due to reduces IRV] / small lungs
o Normal TLC and RV
 normal lungs
o Raised TLC and RV
 Can be normal;
 hyperinflation and gas trapping [ie in obstructive disease despite reduced FVC &
ERV, an RV rise matches the ERV fall and the increased use of “top of lungs” can
lead to hyperinflation (ie elevated TLC)
-
Whole Body Plethysmography (Body box)
o Based on Boyle’s Law, uses pressure and volume relationship to calculate TGV (=
FRC)
o Boyle's Law is used to calculate the unknown volume within the lungs. First, the
change in volume of the chest is computed. The initial pressure and volume of the
box are set equal to the known pressure after expansion times the unknown new
volume. Once the new volume is found, the original volume minus the new volume is
the change in volume in the box and also the change in volume in the chest. With this
information, Boyle's Law is used again to determine the original volume of gas in the
chest: the initial volume (unknown) times the initial pressure (as recorded for the
box) is equal to the final volume (calculated as above) times the final pressure (as
recorded for the box).
o Not suitable if the patient v obese, bed bound, claustrophobic
-
Nitrogen Washout
o At FRC (unknown vol), air in lungs is ~80% Nitrogen; If we can measure volume of N2
then can calculate FRC
o A subject takes a breath of 100% oxygen and exhales through a one-way valve
measuring nitrogen content and volume. A plot of the nitrogen concentration (as a
% of total gas) vs. expired volume is obtained by increasing the nitrogen
concentration from zero to the percentage of nitrogen in the alveoli. The nitrogen
concentration is initially zero because the subject is exhaling the dead space oxygen
they just breathed in (does not participate in alveolar exchange), and climbs as
alveolar air mixes with the dead space air.
o Most people with a normal distribution of airways resistances will reduce their
expired end-tidal nitrogen concentrations to less than 2.5% within seven minutes.
Individuals with low lung volume can take longer than seven minutes to remove all
the nitrogen
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-
Lung volumes measurements will differentiate between normal and restrictive lung disease
[ie gives us info on ventilation but not on diffusion and perfusion; see below sections for
this]
o If patient has normal lung volumes but has other resp symptoms eg dyspnoea or
reduced exercise tolerance (SOBOE) then more information is needed
o If patient has reduced lung volumes, then we need to know why
-
Transfer Factor (TL) [sometimes called “diffusion capacity”]
o Aim: To measure rate of oxygen transfer from lungs to capillary blood; TL is the
ability of the lung to transfer gas [considers diffusion and perfusion]
o Depends on amount of functioning capillary bed and its contact with ventilated
alveoli [Fick’s Law of Diffusion: surface area and thickness and pressure gradient]
o Reflects presence of pulmonary vascular and parenchymal disorders
o TL = K x VA
1. Rate of diffusion (with respect to time) per litre alveolar volume (K)
 Ie a measure of each individual section of lung (per unit alveolar
volume) to transfer gas
 To estimate K: use a marker gas that diffuses out of lungs and
behaves ‘like’ oxygen – carbon monoxide (CO)
o Rate of reaction of CO with Hb similar to O2
o O2 and CO bind to same site on Hb molecule
o In normal non-smokers endogenous CO levels are negligible
o Low [CO] are easily analysed using infra-red gas analysis
o Use of CO in trace quantities does not harm subject
2. Alveolar volume (VA)
 Ie the volume available; is just referring to the volume / SA available
– does not necessarily mean that good OVR diffusion is occuring
 To estimate alveolar volume (VA): requires an insoluble tracer gas;
often He or Methane
o Technique to measure TL:
o Patient exhales to RV
o Inhale (to TLC) gas mixture containing 0.3% CO (+ 0.3% CH4)
o Holds breath for up to 10 seconds to allow transfer of gas from Lung to
Capillaries
o Breathes out (not necessarily to RV)
o Difference in conc CO of the before and after breath-hold gives us a
measure of the TL
o Initial portion of exhaled air is ‘washout’ and not use for analysis [was not
used in gas exchange]
o Non-lung-disease factors affecting diffusion:
 Hb concentration
 anaemia/menstruation/polycythaemia [high concentration of red
blood cells in your blood]
 for accurate results should correct for Hb
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
o
-
Exercise
 increased SA for gas exchange (inc ventilation) and in capillary blood
volume (inc CO)
 for accurate results should do at rest
 Smoking
 Raised endogenous CO
 for accurate results should ask patient not to smoke beforehand /
correct for the CO
Interpreting Transfer Factor
 Emphysema and Fibrosis both have reduced TL but for different reasons…..
 Remember: TL = K x VA
 If TL is reduced, you must look at K and VA to determine why: only
Kco reduced for emphysema, both Kco and VA reduced for fibrosis
(see below for detail)
Emphysema patient:
o Spirometry
 FEV1:
 FVC:
 VC:

o
0.83 22% = very very low
2.90 63% (ie fast VC) = very low
4.10 86% (ie slow VC) = low
Can tell at this point that there is likely some form of obstructive,
small airways disease as VC – FVC > 500ml (would be more < 500ml
for normal / restrictive) and low FEV1 (would be normal/high for
normal / restrictive)
o However cannot be certain it’s an obstructive disease at this
stage due to potential for inaccuracies in spirometry due to
patient behaviour – eg may just have tendancy to start
coughing when breathing out fast
PV loop:
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

o
o
Loop (on right) shows that upon rapid exhale the airways shut very
quickly giving deviation from the normal graph shape (become much
flatter compared to norm) shown in grey – this indicates small
airways disease (aka obstructive).
o If did this second now have enough information to
confidently diagnose obstructive airway disease / COPD (of
which emphysema is just one option)
Loop is also of decreased area indicating reduced FVC (could
potentially be indicating Obstructive or restrictive)
Lung Volumes
 TLC:
8.08 118%
 RV:
3.98 199%
 TLC is mildly raised (can occur when are working at top of lungs for
long period such as in an obstructive disease)
 RV is very high reflecting the fact that the patient can’t get the air
out very well due to obstructive disease;
o If did this second, now have enough information to
confidently diagnose obstructive airway disease / COPD (of
which emphysema is just one option)
o SOBOE experienced will be due to:
 Narrowing of the airways
 Having to breath at top of lungs (which requires
greater work as discussed prev)
 RV / TLC > 30/40% is a further indicator of obstructive airways
disease
Diffusion
 TLco: 5.07 48%
 Kco:
0.80 52%
 VA:
6.33 103%
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

-
TLco is low but must look to see what the reason for this is: here is
due to normal VA but low Kco allowing us to make a more specific
diagnosis than just obstructive – is Emphysema because this gives
retained VA (retained volume and surface area of the lungs) but loss
of diffusion capacity due to loss of alveolar-capillary membrane
surface area [ie is a loss of function within the tissue]
VA should be ~90% of TLC but in this case is lower indicating that
there is a lot of lung not being used (ie indicated the same thing as
the direct high RV measurement)
Pulmonary Fibrosis patient: [in this case the fibrosis is secondary to bleomycin
chemotherapy]
o Spirometry
 FEV1 0.97 37%
 FVC
1.11 36%
 VC
1.20 39%
 All are reduced but have reduced in line with each other so
FEV1/FVC will be normal meaning is unlikely to be obstructive but
strong indication that it is a restrictive condition
o PV Loop:

o
o
PV loop is of the correct shape but is smaller than for a normal
patient so is a normal exhale for a lung of that size but the lung is
small (due to the restrictive disease giving a low IRV)
Lung Volumes
 TLC
2.17 46%
 RV
0.84 55%
 Both TLC and RV are reduced indicating a small lung (due to the
restrictive disease giving a low IRV) [note that Rv has fallen to
generate space more space at the bottom of the lungs for breathing
Diffusion
 TLco 1.35 16%
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

Kco
Va

-
Lobectomy patient:
o Spirometry
 FEV1
 FVC
 VC

o
1.46
43%
1.88 48%
1.87 47%
All are reduced but have reduced in line with each other so
FEV1/FVC will be normal meaning is unlikely to be obstructive but
strong indication that it is a restrictive condition; HOWEVER, in this
case isn’t a restrictive disease – due to a lobectomy instead [not a
restrictive lung disease - does not increase the work of breathing]
PV loop:

o
0.64 37%
2.11 50%
TLco is low because BOTH Kco AND VA are low
o VA is low due to the restrictive disease giving a low IRV; VA
is >90% of TLC so we know that the loss of VA is due to loss
of volume at the top of the lung not the bottom
o Kco is low and we are told in this case that the restrictive
lung disease is pulmonary fibrosis so we can deduce that the
reason for the low Kco is thickening of the alveolar
membrane where gas exchange occurs
Lung Volumes
 TLC
 RV
PV loop is of the correct shape but is smaller than for a normal
patient so is a normal exhale for a lung of that size but the lung is
small (due to the restrictive disease giving a low IRV); HOWEVER, in
this case isn’t a restrictive disease – small lung is due to a lobectomy
instead
3.00
0.90
52%
52%
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
o
Diffusion
 TLco
 Kco
 VA


Both TLC and RV are reduced indicating a small lung (due to the
restrictive disease giving a low IRV) [note that Rv has fallen to
generate space more space at the bottom of the lungs for breathing;
HOWEVER, in this case isn’t a restrictive disease – small lung is due
to a lobectomy instead
4.05 41%
1.55 91%
2.62 51%
TLco is low because VA is low:
o VA is low due to the restrictive disease (however in this case
is lobectomy) giving a low IRV; VA is >90% of TLC so we
know that the loss of VA is due to loss of volume at the top
of the lung not the bottom
Ie mimics the results of mechanical restrictive lung disease (see
below)
-
There are two subsets of restrictive lung disease:
 Mechanical:
o Eg muscle disruption, Eg. Kyphoscoliosis
o Kco NOT reduced
 Parenchymal:
o Eg. Pulmonary fibrosis
o Kco reduced
-
Wegener’s Granulomatosis patients (form of vasculitis; inflam of blood vessels; cough up
blood etc): [normally do not analyse patients coughing up blood (haemoptysis) because may
be TB so infection risk]
o Spirometry
 FEV1
1.91 85%
 FVC
2.45 81%
 VC
2.52 81%
 This patient is a smoker so spirometry readings are a little low
o Diffusion
 TLco
8.81 127%
 Kco
2.31 198%
 VA
3.82 71%
 TLco high due to high Kco; because blood has escaped blood vessels
in the lungs it is in better contact with the air so more efficient
transfer [this is despite a drop of Hb through time in the blood as
blood is lost from the body]
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

The blood may be contributing to the slightly lower VA reading than
normal by taking up space
Treatment:
 Treat the inflammation and the lung function / integrity return to
normal in most cases
 If very severe can embolise the bleeding (prob means use a coil)
28/11/13: The Pulmonary circulation: Dr Luke
Howard
Los from booklet:
Lecture 6: Pulmonary Circulation I. (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able to:
• Compare the systemic and pulmonary circulations with respect to
• (i) the structure of the arteries and arterioles
• (ii) the mean arterial blood pressure and
• (iii) the overall resistance to blood flow.
• Explain how differences in the arterial blood pressures of the two circulations influence the
structure of the two ventricles of the heart.
• Describe and explain the relative difference in blood flow to the bases and apices of the lungs
in a standing human.
• Explain, with reference to the pulmonary circulation, the meaning of the terms vascular
recruitment and hypoxic vasoconstriction.
• Explain the importance of hypoxic vasoconstriction in the fetus. Give one advantage and one
disadvantage of this response in an adult suffering from chronic lung disease
• Understand the route of fluid flux from pulmonary capillaries to lymphatics
Los from slides:
•
•
•
•
Compare the systemic and pulmonary circulations with respect to (i) the structure of the
arteries and arterioles (ii) the mean arterial blood pressure and (iii) the overall resistance to
blood flow.
Explain how differences in the arterial blood pressures of the two circulations influence the
structure of the two ventricles of the heart.
Describe and explain the relative difference in blood flow to the bases and apices of the
lungs in a standing human.
Explain, with reference to the pulmonary circulation, the meaning of the terms vascular
recruitment and hypoxic vasoconstriction.
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•
•
•
•
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Explain the importance of hypoxic vasoconstriction in the fetus. Give one advantage and
one disadvantage of this response in an adult suffering from chronic lung disease
Give two reasons why lung disease may lead to pulmonary hypertension. Explain what is
meant by “cor pulmonale”.
Explain what is meant by pulmonary oedema. Identify 3 pathophysiological mechanisms
that may lead to this state.
Explain the term “pulmonary embolism” and state the typical site of origin of such emboli.
Describe the consequences of a large embolus with respect to i) the right side of the heart
and the pulmonary circulation, ii) the viability of the lung tissue and iii) the implications for
gas exchange.
Appreciate, in the context of the pulmonary circulation, the concept of shunting. Identify
the potential deleterious effects of an increased pulmonary shunt.
Notes:
-
General:
o 1% of systemic cardiac output is used to supply the lungs (high)
o Arterial supply is from the bronchial arteries derived from the aorta
o Drainage is via bronchial veins
 Some anastomoses exist between bronchial and pulmonary blood vessels
but mainly on the venous side (not arterial)
-
Functions of the pulmonary circulation:
o 1. Gas exchange
o 2. Filtering of small emboli (blood clots, air, fats) from the circulation
o 3. Metabolism of vasoactive substances
 ACE present to perform AIAII
 Bradykinin inactivation
 100% removal of serotonin from circulation
 30% removal of adrenaline from circulation
 Removal of prostaglandins and leukotrienes
-
Embryology:
o Ductus arteriosus [anatomical shunt]
 In the full term infant, closure of the ductus arteriosus occurs in two phases:
(1) ‘functional’ closure of the lumen within the first hours after birth by
smooth muscle constriction (Patency of the fetal ductus arteriosus is
regulated by both dilating and contracting factors. The ductus normally has
a high level of intrinsic tone during fetal life. The factors that promote
ductus constriction in the fetus have yet to be identified) and (2) anatomic
occlusion over the next several days due to extensive thickening and loss of
smooth muscle cells from the inner muscle media
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
o
o
o
Nb also, the hypoxic pulmonary vasoconstriction occurring in the foetus will
end when the baby takes its first breath – this prob plays a role in triggering
the above responses
Foramen ovale [anatomical shunt]
 Closure will occur when the heart beat replaces placenta supply because
now the left heart pressure is higher than on the right holding the valve shut
Less than 10% of blood from heart will go through the lungs in foetus with rest
passing systemically via the shunts
Per cycle ~60% of blood is channelled through the placenta for oxygenation with
the rest passing systemically back to the heart
-
Shunts in adult:
o Physiologic shunt
 About 2% of the cardiac output normally bypasses the alveoli
 Thesbian veins, bronchial blood
 Could be considered V/Q defects though are normal
o right to left shunts: [anatomical]:
 don’t oxygenate a proportion of the blood so saturation level can drop – not
a problem unless v severe: ie hypoxemia occurs
 O2 provision won’t help but may be useful in indicating severity / diagnosing
 however the main problem is the reduced filtering of the blood: greater risk
of stroke etc
 give V/Q mismatching / defect
o Left-to-right shunts
 do not cause hypoxemia
 do not cause V/Q mismatching/defect
 Among the causes of left-to-right shunts are patent ductus arteriosus and
traumatic injury
-
lung circ characteristics:
o The lungs have to accommodate the same C.O. as the rest of the body put
together due to it being a double circulation
 The difference is a result of a small amount of coronary venous blood that
drains directly into the left ventricle through the thebesian vein
 The reason that pulmonary blood flow can be equal to systemic blood flow
is that pulmonary pressures and resistances are proportionately lower than
systemic pressures and resistances
o High capacity in pulmonary circulation:
 The lungs normally have spare capacity: Eg Exercise or Fever (also known
as pyrexia or febrile response) will give increases to CO that the lungs must
be able to accommodate. Similarly, blocks of lung areas due to filtration
roles will demand other vessels to take up the slack
o Low resistance in pulmonary circulation: has to be relatively passive to be
compatible with supply from systemic:
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
o
Eg Exercise or Fever (also known as pyrexia or febrile response) will give
increases to CO that the lungs must be able to accommodate. Similarly,
blocks of lung areas due to filtration roles will demand other vessels to take
up the slack
 However, active mechanisms do exist to give certain regulation of bloodflow
in the lungs
 passive by gravity and recruitment/distension (cf)
 active by hypoxic pulmonary vasoconstriction (HPV) (cf)
 PVR = pulmonary vascular resistance = (15-5)/5 = 2 mmHgL-1min
 Compared to SVR (= systemic vascular resistance) = 18 mmHgL-1min
 [ie CO=5Lmin-1 as a standard value]
 Pulmonary systolic = RV systolic as are connected during this time
but the diastolics are not equal as the valves will be closed
 mmHgL-1min = wood units
The lungs are a low pressure system:
 Peak ~34cmH2O (25mmHg) of pressure in lungs compared to ~163mmH2O
in systemic (120mmHg)
Pulmonary
Systemic
 Nb diastole longer than systole so mean is not average of values
 Nb
in below diagram the mean systemic should be 93mmHg insteadcirculation
circulation
25 (mean 15)
8
120 (mean 100)
80
artery
artery
RV
25/0
RA
2
vein

LV
120/0
LA
5
vein
Low pressure together with gravity considerations means that the bottom of
the lungs is more perfused than higher up (except for the very bottom which
is squashed between diaphragm and weight of lung)
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o
o
-
pulmonary arteries/ veins have thinner walls and less smooth muscle compared to
systemic
Unlike the systemic capillaries, which are often arranged as a network of tubular
vessels with some interconnections, the pulmonary capillaries mesh together in
the alveolar wall so that blood flows as a thin sheet / mesh
Differences in blood flow:
o The distribution of pulmonary blood flow within the lung is uneven and the
distribution can be explained by the effects of gravity.
o When a person is supine, blood flow is nearly uniform, since the entire lung is at
the same gravitational level.
o However, when a person is upright, gravitational effects are not uniform, and
blood flow is lowest at the apex of the lungClose proximity of alveoli and
capillaries for gas exchange results in exposure of vessels to alveolar pressure (pA)
o Zone 1: pA > pa > pv high in lungs so no blood flow
 This compression will cause the capillaries to close, reducing regional blood
flow. Normally, in zone 1, arterial pressure is just high enough to prevent
this closure, and zone 1 is perfused, albeit at a low flow rate.
 However, if arterial pressure is decreased (e.g., due to hemorrhage) or if
alveolar pressure is increased (e.g., by positive pressure breathing - CPAP),
then PA will be greater than Pa, and the blood vessels will be compressed
and will close. Under these conditions, zone 1 will be ventilated but not
perfused. There can be no gas exchange if there is no perfusion, and zone 1
will become part of the physiologic dead space.
o Zone 2: pa > pA > pv mid way down lungs so moderate & rapidly increasing blood
flow through this region
 Although compression of the capillaries does not present a problem in zone
2, blood flow is driven by the difference between arterial and alveolar
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o
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pressure, not by the difference between arterial and venous pressure (as it
is in systemic vascular beds).
Zone 3:pa > pv > pA low in lungs so high & slowly increasing blood flow through
this region (until very base of lung where relationship lost due to compression)
 Blood flow in zone 3 is driven by the difference between arterial pressure
and venous pressure, as it is in other vascular beds
Accommodation of increased cardiac output:
o Two main methods of maintaining a low PAP (pulmonary arterial pressure) or PVR
(pulmonary vascular resistance) upon increasing CO burden (eg pneumonectomy,
exercise)
Ie CO inc (or same CO to reduced lung region in the case of pneumonectomy)
BP inc  recruitment / distention
 Recruitment of unused capillary vessels (inc in pa gives transition of upper
lung regions from zone 1 to zone 2 as above)
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Distension of capillary vessels already in use (inc in CO gives inc in pa and pv
so blood vessels transition in zone 3 direction)
Ventilation – perfusion matching (and mismatching):
o At rest VA (alveolar ventilation) and Q (Blood flow (~perfusion)) are the same:
5Lmin-1 [actually the ratio is 0.8]
 Written:


The value of 0.8 for V_/Q_ is an average for the entire lung.
 In fact, in the three zones of the lung, V/Q is uneven, just as blood
flow is uneven.
 As already described, regional variations in pulmonary blood flow
are caused by gravitational effects: Zone 1 has the lowest blood
flow, and zone 3 the highest. Alveolar ventilation also varies in the
same direction among the zones of the lung [accordion analogy: the
weight of the accordion (lung) squeezes air out of the bellows at the
base, and most of the FRC fills the bellows at the apex. When the
next breath is taken, most of the potential space to be ventilated is
at the base of the lung, while the apex is already full  Ventilation is
lower in zone 1 and higher in zone 3]
 However, regional variations in ventilation are not as great as
regional variations in blood flow. Therefore, the V/Q ratio is highest
in zone 1 and lowest in zone 3
 In addition to this source of uneven matching there the anatomical
shunts may also be thought of as relevant to V/Q mismatching as
they (thesbian veins, RL shunts and bronchial blood flow) are
examples of perfusion not being given/matched to a ventilation
o [these are VQ shunts but prob not considered in the 0.8
figure as this is for total lung perfusion and total ventilation
figures – this fiqure is for healthy lung anyway so definitely
wouldn’t be considering RL shunts]
Regulation of Pulmonary Blood Flow
 In the lungs hypoxic vasoconstriction occurs as an adaptive
mechanism, reducing pulmonary blood flow to poorly ventilated
areas where the blood flow would be “wasted.”
o Useful in localised diseases; The compensatory mechanism
fails, however, if the lung disease is widespread
o Altitude/breathing low O2 mixture: The low PAO2 produces
global vasoconstriction of pulmonary arterioles and an
increase in pulmonary vascular resistance. In response to
the increase in resistance, pulmonary arterial pressure
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

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increases. In chronic hypoxia, the increased pulmonary
arterial pressure causes hypertrophy of the right ventricle,
which must pump against an increased afterload.
o Occurs in foetus
 Thromboxane A2, a product of arachidonic acid metabolism (via the
cyclooxygenase pathway) in macrophages, leukocytes, and
endothelial cells, is produced in response to certain types of lung
injury. Thromboxane A2 is a powerful local vasoconstrictor of both
arterioles and veins.
 Prostacyclin (prostaglandin I2), also a product of arachidonic acid
metabolism via the cyclooxygenase pathway, is a potent local
vasodilator. It is produced by lung endothelial cells.
V/Q mismatch occurs in one of two situations:
1. A section of lung is ventilated but not perfused.
2. A section of lung is perfused but not ventilated.
Extreme alterations of V/Q
 An area with no ventilation (and thus a V/Q of zero) is termed
"shunt." [nb giving a patient oxygen will not help with this]
o Shunt is illustrated by airway obstruction and right-to-left
cardiac shunts.
 An area with no perfusion (and thus a V/Q undefined though
approaching infinity) is termed dead space.
o Dead space is illustrated by pulmonary embolism
Global high VQ if heart failure
Focal high VQ if embolism
shunt and dead space can coexist:
 In some lung diseases, the entire range of possible V/Q defects is
exhibited
Eg pneumonia / edema gives fluid in alveoli:
Pneumonia / edema gives a shunt (here is used to refer to a physiological shunt rather than
an anatomical one; refers to the blood passing through the alveoli but not being oxygenated
because of fluid in alveoli)
 Result is a fall in ventilation but not perfusion giving mismatch and low VA/Q
 A pulmonary shunt is a physiological condition which results when the
alveoli of the lungs are perfused with blood as normal, but ventilation (the
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supply of air) fails to supply the perfused region. In other words, the
ventilation/perfusion ratio (the ratio of air reaching the alveoli to blood
perfusing them) is zero. A pulmonary shunt often occurs when the alveoli fill
with fluid, causing parts of the lung to be unventilated although they are still
perfused.
Intrapulmonary shunting is the main cause of hypoxemia (inadequate blood
oxygen) in pulmonary edema and conditions such as pneumonia in which
the lungs become consolidated
Hypoxic pulmonary vasoconstriction occurs (HPV)
1. Alveolar oxygen tension falls
2. Response of lungs is active (ie lung role is not just passive)
vasoconstriction of pulmonary arteries that are <1000µm in
diameter (ie the small arteries) occurs
o Immediate response is achieved by the inhibition of K+
channels that occurs under hypoxic conditions; this
depolarisation gives calcium influx and therefore smooth
muscle contraction
 [note that pulmonary artery myocytes are simiar to
those of carotid body and not like those of other SM
cells (at all other locations hypoxia inhibits
contraction of SM cells)]
o Longer term response is achieved involving HIFs (hypoxyinducible factors) which under hypoxic conditions alter gene
expression such as to restore adequate oxygenation of the
body (not just active in the lungs)
 [this HIF action can lead to permanent remodelling
of tissues]
3. Bloodflow is diverted to other lung regions experiencing a greater
O2 conc
o Nb both PAP and hypoxia/aeration influence bloodflow:
both worsen bloodflow but PAP OVR beneficial as decreases
shunting by recruiting squashed alveoli at bottom of lung
 Note that HPV is problematic when occurs to whole lung such as due
to hypoxia at high altitude
[may be useful to look at the cardio notes on high altitude which
were taken off the cardio learning objectives]
Pulmonary edema:
o Interstitial space is normally a potential space but becomes filled with fluid when
the balance of fluid exit from the blood, fluid return to the blood and lymphatic
drainage is lost:
o “Starling forces”:
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o
o
o
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 The first phase of pulmonary edema is interstitial edema
 The second phase of pulmonary edema is alveolar flooding
Note that the harder work breathing will give greater negative pressures exerted
and so worsen the edema by increasing fluid exit
Effects:
 Impaired gas exchange
 Reduced lung compliance (wet lungs are stiff lungs)
 Increased pulmonary artery pressure (prob via hypoxic vasoconstriction)
Clinically:
 Terrified patient
 Severe breathlessness
 Pink frothy sputum
 Crackles on auscultation
Causes:
 High hydrostatic pressure: [~high pulmonary venous pressure]
 Left heart failure
 Mitral stenosis
 Low plasma colloid pressure [~low plasma pr ot conc]
 Starvation
 Abnormal leakage out at kidney or gut
 High capillary permeability [~endothelial cell damage]
 ARDS [adult respiratory distress syndrome
Pulmonary embolus:
o Can scan for ventilated and perfused areas of the lung separately to allow
identification of VQ mismatches
o Fat / air / blood clot
o Spectrum exists:
 Normal filtration: spare capacity allows toleration of small emboli unless is
chronic and the spare capacity is overwealmed
 Moderate clot: inc in RV/RA pressures, decrease in gas exchange, risk of
some lung infarction
 Clot in a main pulmonary artery: does not equate to a pneumonectomy
(which would be fine) because vasoactive factors leak out of the clot area
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-
causing the remaining functional lung to vasoconstrict thereby giving
pulmonary hypertension
Situations when instantaneous inc in pressure occurs means RV is more likely to
fail than if occurred slower allowing RV to hypertrophy
Pulmonary hypertension:
o Pulmonary hypertension (PH) is an increase of blood pressure in the pulmonary
artery, pulmonary vein, or pulmonary capillaries, together known as the lung
vasculature, leading to shortness of breath, dizziness, fainting, leg swelling and
other symptoms. Pulmonary hypertension can be a severe disease with a
markedly decreased exercise tolerance and heart failure
o Normal ranges for PAPmean:
 Rest:
 <20 mmHg = good
 20  25 mmHg = borderline
 >25 mmHg = threshold for “pulmonary hypertension” is exceeded
 Exercise: often as high as >30mmHg
o Subtypes:
 Pulmonary venous hypertension
 Primary defect usually cardiac
 Elevated pulmonary capillary wedge pressure
 Pulmonary arterial hypertension PAH
 Primary defect in pulmonary arteries
 Elevated pulmonary vascular resistance (PVR
o
o
Broad causes:
 physiological
 pathological
Causes: [any can lead to RV failure]
 1) Pulmonary arterial hypertension (primary defect in pulmonary arteries)
 -primary
 -related to collagen/vascular diseases, congenital heart disease,
drugs, toxins, HIV, etc
 2) Pulmonary venous hypertension (primary defect usually cardiac)
 -left sided atrial, ventricular or valvular disease
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3) Pulmonary hypertension associated with disorders of the respiratory
system and/or hypoxia
 When right ventricular failure develops in the setting of chronic lung
disease and hypoxia, it is termed cor pulmonale [ie not due to left
heart problems etc]
4) Pulmonary hypertension due to chronic thrombotic and/or embolic
disease
5) Pulmonary hypertension associated with miscellaneous disorders
Disease states overview:
o - pneumonia
o - pulmonary oedema
o - pulmonary embolus
o - pulmonary hypertension
o - anatomical pulmonary shunts
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Respiratory failure:
-
Lectures 17 and 18: Respiratory Failure I and II.
Dr Umeer Waheed, Umeer.Waheed@imperial.nhs.uk, Dr Richard
Stumpfl,Richard.Stumpfle@imperial.nhs.uk
At the end of these lectures you should be able to
o
o
o
-a gradient in Type 1 and 2 Respiratory Failure
o
ory Distress syndrome
o
29/11/13: Respiratory failure I: Dr Richard Stümpfle
Los from slides:
•
1) Understand how the pathological processes of respiratory failure interfere with normal
respiratory physiology
•
2) Explain how alterations in different aspects of respiratory physiology result in the
different types of respiratory failure
•
3) Following lectures 1 and 2, have a basic understanding of treatment principles of
respiratory failure
Notes:
-
Introduction
o The reported incidence of ARF varies between around 78–149 per 100 000 people
>15 years of age per year
o Ninety-day mortality is close to 40% for ARF and 31–60% for ALI / ARDS
o The majority of patients have ARF of pulmonary origin with pneumonia as the
predominant diagnosis
-
Definition:
o Respiratory system unable to maintain adequate gas exchange to satisfy
metabolic demands, i.e. the demands for:
 Oxygenation
 Elimination of carbon dioxide
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Consequences
o Hypoxaemia is inadequate oxygenation of blood
o Anaerobic metabolism starts ~ when PaO2<4.5kPa
o Leads to reduced cellular function, lactic acidosis & cell death
o Different tissues have different tolerances
o Reversible loss of function starts at:
 Cerebral tissue 1min
 Myocardial tissue 4mins
 Skeletal muscle 2hrs
o Can lead to multiorgan failure and death
-
Classification:
o (Type 1): Hypoxaemic [lack of O2 in blood]: Failure of gas exchange at alveolar
level
 PaO2 <8.0 kPa
 Normal or low CO2
o (Type 2): Hypercapnic: Ventilatory failure
 PCO2 >6.0 kPa
-
Non-respiratory Functions of the lungs:
o Reservoir of blood available for circulatory compensation
o Filter for circulation:
 Thrombi, microaggregates etc.
o Metabolic activity:
 Activation:
 Angiotensin I→II
 Inactivation:
 Noradrenaline
 Bradykinin
 5 H-T: 5-Hydroxytryptophan
 Some prostaglandins
o Immunological:
 IgA secretion into bronchial mucus
-
Oxygen Cascade:
o Three key drops / losses in PO2:
 1. Humidification and mixing with CO2
 2. Diffusion from alveoli to capillaries
 3. Physiological shunts
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o
o
o
PAO2 dependent on total alveolar pressure & partial pressures of other gases in
alveolus:
 Alveolar Pressure=PAO2+PACO2+PAH2O+PAN2
 Ie if CO2 conc greatly increases then will dilute O2 (other gases get pushed
out of the alveoli) or if high altitude then amount of O2 present will fall
Factors that can result in changes to PAO2 include:
 PACO2
 Alveolar pressure
 FiO2 [fraction/percentage of oxygen participating in gas-exchange]
 Ventilation
alveolar ventilation equation:
 the fundamental relationship of respiratory physiology
 describes the inverse relationship between alveolar ventilation and alveolar
PCO2 (PACO2).
 The constant, K, equals 863 mm Hg for conditions of BTPS: means body
temperature (310 K), ambient pressure (760 mm Hg), and gas saturated with
water vapour.
 if CO2 production is constant, then PACO2 is determined by alveolar
ventilation
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o
[nb knew that it would be a reciprocal relationship (y=1/x) rectangular
hyperbola from the equation]
Alveolar gas equation
 PAO2=PIO2-(PACO2/R)
 PAO2, PiO2 are the partial pressures of oxygen in alveolar and inspired gas
 R = respiratory quotient (Respiratory Exchange Ratio) = 0.8 usually
 Ie indicates some things that could be a means of giving hypoxia



alveolar gas equation: is used to predict the alveolar PO2, based on the
alveolar PCO2; or change in PAO2 that will occur for a given change in
PACO2
[nb can use for a variety of locations as shown]
The correction factor is small and usually is ignored.
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Carbon Dioxide Elimination:
o CO2 has high diffusion coefficient & is very water soluble (cf. O2 is much less
soluble, therefore Hb used)
o CO2 elimination dependent on alveolar ventilation
o Alveolar Ventilation=Respiratory Rate x (Tidal Volume-Dead Space)
o Factors that can result in changes to PACO2 include:
 Respiratory Rate: if fever or seizure are metabolically more active so can
generate more CO2
 Tidal Volume
 V/Q matching
o If carbon dioxide levels are high, the body assumes that oxygen levels are low, and
accordingly, the brain's blood vessels dilate to assure sufficient blood flow and
supply of oxygen. Conversely, low carbon dioxide levels cause the brain's blood
vessels to constrict, resulting in reduced blood flow to the brain and
lightheadedness.
-
Dead Space
o Fraction of tidal volume that does not take part in gas exchange
o Dead space is the volume of air which is inhaled that does not take part in the gas
exchange, either because it (1) remains in the conducting airways, or (2) reaches
alveoli that are not perfused or poorly perfused
o Anatomical dead space relates to volume of conducting passages
 Mouth, trachea etc.
 2.2ml/Kg body weight, or
 ⅓ tidal volume
 Measured by Fowler’s method (N2 washout)
o Alveolar dead space relates to V/Q mismatch
o Physiological dead space = Alveolar + Anatomical dead space
-
Ventilation
o Ventilation results in renewal of the A-a gradient
o Hypoventilation results in a rise in PaO2 & PaCO2
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Causes of Respiratory Failure
o Hypoventilation (nb CO2 levels are more sensitive to hypoventilation than O2
levels)
 Brainstem
 Injury due to trauma, haemorrhage, infarction, hypoxia,
 infection
 Metabolic encephalopathy
 Drugs
 Spinal cord
 Trauma, tumour, transverse myelitis
 Nerve root injury
 Nerve
 Trauma
 Neuropathy
 Motor neuron disease
 Neuromuscular junction
 Myasthenia gravis
 Drugs
 Respiratory muscles
 Myopathy
 Atrophy
 Muscular dystrophy
 Fatigue
 Respiratory system
 Airway obstruction
o Resistance is obstruction to air flow by conducting airways
o Resistance is main contributor to respiratory work
 Reduced compliance (lung, pleural, chest wall)
o Compliance relates to distensibility or ‘stretchiness’
 Lung compliance
o Chest wall compliance
o Diffusion impairment
 Lungs provide 50-100m2 surface area for diffusion
 O2 diffuses from alveolus to capillary until partial pressures equal
 The diffusion is a passive process
 Equilibrium completed in ⅓ time of capillary blood flow (0.75s) [ie as
mentioned at such healthy regions there is not an Aa gradient but elsewhere
physiological shunts occur]
 Allows for compensation in higher cardiac output states
 Does not affect CO2 as more soluble
 Causes include:
 Pneumonectomy
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o
o
 Pulmonary fibrosis [the diffusion distance increases]
 Emphysema
 Pulmonary oedema
Anatomical Shunting
V/Q mismatch:
 OVR Aa gradient exists due to physiological shunting (a capillary at a healthy
ventilated alveolus would become fully oxygenated); Aa gradient increases
with age
 Perfusion:
 Determined largely by gravity
 Perfusion pressure highest at bases
 At apices perfusion pressure may fall below alveolar pressure
 Ventilation
 Varies according to position of alveoli on compliance curve [ie
greater work of emphysema / fibrosis etc can lead to
hypoventilation]
 Compliance greater at apex of lung (stretchier, less weight on them,
ventilate better)
o Means that force exerted on the capillaries (which are
already poorly perfused at the apex) is greater so tend to be
squashed flat
 Compliance lower at base of lung (less stretchy, more weight on
them, ventilate worse)
o CPAP allows greater utilisation of these alveoli in a healthy
lung [will cause greater occlusion of capillaries at apexes of
lungs giving deadspaces but will give increased ventilation at
bottom of lung reducing the number of partial shunts
occurring; many more alveoli at bases so OVR positive
effect]
 Ideal ventilation occurs somewhere midway up the lungs where neither
perfusion nor ventilation are too dominant but instead are balanced
 Alveolar Dead space
 Well ventilated alveoli but no perfusion
 Causes include:
o Pulmonary embolus
o Low cardiac output states
o High intra-alveolar pressure
 Shunting
 Alveoli not ventilated but perfused
 Therefore blood not oxygenated
 Resulting hypoxia resistant to increases in FiO2
 Hypoxic pulmonary vasoconstriction limits perfusion to poorly
ventilated alveoli
 Commonest cause of hypoxia in critically ill
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
-
Causes include:
o Any cause of left to right intra-cardiac shunt [ie
anastomoses exist where certain bronchial arteries drain to
pulmonary veins]
o Pneumonia
o Pulmonary oedema/haemorrhage
o Atelectasis [defined as the collapse or closure of the lung
resulting in reduced or absent gas exchange] – increases
with age; these areas are at base and fail to be ventilated
Assessment:
o History
 Presenting complaint
 Past medical history
 Medications
 Social history
o Examination
 Signs of respiratory compensation
 Tachypnoea [the condition of rapid breathing]
 Use of accessory muscles
 Nasal flaring
 Intercostal, suprasternal or supraclavicular recession
 Increased sympathetic tone
 Tachycardia [he condition of rapid breathing]
 Hypertension
 Sweating
 Haemoglobin desaturation
 Cyanosis [the appearance of a blue or purple coloration of
the skin or mucous membranes due to the tissues near the skin
surface having low oxygen saturation]
 Hypercapnoea
 Respiratory flap [Asterixis (also called the flapping tremor, or liver
flap) is a tremor of the hand when the wrist is extended, sometimes
said to resemble a bird flapping its wings]
 Hypertension
 Coma
 End-organ hypoxia
 Altered mental status
 Bradycardia/hypotension



‘A’ is for airway
‘B’ is for breathing
‘C’ is for circulation
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o
o
-
Summary
o
o
o
o
 ‘D’ is for disability
Investigations
 Arterial blood gases
 Lung function tests
 Chest X-ray
 Computed tomography scan (CT scan)
 Microbiological tests
Management
 Oxygen
 Non-invasive ventilation
 Invasive ventilation
 Treat underlying cause
Respiratory failure results in hypoxia & hypercapnoea
Acute respiratory failure associated with high mortality
Causes related to disruption in physiology
Simple approach to assessment & management
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29/11/13: Respiratory failure and treatment: Umeer
Waheed
Los from slides:
•
•
•
•
•
Differentiate between Type 1 and 2 Respiratory Failure
Outline the management of Type 1 and 2 Respiratory Failure
Describe the importance of A-a gradient in Type 1 and 2 Respiratory Failure
Describe the pathophysiology of Acute Respiratory Distress syndrome
Outline the treatment modalities for Acute Respiratory Distress syndrome
Notes:
-
General details:
o All acute lung conditions with the exception of obstructive lung disease that
require active therapy.
o Not a specific disease, but a reaction to an underlying condition
o The underlying condition strongly influences prognosis.
 Lung Cancer
 Pneumonia
o Incidence of people >15 years of age per year admitted to Hospital
 78 /100000
 90 day mortality 40%
 ARF ( Acute Respiratory Failure) PaO2 < 8kpa
 ALI( Acute Lung Injury) PaO2/FiO2* <300 mmHg (40 kPa)
 ARDS ( Acute respiratory Distress Syndrome)
 PaO2/FiO2 <200 mmHg (26.7 kPa)
 ARF pulmonary origin 52%
 Pneumonia 23%
o Acute respiratory failure occurs when:
 Pulmonary system is no longer able to meet the metabolic demands of the
body
 Failure of oxygen transfer across the alveoli
 Failure of oxygen transport to the tissues
 Removal of CO2 from the blood / alveolus to the environment
o Hypoxaemic respiratory failure Type I
 PaO2 <8kPa when breathing room air
o Hypercapnic respiratory failure Type II
 PaCO2 >6.7 Kpa
o Ventilatory Capacity (VC) V Ventilatory Demand (VD)
 VC maximal spontaneous ventilation that can be maintained without
fatgue
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o
o
o
-
Type I
o
o
-
 VD Spontaneous minute ventilation that results in a stable PaCO2
 Usually VC > VD
 Respiratory failure may result from reduced VC or increase VD or both.
Acute
 Life threatening derangements in ABG’s and acid base status
 Develops in mins / hours , pH <7.3
Chronic
 Usually less dramatic and may not be readily apparent, unless associated
with acute deterioration
 Develops in days allowing time for renal compensation, increase in [HCO3}
and normal pH
NB acute on chronic may occur: prob will give an even worse prognosis than
normal acute resp failure
Type II
o
o
Normocapnic / Hypocapnic, hypoxaemia
[ie ventilation but still not enough gas exchange for O2 needs: hypoxia without
hypercapnia – ie some exchange occurs and is enough for CO2 removal]
 ARDS (see below)
 Severe Pneumonia
 Pulmonary embolus ie Pulmonary Embolism
 Pulmonary odema
 Emphysema [Acute exacerbations of chronic obstructive pulmonary disease
(AECOPD)]
 Asthma (ie but not as severe as for type II: asthma first gives type I and then
when more severe then gives type II)
 Pulmonary haemorrhage / Trauma
 Foreign body (ie but not as severe as for type II)
 Ob. Sleep Apnoea (ie not severe enough to give type II)
 Interstitial Lung disease
 Sickle cell crisis
 Pneumothorax
 Pleural Effusion
Hypercapnic, Hypoxaemia
inadequate ventilation; both oxygen and carbon dioxide are affected
 CNS:
 Neuromuscular disease
 Respiratory centre depression CVA, Drugs, Infection, Tumours,
 Trauma head and neck
 Alveolar hypoventilation [a hypoventilation syndrome]
 Nerve injuries
 Drug OD,
 CVA, = cerebrovascular accident = stroke
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



 tumor,
 Central hypovent’ (Ondine's curse),
 hypothyroid
Muscle cell:
 Guillain Barre, [is an acute polyneuropathy, a disorder affecting the
peripheral nervous system]
 Myaesthenia Gravis,
 Post polio syndrome, [muscular atrophy (decreased muscle mass)
etc]
 Botulism, MND
 Spinal shock
 Myopathies
Peripheral airways
 COPD, Asthma
Musculoskeleto-pleural
 Kyphoscoliosis, Chest wall, pleural problem
Other
 Foreign Body,
 Laryngeal edema,
 subglottic stenosis,
 Obstructing tumor
-
Refractory Hypoxaemia
o Presence of a low PaO2 despite increasing O2 : giving them oxygen doesn’t solve
the problem
o implies more to the hypoxaemia than a simple diffusion problem at alv-cap
interface.
o Problems with perfusion likely occurring:
 V/Q matching (& HPV)
-
ARDS I: Acute respiratory distress syndrome: adults [also known as adult respiratory
distress syndrome]
o Is TYPE 1 respiratory failure
o defined by oxygenation: arterial oxygen tension / fractional inspired oxygen
(Pa02/Fi02) < 200mmHg (27 kPa) for ARDS
o spectrum of acute lung injury: [mild - acute lung injury (ALI) and] severe - acute
respiratory distress syndrome (ARDS)
o very high mortality if in conjunction with failure of other organs
o refractory hypoxaemia
o CXR - bilateral diffuse infiltrates
o absence of cardiogenic pulmonary oedema
o Direct vs indirect causes: [ie there are many different causes of ARDS]
 e.g. pneumonia vs acute pancreatitis,
 e.g. pulmonary contusion vs abdominal sepsis
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o
o
o
o
-
Pathophysiology

- High permeability pulmonary oedema

- V/Q mismatch
 *loss of HPV
 *atelectasis / volutrauma
 Mix of diseased lung (gravity dependent) and normal lung
Traits:
 Cytokines that are present due to whatever the specific cause in that patient
is will cause plasma leak from post capillary venules  inc alv-cap distance
 dec diffusion
 Deregulation of vascular reactivity  loss of HPV  Intrapulmonary
microvascular shunt [shunting is mainly happening at the lower, well
perfused lung regions where the fluid collects]
 Dead space ventilation in other areas [due to higher lung regions being
ventilated well but poor perfusion (normally there areas not required so
would be fine but fluid elsewhere means they need to be used but HPV
dysregulation means are not being used either]
 V/Q mismatching [due to the shunting]
 Refractory hypoxaemia
Gravity results in the region of the lung that is lower being fluid filled; however
this is strong overlap with the areas of the lung that have the best blood supply so
put patient on front where fewer well perfused lung units (even when have
turned over in this way because there are fewer lung units that side) thereby
symptoms can be eased
Disparities within the lungs:
 normal lung
 better compliance
 risk of volutrauma due to greater pressures [patient physiological
response / CPAP / ventilation increases openings and closings of
aerated units giving high shear stress
 Dependent lung
 reduced compliance [think of compliance of a wet sponge]
 greater pressure support to recruit collapsed alveoli [ie dependant
lung ~ lower lung regions so here CPAP can act to allow recruitment
of collapsed alveoli
Monitoring
o Respiratory compensation
 Tachypnoea
 Use of accessory muscles
 Recession
 Nasal flaring
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o
o
o
Sympathetic stimulation (adrenaline gets secreted, etc which gives
bronchodilation but also other effects)
 Tachycardia
 Hypertension
 Palor
 Sweating
 Cool peripheries
Tissue hypoxia [ie can lead to failure of other organs]
 Altered mental state
 Hypotension
 Bradycardia
 Renal failure
Haemaglobin desaturation
 Cyanosis
-
Pulse Oximetry
o Pulse oximetry is a non-invasive method allowing the monitoring of the
oxygenation of a patient's hemoglobin.
o Light at red (660nm) and infrared (940nm) wavelengths is passed sequentially
through the patient to a photodetector
o The changing absorbance at each of the two wavelengths is measured, allowing
determination of the absorbances due to the pulsing arterial blood alone
o Based upon the ratio of changing absorbance of the red and infrared light caused
by the difference in color between oxygen-bound (bright red) and oxygenunbound (dark red or blue, in severe cases) blood hemoglobin, a measure of
oxygenation (the percentage of hemoglobin molecules bound with oxygen
molecules) can be made.
o Sources of error
 Poor peripheral perfusion
 Poorly adherent probe
 False nails/nail varnish
 Lipaemia
 Bright ambient light
 Excesive motion
 Carboxy/Met haemaglobin
o It is also important to be aware that the saturation may remain normal in the face
of significantly impaired ventilation, particularly if the patient is receiving oxygen
therapy
-
Treatment
o Supportive
 Oxygen Therapy
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o
Continuous positive airways pressure
 CPAP
 continuous positive airway pressure
 reduces shunt by recruiting partially collapsed alveoli at base of lung
(ie prob recruits more alveoli than the number of alveoli that
become impinged with regard to their bloodflow due to the inc in
pressure)
 maintains patency of more alveoli at end-expiration (PEEP)
 useful post surgery - retained secretions due to pain-induced
shallow breaths and basal atelectasis; as an adjunct to analgesia and
physiotherapy.
 reduces work of breathing: as below it shifts patients position on the
curve right by giving an initial contribution to pressure
o
Mechanical Ventilation
 When deciding if should do this must consider:
 Severity of respiratory failure
 Cardiopulmonary reserve
 Adequacy of compensation
 Expected speed of response
 Risks of mechanical ventilation
 Non respiratory indication for intubation
 Varients:
 Frequency Oscillatory Ventilation
o Shallow tidal volumes used
 Extracorporeal Membrane Support
o Blood oxygenated externally
28/11/13: Exercise: Dr Luke Howard
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Los from booklet:
Lecture 15: Exercise Physiology. (Dr Luke Howard l.howard@imperial.ac.uk)
At the end of this lecture you will appreciate and understand
ion
Notes:
-
Basic exercise metabolism:
o CO2 levels are responded to by heart and lungs to give sufficient clearance and
because one O2 is required per 0.8 CO2 produced this it is relatively intuitive that
the heart and lung activities will also be sufficiently matched to the metabolic
demands of the body in this manner
 However upon anaerobic metabolism at peak exercise the amount of O2
being used is nolonger increasing but amount of CO2 formed is still
increasing so signals for inc RR and subject in fact begins to breath higher
than their O2 needs
 CO2 signals for resp change via chemoreceptors (see prev notes)
 Heart rate changes are due to several inputs [presumably then all signal via
the sympathetic system]:
Your brainstem receives signals from many parts of your body that help it
determine how much to speed up heart rate when you exercise. Some
signals come from the motor cortex, a part of your brain that coordinates
movement. Other signals come from receptors in your muscles and joints
that sense movement as you start exercising. The hypothalamus is a part of
your brain that controls body temperature. When you exercise, your body
temperature increases, causing the hypothalamus to signal the brainstem to
further increase your heart rate.
o
o
o
o
o
Muscle contraction requires energy for contraction in the form of phosphate,
“delivered by ATP”
Sources of phosphate:
 Anaerobic metabolism, incl. Creatine phosphate
 Aerobic metabolism
Largest source is aerobic
Cardiac output needs to increase by 5-6 l/min per l/min oxygen consumption [at
rest CO ~5lmin-1 but can increase to ~25lmin-1 upon exercise]
If it fails, anaerobic metabolism required
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o
o
o
o
o
o
o
o
o
Total body H+ is 3.4 micromoles
H+ generated at walking speed is 40,000 micromoles per minute from CO2
production
Cardiovascular system must remove CO2 to lungs where it is eliminated in
proportion to rate of delivery
Small errors lead to large changes in pH but in fact remains very constant during
exercise to ensure disruption to enzymatic systems does not occur
 At end of maximal exercise high lactic acid production means that
bicarbonate reserves must be used up to be combined with H+ to give CO2
which can be breathed out – when bicarbonate reserves are depleted pH
will start to fall so will be forced to stop exercising
 Ie presumably the rate of CO2 production will level off / fall as are no longer
generating CO2 from acids
 CO2 + H20 ↔ H2CO3 ↔ H+ + HCO3Very tight relationship between ventilation (Lmin-1) and CO2 production
 The relationship of ventilation to carbon dioxide production relates to the
efficiency of the lungs [ie what gradient this tight line takes]
 Is a good measure of VQ mismatching: eg if pulmonary embolism /
pneumonectony then will require a greater ventilation rate for a given
amount of CO2 clearance
 Relationship may be lost if eg hyperventilation at rest
Sources of CO2 Output during Exercise
 1) Aerobic substrate catabolism
 2) Bicarbonate buffering from H+ produced alongside lactate
 3) Pulmonary hyperventilation due to acidosis [ie breathing faster gives
greater clearance (in short term) despite not actually making any more CO2
in the body] – occurs at the end of exercise
RER: Respiratory exchange ratio: The ratio between the amount of CO2 produced
and O2 consumed in one breath (determined from comparing exhaled gasses to
room air) is the respiratory exchange ratio (RER). In one breath, humans normally
breathe in more molecules of oxygen (O2) than they breathe out molecules of
carbon dioxide (CO2).
 RER is about 0.8 at rest with a modern diet but tends to exceed 1 with
intense exercise (see below)
CO2 production / O2 consumption = ~0.7 (ie less than 1) if metabolising fats as the
ratio in its metabolism is 16:23
 1 palmitate + 23 O2 → 16 CO2 +129 ATP
If anaerobic metabolism of glucose/glycogen then CO2 production / O2
consumption > 1 as lactate gives CO2 without O2 consumption
 glucose → 3 ATP + 2 H+ + 2 Lactate 2 H+ + HCO3- → 2 CO2
 [anaerobic threshold has been surpassed: ie can see when threshold passed
by the sudden increase in the CO2 production : O2 consumption ratio]
 Above anaerobic threshold, CO2 production exceeds O2 consumption.
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
o
-
DO NOT HAVE TO BE ABLE TO INTERPRET EXERCISE TEST FOR THE EXAM; ONLY
UNDERSTAND THE PHYSIOLOGY ETC
o
o
-
Seen as clear upward deflection on CO2 production vs O2
consumption graph.
 Higher RER on exercise indicates how far past anaerobic threshold
have gone
 As ventilation is coupled to CO2 production, ventilation rises
disproportionately to O2 consumption
 CO2 production per ATP generated rises massively compared to either
aerobic metabolism type (fat / glu)
 Lactate itself is converted back to glucose in the liver
 This process requires O2: “oxygen debt”
If mainly metabolising glucose (/glycogen etc) then (assuming aerobic) CO2
production / O2 consumption = ~1 because one O2 used per CO” made
 1 glucose + 6 O2 → 6 CO2 +37 ATP [is actually 38ATP]
 For incremental work: Aerobic metabolism more efficient than anaerobic
[more ATP per O2] and produces less CO2 per ATP generated
 Slightly more ATP per O2 than achieved with fat metabolism
At exercise may be breathing 30/35 breaths per min max [and each exhale is
therefore effectively an FEV1]; so maximum breathing capacity (=maximum
voluntary ventilation) (he called it max ventilatory capacity) will be ~30*FEV1 =
~200Lmin-1 for me
 Ie max breathing rate and FEV1 both variables that determine the max O2
supply to lungs that an individual can achieve
Good rule of thumb is 220 – [age] to give predicted max HR of a person
O2:
o
o
Factors affecting amount of O2 consumption upon exercise:
 Muscle bulk
 Effort & neuromuscular coupling
 Capillary & mitochondrial density
 Cardiac output = Stroke vol. x HR
 Haemoglobin
 Oxygen saturation
 V/Q matching
 FEV1
 Respiratory muscle function
NB also “heart rate reserve” and “breathing / ventilation reserve” are key limiters
to amount of O2 that can be supplied on exertion
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o
o
o
o
o
o
o
o
-
VO2 = rate of delivery of delivery of oxygen to tissues
CaO2 and CvO2 = conc of O2 at arteries and veins
Fick equation
 VO2 = CO x (CaO2 – CvO2)
 VO2 = SV x HR x 1.34 x Hb x (SaO2 – SvO2)
1.34 is just a constant
Nb Sv increases before HR; both OVR inc during exercise
(SaO2 – SvO2) is usually about the same for all healthy people
 At peak exercise:
 CaO2 21 ml/100ml
 CvO2 5 ml/100ml
“oxygen pulse” = VO2 / HR
 VO2 / HR α SV x (SaO2 – SvO2)
VO2 max: value relative to body weight is what indicated fitness
 the maximum capacity of an individual's body to transport and use oxygen
during incremental exercise, which reflects the physical fitness of the
individual.
 VO2 max is expressed either as an absolute rate in litres of oxygen per
minute (L/min) or as a relative rate in millilitres of oxygen per kilogram of
bodyweight per minute (i.e., mL/(kg·min)).
CO2:
o
o
o
VCO2 = rate of CO2 production: Ventilation increases in proportion to CO2
production
Vd/Vt = deadspace as a fraction of total lung volume: The more deadspace in your
lung, the more you have to breathe to clear CO2
 Eg emboli etc
 Decreases upon exercise as tidal volume increases as deadspace of trachea
etc doesn’t change while new lung recruited
Ventilation rate, VE = VCO2 * (863 / (PaCO2 * (1-[Vd/Vt]))
In fact VE might be ventilatory efficiency (as in the efficiency of CO2 removal from
the body) but the same proportional relationships will exist
 Ie with inc ventilation first efficiency rises as fractional deadspace falls but
eventually hyperventilate and if PaCO2 falls then would give decrease in
efficiency
VE  VCO2 .
o
o
863
PaCO2 .(1  VD VT )
PaCO2: NB high ventilation rate corresponds to low PaCO2 thus the two values are
inversely related
Nb patient with heart failure will have a high VE / VCO2
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-
HR and SV and dilation influences:
o Heart rate
 Autonomic nervous system
 Drop in vagal tone
 Rise in sympathetic stimulation
 Activated by cortical and muscle ergoreceptor mechanisms (detail
was touched on above)
o Stroke volume
 Increased venous return from contracting muscles
 Decreased intrathoracic pressure with deep inspiration “sucking blood in to
the lungs”
 Sympathetic response (increasing inotropy: inc force of muscular
contractions)
 Reaches peak at 50% of peak VO2 [ie then levels off]
o Preferential dilatation of active vascular beds
 Autonomic nervous system
 Local factors
 H+
 CO2
 K+
 Omsolarity
 Nitric oxide
 Adenosine
 Temperature
 PO2
-
Ventilation change influences:
o Comfortable tidal volume is approx. half of vital capacity
o Three stages of ventilator change:
 Initial sharp rise:
 Cortical: direct signalling from brain
 Ergoreceptors: afferents sensitive to
muscle contraction



Cardiodynamic: SV increases [somehow this gives inc ventilation;
don’t worry about mech; 'cardiodynamic hyperpnoea' considers a
possible effect of increasing cardiac output on ventilation]
Parabolic rise
 CO2 inc production rate signalling back for inc ventilation
Flattening off
 Maximum ventilation reached
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Exercise:
o Excellent matching occurs between O2 consumption, CO2 production, and the
ventilation rate.
o mean values for arterial PO2 and PCO2 do not change during exercise [thought
that very slight oscillations are enough to give the necessary signalling to
ventilation rate] [nb but hyperventilation in late exercise as anaerobic gives HCO3production]
o The arterial pH may decrease, however, during strenuous exercise because the
exercising muscle produces lactic acid [ie if HCO3- compensation incomplete]
o decrease in the physiologic dead space:
 CO inc  pulmonary blood flow increases  perfusion of more pulmonary
capillary beds: pulmonary blood flow becomes more evenly distributed
throughout the lungs, and the V/Q ratio becomes more “even,”
 There is a decrease in pulmonary resistance associated with perfusion of
more pulmonary capillary beds [useful in catering for the inc CO]
o The PCO2 of mixed venous blood increases during exercise
o During exercise, the O2-hemoglobin dissociation curve shifts to the right
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[ONLINE SELF LEARNING FROM SLIDES]: Altitude and
air travel: Dr Robina Coker
-
Read pdf in folder if possible as good detail on the physica, physiology
and pathophysiology
Los from booklet:
tests
Notes:
-
Why is air travel important
o 2002 414 commercial flight diversions, each costing £100,000; Respiratory
conditions are the 3rd commonest cause
o 2005 15,550 in-flight medical emergencies
o 2006 17,300 in-flight medical emergencies (30% of airlines)
o 2006 89 in-flight deaths
o 2007 77 in-flight deaths (1 in 5.7m passengers)
-
Altitude and hypoxaemia:
o O2 concentration of dry air at sea level is 20.9% (~21%)
o Inhaled air is warmed and saturated with water vapour. Partial pressure of water
vapour at 37oC is 47mmHg
o PIO2 at sea level = 0.21x (760-47) = 149 mmHg [At sea level, the atmospheric
pressure is 760mmHg]
o PIO2 at 3,450m (Jungfrau Joch train station) = 0.21 x (497-47) = 94 mmHg ie 2/3
that at sea level [ie PIO2 drops significantly with altitude]:
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Humidified gas expansion
o
gas expansion for saturated gas is greater than for dry
gas:
o
relative expansion=(initial pressure of gas in cavity at sea level – 47 mmHg)
for humidified gas
(final pressure of gas in cavity – 47 mmHg)
[47 mmHg = pressure of water vapour]
 Eg. (760 - 47) / 566 - 47) = 713/519 = 1.37
 Vs for dry gas = 760/566 = 1.34)
 volume of saturated gas in a non-communicating bulla rises by 37% on ascent
to 2438 m (8,000 ft)
Cabin Humidity and Dehydration
 To achieve pressurisation in the cabin they take ambient air and compress it.
Since the gas heats up in this process, it must subsequently be cooled. The
resulting air is of low humidity which helps avoid stress on the plane upon
change in altitude and reduces the threat of corrosion but can cause skin
dryness and discomfort in the eyes, mouth, and nostrils and favour
dehydration. The air is therefore recycled repeatedly to rise humidity but it
remains low: usually less than 10% to 20% humidity [in the home is normally
over 30%].
o
o
o
-
Respiratory Indications for Clinical Evaluation Prior to Air Travel: [ie anything that may
indicate predisposition for or sensitivity to low O2 saturation levels]:
o Moderate to severe chronic obstructive pulmonary disease
o Persistent severe asthma
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o
o
o
o
o
o
o
o
o
-
Clinical pre-flight assessment
o Various possible methods:
o 50 metre walk [In such a test, the aim is to verify that the patient is capable of
walking 50 m without limitation due to dyspnea]
o FEV1
o Oximetry
o Regression equations
o Hypoxic challenge test (HCT)
o Hypobaric chamber testing
o
o
-
Severe restrictive disease (including diseases of the chest wall and respiratory
muscles), especially with hypoxemia or hypercapnia
Cystic fibrosis
History of intolerance of air travel due to respiratory symptoms (dyspnea, chest
pain, confusion, or syncope)
Comorbid conditions that are worsened by hypoxemia (cerebrovascular disease,
ischemic heart disease, heart failure)
Pulmonary tuberculosis
Patients from areas with recent local outbreaks of severe acute respiratory
syndrome
Recent pneumothorax
Risk or previous episode of venous thromboembolic disease
Prior use of oxygen therapy or ventilatory support
Predictive role of FEV1 and oximetry currently unclear
Medical history: special attention should be paid to recognizing all
cardiorespiratory disease, with particular interest in comorbidity that could be
worsened with hypoxemia (cerebrovascular disease, ischemic heart disease, heart
failure).
Air travel with oxygen
o Supplementary oxygen is recommended during air travel for patients who have an
estimated in-flight PaO2 of less then 50 mm Hg
o In COPD [see COPD detail later below], O2 at 2L/min improves but does not fully
correct hypoxaemia at 2438 m; O2 at 4L/min over-corrects
o Aircraft delivery usually 2 or 4L/min from cylinder: ie are not allowed to bring your
own oxygen on the flight (due to safety/terrorism concerns)
o Nasal prongs recommended (for access of the oxygen from the cylinder to the
body)
o Check regulations and charges with airlines
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-
Key learning points
o With increasing altitude, barometric pressure falls
o This causes a progressive fall in the partial pressures of inspired and arterial
oxygen
o It also leads to an increase in gas volumes (especially if the gas is saturated)
o Hypoxaemia triggers a series of adaptive physiological responses, termed
acclimatisation
o Failure of acclimatisation can lead to altitude related illnesses
o Clinical assessment of those with lung disease prior to air travel or (less
commonly) high altitude exposure may require evaluation of cardio-respiratory
status, hypoxic challenge and/or hypobaric chamber testing
-
Other info from internet
o Hypobaric = Below normal pressure
o Commercial aircraft generally fly at an altitude of around 11 000 to 12 200 m:
Flights occur in the troposphere: extends from sea level to 9144 m (30 000 feet) at
the poles and to 18 288 m (60 000 feet) at the equator
o The pressurization system used by commercial aircraft is known as isobaric.27
Initially, as the aircraft climbs in altitude, it maintains the same ambient pressure
as its environment, and then, from a certain altitude, it maintains a constant
(isobaric) pressure, irrespective of changes in altitude.
o Aircraft pressure is not maintained at that of sea level but rather at an
intermediate pressure; that pressure depends on the type of aircraft but is usually
approximately equivalent to that of an altitude of 2400 m; At that altitude, the
atmospheric oxygen tension is equivalent to breathing 15.1% oxygen at sea level.
o
o
o
o
In healthy subjects, this can represent a
reduction in PaO2 from 98 to 55 mm Hg,
which is
usually well tolerated and does not produce symptoms
However, in patients with chronic respiratory diseases and some degree of
baseline hypoxemia, the reduction in PiO2 during the flight can cause more
marked reductions in oxyhemoglobin saturation
Acute exposure to a hypobaric environment triggers hyperventilation, which is
essentially induced by stimulation of peripheral chemoreceptors and is usually
mediated by an increase in tidal volume. It also generates an increase in cardiac
output to compensate for the residual systemic hypoxia. This increase is mainly
mediated by tachycardia and is usually proportional to the drop in oxygen
saturation.
The increased pulmonary perfusion caused by the rise in cardiac output is
associated with hypoxic vasoconstriction [ie due to low oxygen levels] of the
pulmonary artery and increased systolic pulmonary pressure. As a consequence of
the increase in pulmonary vascular resistance, there is a redistribution of
pulmonary blood flow and an increase in perfusion of certain areas of the lungs
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o
o
o
compared with the situation at sea level [ie high perfusion due to vasoconstriction
elsewhere and due to high CO; therefore prob a risk of pulmonary edema at these
highly perfused areas].
Altitude is also associated with limitation of oxygen diffusion from the atmosphere
into the pulmonary capillaries as a consequence of the interaction of various
factors. Both the reduced PiO2 and the reduction in affinity of hemoglobin for
oxygen in conditions of low PaO2 lead to a more marked drop in the oxygen
content of the pulmonary capillaries than at sea level. Finally, there is a shortened
transit time of blood through the pulmonary capillaries due to the tachycardia
caused by the altitude and this limits the time available to establish an adequate
oxygen equilibrium. The net result is an increase in the alveolar–arterial oxygen
difference [increase in Aa gradient].
Exercise and hypobaric hypoxia: In addition, the oxyhemoglobin saturation is
significantly reduced during physical exercise in a hypobaric environment. Exercise
at high altitudes also increases the alveolar–arterial oxygen difference in subjects
who normally reside at sea level, while it does not affect those native to high
altitudes. Studies performed using the multiple inert gas elimination technique
have shown that hypobaric hypoxia is associated with a greater heterogeneity in
the ventilation–perfusion ratio and a limitation of diffusion that together worsen
hypoxemia as exercise intensity increases. Limited diffusion secondary to reduced
PiO2 appears to exert the greatest influence on blood gas alterations during
exercise in a hypobaric environment. Additionally, the interstitial edema caused
by extravasation of fluids into the extravascular space appears to potentiate the
ventilation–perfusion imbalance. The changes described have few consequences
in healthy subjects, who might only note a slight increase in tidal volume and
heart rate. However, hypobaric hypoxia represents a risk for some patients with
chronic respiratory disease, in whom it can aggravate pre-existing hypoxemia and
favour the development of cardiovascular complications. In fact, it is recognized
that hypoxia reduces the ischemic threshold in men with exercise induced
ischemic heart disease as well as favouring some atrial arrhythmias and being
associated with ectopic ventricular beats as a result of increased sympathetic
activity
Expansion of trapped gases:
 Common body areas with gases which will expand:
 Ears
 Paranasal sinuses
 Barodontalgia [dental pain]
 GIT [gastrointestinal tract usually contains some quantity of gas, and
consequently, gastrointestinal discomfort is common during air
travel]
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

o
-
Lungs [eg apical bullae can burst during ascent and cause a
pneumothorax]
Given that the gas in the body cavities is saturated with water vapour, the
expansion caused by increased altitude is greater than that calculated
according to Boyle’s law.
 The problem is much more severe in patients with chronic
obstructive pulmonary disease (COPD), since those patients usually
have regions of emphysema that are poorly connected with the
exterior or separated from it and can cause rupture and
pneumothorax, in addition to the problems generated by hypoxia.
Diving:
 it is recommended that individuals do not fly within 24 hours following
scuba diving
 Dissolved nitrogen can accumulate in the tissues (residual nitrogen) during
scuba diving, particularly when diving is deep and repeated. During ascent,
that nitrogen may be released and give rise to symptoms of decompression
HIGH ALTITUDE:
o one of several causes of hypoxemia
o Eg: at 18,000 feet, PO2 = 70 mm Hg ([380 mm Hg - 47 mm Hg] x 0.21 = 70 mm Hg
o Despite severe reductions in the PO2 of both inspired and alveolar air, it is
possible to live at high altitudes if the following adaptive responses occur:
 Hyperventilation:
 if alveolar PO2 is less than 60 mm Hg  respiratory alkalosis [can be
treated with carbonic anhydrase inhibitors (e.g., acetazolamide)]
dec ventilation  renal compensation  continued
hyperventilation
 Polycythemia
 increase in red blood cell concentration
 O2-carrying capacity is increased,which increases the total O2
content of blood in spite of arterial PO2 being decreased.
 disadvantageous in terms of blood viscosity  inc resistance  dec
flow
 stimulus for polycythemia is hypoxemia, which increases the
synthesis of erythropoietin in the kidney. Erythropoietin acts on
bone marrow to stimulate red blood cell production.
 increased synthesis of 2,3-DPG by red blood cells
 advantageous in tissues but not in lungs
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
o
-
Pulmonary Vasoconstriction  pulmonary arterial pressure also must
increase
 The right ventricle must pump against this higher pulmonary arterial
pressure and may hypertrophy in response to the increased
afterload.
Acute Altitude Sickness
 The initial phase of ascent to high altitude is associated with a constellation
of complaints, including headache, fatigue, dizziness, nausea, palpitations,
and insomnia. The symptoms are attributable to the initial hypoxia and
respiratory alkalosis, which abate when the adaptive responses are
established.
HYPOXEMIA
o Hypoxemia is defined as a decrease in arterial PO2
o Aa gradient may exist in some cases
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o
o
Supplemental O2 amay or may not be useful
Causes:





-
High altitude
Hypoventilation
Diffusion defect
V/Q defect
Right to left shunt
HYPOXIA:
o Hypoxia is decreased O2 delivery to the tissues
o Since O2 delivery is the product of cardiac output and O2 content of blood,
hypoxia is caused by decreased cardiac output (blood flow) or decreased O2
content of blood.
o Causes:
 Hypoxemia (due to any cause) is a major cause of
hypoxia
 Dec CO
 Anaemia
 CO poisoning
 Cyanide poisoning [interferes with O2 utilization at
tissue]
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13/12/13: Lung cancer: Dr Shovlin
[this lecture was actually given by someone else who didn’t put their slides up: will largely work from
claire’s slides (largely because question bank q’s will prob have been written by her)]
Los (from booklet):
summarise the different cell types and function within the lung
moking in different individuals
Notes:
-
Lung cancer:
o 4th most common cause of death in Uk
o 5yr survival = 10%
o Surgery is the only curative treatment
 But even then may have metastasised, etc
o Resection not usually possible [lobectomy/pneumonectomy]
 Disease likely to have spread significantly through the lung
 Resection would reduce cardiopulmonary reserve
 Especially cannot resect if is at carina [unless pneumonectomy]
o Symptoms:
 Cancer general symptoms:
 Night sweats
 Weight loss
 Fatigue
 Lung cancer:
 SOB
 Haemoptysis
 Local invasion
 Persistent / unexplained: chest/shoulder pain, hoarse voice, cough,
dyspnoea
 Distant spread (metastases)
 Bone, brain, liver, adrenals, skin etc effects
 paraneoplastic syndrome:
 is a disease or symptom that is the consequence of the presence of
cancer in the body, but is not due to the local presence of cancer
cells.[1] These phenomena are mediated by humoral factors (by
hormones or cytokines) excreted by tumor cells or by an immune
response against the tumor.
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o
o
o
o
 Clubbing, malaise, weight loss
 Eg ADH production: causes low sodium – life threatening
 Eg PTH production: causes high Ca – life threatening
The primary metastatic spread is by the lymphatics (not the blood)
 Metastasis is actually surprisingly uncommon
 Specific organs seem to be affected:
 Seed and soil hypothesis
o The "seed and soil" hypothesis states that specific organs
harbor metastases from one type of cancer by stimulating
their growth better than other types of cancer. This
interaction is dynamic and reciprocal, since cancer cells
modify the environment they encounter.
to diagnose:
 X ray
 Blood tests
 Lung function tests
If cancer:
 CT
 Cytology of cells in sputum to identify type
 Histology of a biopsy
Types of (primary) lung cancer:
 Small cell carcinoma [20% of cases]
 Closely packed neuroendocrine cells
 Rapidly spreads and metastasises
 The most aggressive type of lung cancer
 Treat with cisplatin or atoposide; ie chemotherapy [most of these
patients respond but still poor survival]
 Non small cell carcinoma: [80% of cases]
-Relitively chemoresistant [ie chemotherapy fails to gain response; any
chemoresistant cells will be selected for so will relapse and then
chemotherapy will have no effect second time]
-most patients offered radiotherapy instead
 Squamous cell carcinoma [1/3]
o Large pink tumour cells
o Slow growing, late metastases
o Necrosis in center of the tumour occurs
 Adenocarcinoma: [1/3]
o Tumour cells from glandular tissues
o May produce mucin
 Large cell anaplastic carcinoma [1/5]
o Undifferentiated [Anaplasia refers to a reversion of
differentiation in cells]
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
o
Rarely:
 Mesothelioma:
o Mesothelioma (or, more precisely, malignant
mesothelioma) is a rare form of cancer that develops from
cells of the mesothelium, the protective lining that covers
many of the internal organs of the body. Mesothelioma is
most commonly caused by exposure to asbestos.[1] The
most common anatomical site for mesothelioma is the
pleura (the outer lining of the lungs and internal chest wall)
Management:
 Early diagnosis
 Early surgery where appropriate
 Chemotherapy alone or as adjunct to surgery
 Transplant
 Palliative care
-
Smoking and lung cancer
o 85% of lung cancer occurs in smokers
o Linear relationship of no. cigarettes smoked and lung cancer incidence
o Mechanism is via inducing DNA damage
 At least 60 components of cigarettes are carcinogens
 P53 mutated in ~80% lung cancers [thought due to the carcinogens]
 P53 has key role in cell cycle arrest / apop
 Clara cell metabolism plays key role in activating the DNA damaging ability
of many of the chemicals: both phase I and phase II enzyme action can lead
to active metabolites eg from polycystic aromatic hydrocarbon precursors
o DNA adduct is a piece of DNA covalently bonded to a (cancer-causing) chemical:
are biomarkers of carcinogen exposure
 Increases with no. cigarettes smoked per day
 In smokers the adducts preferentially form at the codons most commonly
known to mutate in p53 [implies direct smoking cause of the mutations]
o Cigarettes have been made more healthy through time
-
Smoking and genetics:
o A positive family history increases adjusted risk by 2/3 times
 Thought due to both shared genetic and shared env
o Epigenetics may be part of the reason for heritability
o EGFR-TK1 is involved in mitosis signalling via EGF signalling [ie is referring to the
receptor]
 Inhibitors to the receptor can be used in treatment
 Better response if non smoker as is more likely to be a genetic problem of
this pathway than just p53 dysfunction as is common in smokers
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13/12/13: Hypoxia: Dr R. Davies Dr Sholvin
[this lecture was the colossal disaster one and she hasn’t put any slides up; the Los are for dr
shovlins but the corresponding lec cannot be found online]
Los (from booklet) [but are for Dr shovlins lec which isn’t
online either]:
Lecture 12: Hypoxia (Dr Claire Shovlin, c.shovlin@imperial.ac.uk)
At the end of this lecture you should be able to:
(i.e. the O2 and CO2 dissociation curves), and factors affecting these curves with particular reference
to oxygen uptake in the lung and the downloading of oxygen in the tissues.
delivery to tissues and
oxygen consumption; and the development of tissue hypoxia when delivery fails to meet demand
with onset of anaerobic metabolism (lactic acid production)
igh altitude
There is an accompanying computer aided learning quiz which you can run through with Dr Shovlin
which will assist your understanding of:
rventilation, distinguishing hyperventilation from the „hyperpnoea‟ of
exercise.
-pulmonary capillary PO2 and PCO2.
Explain the consequences of this for systemic arterial PO2 and PCO2.
l) a reduction in Hb concentration in the blood (anaemia) affects PaO2, PaCO2 and
oxygen content.
-enriched gas mixture in correcting any
abnormalities associated with anaemia.
affects PaO2, PaCO2 and oxygen content, explaining the effectiveness (or lack
of it) of breathing an oxygen-enriched gas mixture in correcting any abnormalities associated with
hypoventilation.
NB:
lood Gases
Notes:
-
Humidification:
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o
o
o
The alveoli of the lung must be kept moist, forotherwise respiratory exchanges
cannot be carried on; the origin of this necessity is to be found in fish which left
the sea to pass part of their lives on land
Cold air cannot carry much moisture; therefore. if the air reaching the larynx is to
be almost saturated with moisture it must first be warmed to bring its potential
absolute humidity to a high level. Having warmed the inspired current, the nose
can then charge it with the required amount of water
Similarly, the higher the altitude the less moisture the air can hold; therefore this
is a further challenge when trying to keep alveoli moist to allow gas exchange
when at altitude
-
Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates
in general and in almost all mammals. It is related to hemoglobin, which is the iron- and
oxygen-binding protein in blood, specifically in the red blood cells. Myoglobin is only found
in the bloodstream after muscle injury. It is an abnormal finding, and can be diagnostically
relevant when found in blood
o Is not affected by 23DPG
-
Oxygen disociation haemaglobin curve to the left:
o increase pH,
o decrease oCO2,
o decrease temperature
o decrease 2,3,DPG
To the right:
o decrease pH
o increase co2
o increase temperature
o increase 2,3 DPG
-
-
Half of airway resistance lies in the nose, pharynx and larynx
2,3 DPG lowers the affinity of o2 for haemalgobin
O2 binding to Hb releases H+ due to conformational changes in the Hb
-
The Bohr effect is a physiological phenomenon first described in 1904 by the Danish
physiologist Christian Bohr, stating that hemoglobin's oxygen binding affinity is inversely
related both to acidity and to the concentration of carbon dioxide
-
The Haldane effect: oxygenated blood has a reduced capacity for carbon dioxide.
(Conversely, Deoxygenation of the blood increases its ability to carry carbon dioxide; this
property is the Haldane effect)
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-
Foetal Hb: Functionally, fetal hemoglobin differs most from adult hemoglobin in that it is
able to bind oxygen with greater affinity (ie shift to left) than the adult form, giving the
developing fetus better access to oxygen from the mother's bloodstream.
-
General possibilities for forms of gas in the blood:
o Dissolved gas
 only dissolved gas molecules contribute to the partial pressure
 N2 is only carried in this form
o Bound gas
 Eg O2, CO2, CO
o Chemically modified gas
 EG CO2  HCO3-
-
(Bohr: left to right; Haldene: right to left)
-
Bohr effect:
- Affinity of hemoglobin to O2 decreases when pH of blood falls / co2 inc
- Facilitates release of O2 in tissues: Increased CO2 in blood --> Increased H+ production -> H+ binds to deoxyhemoglobin --> accesibility of O2 to Hemoglobin decreases --> O2
released
-
Haldene effect:
- Binding of 02 with Hemoglobin tends to displace CO2 from blood (opposite of Bohr's
effect)
- Facilitates release of CO2 in lungs: HHb + O2 --> HbO2 + H+; H+ + HCO3- --> CO2 + H20
-
Methods of CO2 transport in the blood: CO2 is carried in blood in three different ways. (The
exact percentages vary depending whether it is arterial or venous blood):
o 10% is dissolved in the plasma,
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o
o
5% – 10% is bound to hemoglobin as carbamino compounds.
 Hemoglobin, the main oxygen-carrying molecule in red blood cells, carries
both oxygen and carbon dioxide. However, the CO2 bound to hemoglobin
does not bind to the same site as oxygen. Instead, it combines with the Nterminal groups on the four globin chains. [carbaminoheamoglobin; nb
carboxyhaemoglobin is different and is the binding of CO to HB]. However,
because of allosteric effects on the hemoglobin molecule, the binding of
CO2 decreases the amount of oxygen that is bound for a given partial
pressure of oxygen. The decreased binding to carbon dioxide in the blood
due to increased oxygen levels is known as the Haldane effect, and is
important in the transport of carbon dioxide from the tissues to the lungs. A
rise in the partial pressure of CO2 or a lower pH will cause offloading of
oxygen from hemoglobin, which is known as the Bohr effect.
Most of it (about 70% to 80%) is converted to bicarbonate ions HCO−3 by the
enzyme carbonic
anhydrase in the red blood cells, by the reaction CO2 +
H2O → H2CO3 → H+ + HCO−
 In the tissues, CO2 is produced from aerobic metabolism. CO2 then diffuses
across the cell membranes and across the capillary wall, into the red blood
cells. The transport of CO2 across each of these membranes occurs by
simple diffusion, driven by the partial pressure gradient for CO2.
 2. Carbonic anhydrase is found in high concentration in red blood cells. It
catalyzes the hydration of CO2 to form H2CO3. In red blood cells, the
reactions are driven to the right by mass action because CO2 is being
supplied from the tissue.
 3. In the red blood cells, H2CO3 dissociates into H+ and HCO3-. The H+
remains in the red blood cells, where it will be buffered by
deoxyhemoglobin, and the HCO3 is transported into the plasma in
exchange for Cl (chloride).
 4. If the H+ produced from these reactions remained free in solution, it
would acidify the red blood cells and the venous blood. Therefore, H+ must
be buffered so that the pH of the red blood cells (and the blood) remains
within the physiologic range. The H+ is buffered in the red blood cells by
deoxyhemoglobin and is carried in the venous blood in this form.
Interestingly, deoxyhemoglobin is a better buffer for H+ than
oxyhemoglobin: By the time blood reaches the venous end of the capillaries,
hemoglobin is conveniently in its deoxygenated form (i.e., it has released its
O2 to the tissues). There is a useful reciprocal relationship between the
buffering of H by deoxyhemoglobin and the Bohr effect. The Bohr effect
states that an increased H concentration causes a right shift of the O2hemoglobin dissociation curve, which causes haemoglobin to unload O2
more readily in the tissues; thus, the H generated from tissue CO2 causes
hemoglobin to release O2 more readily to the tissues. In turn,
deoxygenation of hemoglobin makes it a better buffer for H.
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

-
5. The HCO3 produced from these reactions is exchanged for Cl across the
red blood cell membrane (to maintain charge balance), and the HCO3 is
carried to the lungs in the plasma of venous blood. Cl-HCO3 exchange, or
the Cl shift, is accomplished by an anion exchange protein called band three
protein (so called because of its prominence in an electrophoretic profile of
blood).
All of the reactions previously described occur in reverse in the lungs
Diffusion vs perfusion limited:
o Diffusion-limited gas exchange:
 means that the total amount of gas transported across the alveolarcapillary
barrier is limited by the diffusion process. In these cases, as long as the
partial pressure gradient for the gas is maintained, diffusion will continue
along the length of the capillary.
 Eg
 CO
 O2 during strenuous exercise / emphysema / fibrosis
o Perfusion-limited gas exchange
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

means that the total amount of gas transported across the alveolar/capillary
barrier is limited by blood flow (i.e., perfusion) through the pulmonary
capillaries. In perfusion-limited exchange, the partial pressure gradient is not
maintained, and in this case, the only way to increase the amount of gas
transported is by increasing blood flow
Eg
 N2O
 CO2
 O2 under normal conditions
 O2 at altitude [unless compounded by exercise / emphysema /
fibrosis]
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-
Exercise:
o Adaptations during exercise:
 Increased alveolar ventilation
 Increased cardiac output
 Hb is near the O2 of the alveoli 3x longer than is necessary while
person is at rest so the cardiac output can be increased without
reduction in O2/Hb binding events
 Recruitment of upper lobe capillaries
-
High altitude;
o Potential pathologies:
 HAPE
 Cerebral oedema
o Adaptations at altitude:
 Increased ventilation
 Increased RBC levels
 Increased diffusion capacity of lungs [referring to lobe recruitment?]
 Increased vascularity: more capillaries
 Increased ability of cells to utilise O2: increased glycolysis and aerobic
metabolism
-
Hypoventilation:
o Neuromuscular disease
o Obstructive/restrictive respiratory disease
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Resp failure:
o Type I
 Hypoxaemia (low PaO2) with normal PaCO2
 Occurs because CO2 has a lower solubility coefficient so provided it is not a
breathing problem / hypoventilation the blood CO2 levels will be normal
 Eg pneumonia, anaemia, pulmonary fibrosis
 It is often caused by a ventilation/perfusion (V/Q) mismatch; the volume of
air flowing in and out of the lungs is not matched with the flow of blood to
the lungs.
 Eg. Pulmonary embolism
o Type II:
 Both O2 and CO2 blood levels are affected:
 Emphysema: gives direct loss of SA so will affect the transfer of both gases
 Anything causing hypoventilation
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13/12/13: Airways I: Asthma and COPD: Philip W Ind
Los (from booklet): [are combined Lec20/21 Los]:
Lectures 20 and 21: Airways Disease. (Dr Philip Ind p.ind@imperial.ac.uk)
At the end of these lectures you should be able to understand and describe.....
t of airflow obstruction –distinction from restriction
-responsivenesss
utrophilia
-COPD overlap
Notes:
-
Preview:
o
o
o
o
o
o
o
o
airways obstruction -distinction from restriction
spirometry, peak flow (PEF), other measurements
asthma -clinical importance, diagnosis
atopy, asthma triggers, bronchodilator response
sputum eosinophilia
COPD -clinical importance, diagnosis
Asthma/COPD overlap
practical management; treatment Guidelines
-
Asthma and COPD:
o Asthma is a disease of the upper airways whereas COPD is a disease of the lower
airways
-
ASTHMA
o
o
o
o
5.2 million in Britain
↑prevalence 8-fold in 30 y
1381 deaths in 2004 including 40 children <14 y
Costs £889 m per year; 12.7 million working days lost /year
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o
o
o
o
o
10-fold difference in prevalence in different countries eg UK vs Indonesia/Albania
‘Western life-style’
low prevalence in rural areas (farm animals, unpasteurized milk)
large family size, house-hold pets in urban areas  protective
‘hygiene hypothesis’
boys > girls, women >men [more boys than girls have asthmain childhood, yet
more adult women than men are afflicted with asthma]
o
Variability:
 typically young atopic individuals but also older non-atopic patients: have no
such allergies and the cause of their airway inflammation is unclear
[Asthma may be classified as atopic (extrinsic) or non-atopic (intrinsic)
where atopy refers to a predisposition toward developing type 1
hypersensitivity reaction]
 In both family history and due to rhinitis [inflammation of the inside of the
nose caused by an allergen]
 Variable ‘triggers’: URTI [upper resp tract infection]; house dust; pollen;
animal fur; exercise; cold air; pollution
 Variable suspected causes: obesity; atopy; smoking; aspirin-induced
asthma; occupational asthma
 eosinophilic vs non-eosinophilic
 variable symptoms
 Variable degree of airflow obstruction / severity
 mixed disease: asthma/COPD overlap
o
Asthma symptoms [variability exists]
 wheeze
 breathlessness
 chest tightness
 cough (phlegm)
 nocturnal and early morning symptoms
o
Diagnosis of asthma
 typical symptoms
 atopic ‘background’
 reversible airway narrowing
 bronchodilator response
 bronchial challenge gives response (re spirometry see below)
 airway inflammation: ↑eosinophils in sputum (induced)
o
o
o
hyper-responsivity to various stimuli occurs
characteristic airway inflammation; mast cells localise to smooth muscle
corticosteroid responsive; help treat bronchial hyperresponsiveness [easily
triggered bronchospasm]
b2 agonists; Long acting b2 agonists: give bronchodilation [nb salbutamol]
o
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o
Aspects contributing to the narrowing: [see image below]
 Smooth muscle contraction [if atopic is via allergen  imm cells 
mediators  nerves  bronchoconstriction]
 Increased bronchial smooth muscle: enlarged smooth muscle blocks lying
relatively close to the surface epithelium.
 Epithelial shedding / damage [even when feeling well]
 Inflammation and oedema
 Mucus hypersecretion and plasma exudation
 Mucus plugging can occur: Excessive mucus production admixed
with inflammatory exudate forming highly tenacious plugs which
block airways and are difficult to clear
 Gives reduced gas exchange and can cause death
o
Spirometry:
 Spirometers
 FEV1 measuring tubes
 Results typical of obstructive disease:
 Low FEV1; also: exercise induced fall in FEV1
 Normal FVC
 Low FEV1 / FVC
 Bronchodilators improve results
 A bronchial challenge test is a medical test used to assist in the diagnosis of
asthma.[1] The patient breathes in nebulized methacholine or histamine.
Thus the test may also be called a methacholine challenge test or histamine
challenge test respectively. Both drugs provoke bronchoconstriction, or
narrowing of the airways. The degree of narrowing can then be quantified
by spirometry. People with pre-existing airway hyperreactivity, such as
asthmatics, will react to lower doses of drug.
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Airway obstruction vs lung restriction
o Obstruction: ↓FEV1/VC ratio, (↓flow): asthma COPD
o Restriction: ↓lung volumes (ratio may be ↑): pulm fibrosis; pleural, chest wall or
resp muscle disease
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13/12/13: Airways II: Asthma and COPD: Philip W Ind
Los (from booklet): [are combined Lec20/21 Los]:
Lectures 20 and 21: Airways Disease. (Dr Philip Ind p.ind@imperial.ac.uk)
At the end of these lectures you should be able to understand and describe.....
ruction –distinction from restriction
-responsivenesss
ma-COPD overlap
Notes:
-
-
Preview:
o
o
o
o
o
o
o
o
o
o
Asthma vs COPD clinically
Importance of these conditions
Diagnosis
Asthma ‘triggers’
Bronchodilator response
Airway hyper-responsivenesss
Sputum eosinophilia and neutrophilia
Asthma-COPD overlap
Practical management
Introduction to Guidelines for asthma and COPD
Asthma Genetics
o Complex: >100 genes implicated: IgE, BHR: bronchial hyperresponsiveness
o twin studies heritability 0.36-0.77: therefore ~50% environmental
o positional cloning: ADAM33, PHF11, DPP10, GRPA, SPINK5
o candidate genes:
TLRs, epithelium, beta2 receptor, Th1, Th2, cytokines eg IL4,
IL5, IL13, T factors, GATA 3, STAT6, FCERIB
o early onset: ORMDL3, GSDML chr 17q21 signal,PDEAD chr 5q12, DENNDIB chr
1q31
o late onset: MHC genes
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Atopy:
o
o
o
o
eczema, hay fever, asthma: = increased IgE
skin prick test can be used to determine atopy
 Many asthmatic patients give a positive skin prick test to a number of
allergens, all of which may contribute to their condition
Serum can be analysed to determine IgE levels
as mentioned atopic young people are a major subset of asthmatics
-
Inhaled corticosteroids: cornerstone of asthma Rx [Rx = prescription drug]
o Inc lung function
o
o Inc bronchial responsiveness
o Inc FEV1
o Dec Ag-induced bronchoconstriction
o Dec asthma exacerbations
o
o Dec airway inflammation
o ? prevent lung damage
-
inhaled corticosteroid and long-acting beta agonist (ICS/LABA) combination products:
[convenient etc to use as combined inhaler]
o ICS
 improve symptoms, lung function, quality of life
 reduce exacerbations
o LABA
 improve FEV1, symptoms, quality of life
 reduce exacerbations
-
Leukotriene antagonists in asthma
o effective in mild asthma
o particularly NSAID-induced asthma
o modest effects in more severe asthma
o useful for nasal allergy (with asthma)
o oral, well tolerated
o few adverse effects
o differential use in different countries
-
THEOPHYLLINE
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o
o
o
o
o
non-specific phosphodiesterase inhibitor
 competitive nonselective phosphodiesterase inhibitor, which raises
intracellular cAMP, activates PKA, inhibits TNF-alpha and inhibits leukotriene
synthesis, and reduces inflammation and innate immunity
oral bronchodilator (large and small airways)
anti-inflammatory
beneficial effects on respiratory muscles & heart failure
BUT poorly tolerated, variable pharmacokinetics and other interactions
-
Acute severe asthma
o immediate Rx
o reassurance
o oxygen
o high dose inh/neb salbutamol
o oral prednisolone or IV hydrocortisone
o high dose inh/neb ipratropium
o IV Mg++ hydration, replace K+
o consider IV aminophylline (IV salbutamol)
o ITU mechanical ventilation
LIFE SAVING (rare)
-
asthma syndrome-related Asthma comorbidities:
o rhinosinusitis
o atopic dermatitis
o asthma disease-related
o small airways disease
o bronchiectasis
o Gastro Oesophageal Reflux
o Obesity
o Obstructive Sleep Apnoea
-
COPD:
o
o
o
Chronic obstructive pulmonary disease (COPD) is a disease state characterized by
airflow limitation that is not fully reversible. The airflow limitation is is usually
both progressive and associated with an abnormal inflammatory response of the
lungs to noxious particles and/or gases
May involve:
 chronic bronchitis
 emphysema
 small airways disease
Facts:
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o
 most common respiratory disease in UK
 4th leading cause of death
 costs ~£1billion/y in UK [twice asthma]
 largely preventable [90% due to smoking]
 often undiagnosed [~50% ‘missing millions’]
 10-15% die within 3/12 of hospital admission
Mechanism:
 oxidative stress
 protease/anti-protease imbalance



o
NOXIOUS AGENTs can play role
 eg tobacco smoke, pollutants, occupational exposure
Genetic factors can play role
 a1-anti-trypsin deficiency: recesssive inheritance 1% of all COPD
o Alpha 1-antitrypsin (A1AT) is produced in the liver, and one
of its functions is to protect the lungs from neutrophil
elastase [nb neutrophil levels are high in COPD], an enzyme
that can disrupt connective tissue: in individuals with the
PiZZ phenotype, A1AT levels are less than 15% of normal,
and patients are likely to develop panacinar emphysema at
a young age
 Is also mentioned in the alimentary course
Respiratory infection can play role
Symptoms in COPD
 shortness of breath -progressive
 exercise/lifestyle limitation
 cough+/- phlegm
 difficulty producing phlegm
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





wheeze
chest tightness
nocturnal or early morning symptoms
[spirometry typical of obstructive]
[the emphysema can give air trapping]
[stopping smoking helps; see image below]
-
COPD co-morbidities related to smoking
o ischaemic heart disease
o lung cancer
o peripheral vascular disease
o osteoporosis
-
Treatment of COPD
o bronchodilators (anticholinergic or long acting β2-agonist)
 Tiotropium bromide: once daily inhaled cholinergic M3 receptor antagonist:
 ↑ lung function ↑quality of life ↑exercise endurance
 ↓breathlessness ↓hyperinflation
 ↓ exacerbations (↓hospitalisations over 12 months
o inhaled steroids (for FEV1 <50%)
o theophylline
o STOP SMOKING
o [ie Combination ICS/LABA therapy is used in COPD too (TRUE)]
-
Acute severe COPD [is same as for asthma]
o immediate Rx
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o
o
o
o
o
o
o
o
-
COPD:
o
o
o
o
reassurance
oxygen
high dose inh/neb salbutamol
oral prednisolone or IV hydrocortisone
high dose inh/neb ipratropium
IV Mg++ hydration, replace K+
consider IV aminophylline (IV salbutamol)
ITU mechanical ventilation
LIFE SAVING (rare)
 Non-invasive ventilation used involving mask
 ↑ gas exchange
 Normalises breathing
 ↓ diaphragm activity
Determining if there is a Aa gradient:
 The alveolar gas equation can be used to calculate PAO2, if the PIO2, PACO2,
and respiratory quotient are known. PIO2 is calculated from the barometric
pressure (corrected for water vapor pressure) and the percent O2 in inspired
air (21%). PACO2 is equal to PaCO2, which is given. The respiratory quotient
is assumed to be 0.8. We are told that PaO2 ; 60 mm Hg (normal; 100 mm
Hg)
Since the measured PaO2 (60 mm Hg) is much less than the calculated PAO2 (113
mm Hg), there must be a mismatch of ventilation and perfusion. Some blood is
perfusing alveoli that are not ventilated, thereby diluting the oxygenated blood
and reducing arterial PO2.
The man’s PaCO2 is lower than normal because he is hyperventilating and blowing
off more CO2 than his body is producing. He is hyperventilating because he is
hypoxemic. His PaO2 is just low enough to stimulate peripheral chemoreceptors,
which drive the medullary inspiratory center to increase the ventilation rate. His
arterial pH is slightly alkaline because his hyperventilation has produced a mild
respiratory alkalosis.
The man’s FEV1 is reduced more than his vital capacity; thus, FEV1/FVC is
decreased, which is consistent with an obstructive lung disease in which airway
resistance is increased. His barrel-shaped chest is a compensatory mechanism for
the increased airway resistance: High lung volumes exert positive traction on the
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airways and decrease airway resistance; by breathing at a higher lung volume, he
can partially offset the increased airway resistance from his disease.
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Comparisons of asthma & COPD:
o COPD differs from asthma in both the type of inflammation involved and in the
pattern of respiratory symptoms caused
o Physiologically severe asthma resembles COPD
o Overlap occurs in terms of the patients: ~10-20% of patients have both conditions
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Treatments common to Asthma + COPD
o beta2 agonist relievers
o inhaled steroids
o long-acting beta2 agonists
o inhaled combinations (ICS/LABA)
o theophylline in severe disease
o tiotropium
o prednisolone for exacerbations
o omalizumab (anti-IgE)
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Summary
o
o
o
o
o
o
o
o
o
Airway obstructive diseases are common
Asthma is common in young, atopic people but occurs at any age
COPD -in smokers almost exclusively
Asthma & COPD can co-exist
inhaled therapy preferred as far as possible
a multitude of inhaler devices
Asthma Nurse specialists important in management esp in 10 care
Self Management Plans in asthma (also in COPD)
short acting beta2 agonists as ‘reliever’ bronchodilators
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o
o
o
o
o
o
o
o
o
o
o
o
o
inhaled steroids in asthma and more severe COPD
long-acting beta2 agonists (LABAs) in asthma and COPD
combination ICS/LABA inhalers in widespread use in asthma + COPD
long-acting antimuscarinic (LAMA) tiotropium (Spiriva) in COPD
tiotropium also in uncontrolled asthma
anti-leukotrienes effective in mild asthma
theophylline effective in severe asthma and COPD
anti-IgE (omalizumab) in very selected, severe allergic asthma
Respiratory Nurse specialists and integrated care evolving
exacerbations of asthma + COPD common
severe exacerbations of asthma + COPD common, life-threatening
require hospital management
Pulmonary Rehabilitation very cost-effective medical intervention
COMMS C TUTORIAL :
14/01/14
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The altitude, diving, sleep, coughing are prob unlikely to play big part; just odd question
Says our new course convenor will stick to Los; really need to cheack that I have covered
than all
For him the SAQ was worth 10 marks and was split into multiple parts worth ~2 marks each;
may be more than 1 now as have been doing for a few years; likely topics for that Q/Qs are:
o Blood gases scenario [was his one]
o Asthma and COPD
o Resp failure case study
 If asked how would manage such a very ill patient should start with the
basics before any specifics:
 “first take an ABCDE approach”
 Give O2
 Lifestyle: eg stop smoking
 ……then any specifics
Diaphragm will inc intra ab pressure during inhale
Pneumothorax = air in pleural space
Surface tension is the molecules of water on alveoli attracting each other
Surfactant produced at 25-26 weeks ie at end of pseudoglandular stage
Bronchioles can constrict: think pouseille’s law
Physiological deadspace def: air inside body but unable to contribute to gas exchange
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Physiological deadspace = alveolar deadspace + anatomic deadspace
Men TLC = 6L; women TLC = 4.7L
Obstructive: bronchiectasis, cancer, asthma, COPD/emphysema
Restrictive: mesothelioma, obesity, infection (eg pneumonia), pregnancy, kyphoscoliosis,
fibrosis
FVC defined as max exp after max insp
FEV1/TLC = 0.8; V/Q = 0.8
Exp typically passive therefore explaining why obstructive disease is mainly a problem of
expiration
Curve right shift: hyperthermia, hypercapnia, acidosis
o Cells working hard; require better release at tissues
Curve left shift: hypothermia, hypocapnia, alkylosis
o Cells don’t need more O2; dec release at tissues / uptake at lungs will occur
Nb paO2 is highly dependent on the barometric pressure; normally is 760 so can achieve 100
but altitude compounded with mixing with air of high CO2 conc from prev breath means
pAO2 can then start to fall below 100 meaning paO2 will too; or even lower than the PAO2 if
there is a diffusion defect / altitude&exercise makes transfer perfusion limited
o Note that the mixing drop means that at altitude the paO2 will never get up to
barometric partial pressure (cannot equate these)
ABG = arterial blood gases:
o Lactate normally <2mmol/L
o Can distinguish chronic meta/resp conditions by the pH: the compensation is
never complete and never overshoots so if acidic then was always an acidosis
o Hypoventilation: neuro, MS, drug (barbiturates, alcohol, benzodiazapenes,
opiates, anaesthetics), MG, muscle wasting, restrictive lung diseases
o Hyperventilation: pain, panic, anaemia
o Vomiting  alkylosis mech: are losing Cl from HCl so body holds onto another
anion: HCO3-  alkylosis
o “anion gap”; will be covered in renal; cations minus anions but only Na K CL, HCO3
looked at so if gap may be ketones (ie more neg ions that the Na/K must be
balancing)
1-2% of the left heart's output traverses the bronchial circulation.
HPV in one area prob gives more even zonal distribution of perfusion though the
paralleled underperfusion and overperfusion of diff alveoli through lung will give dec paO2
(ie the overperfusion will not yield any compensation of low O2 elsewhere as 100%
saturationis max)
Muscarinic antagonists could be used in asthma but are not as are never necessary; other
drugs do the job
Cancer general symptoms:
o Night sweats
o Weight loss
o Fatigue
TI RF said to be associated with VQ mismatch (ie underperfusion at some areas,
overperfusion elsewhere)
TII RF said to be associated with hypoventilation
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COPD and asma can be either class, just depends on the specific patient
Failure symptoms:
o Cyanosis/palor
o Accessory muscle use
o SOB
o Nasal flaring
o Pursing lips if COPD
 Pursing helps move the end pressure point BUT:
Positive end-expiratory pressure can contribute to:
 Decrease in systemic venous return
 Pulmonary barotrauma can be caused. Pulmonary barotrauma is
lung injury that results from the hyperinflation of alveoli past the
rupture point.
 Increased intracranial pressure — In people with normal lung
compliance, PEEP may increase the intracranial pressure (ICP) due to
an impedance of venous return from the head.[7]
 Renal functions and electrolyte imbalances, due to decreased
venous return metabolism of certain drugs are altered and acidbase balance is impeded
SUMMARY:
Lung volumes and capacities are measured with a spirometer (except for those volumes and
capacities that include the residual volume).
Dead space is the volume of the airways and lungs that does not participate in gas exchange.
Anatomic dead space is the volume of conducting airways. Physiologic dead space includes
the anatomic dead space plus those regions of the respiratory zone that do not participate in
gas exchange.
The alveolar ventilation equation expresses the inverse relationship between PACO2 and
alveolar ventilation. The alveolar gas equation extends this relationship to predict PAO2.
In quiet breathing, respiratory muscles (diaphragm) are used only for inspiration; expiration
is passive.
Compliance of the lungs and the chest wall is measured as the slope of the pressure-volume
relationship. As a result of their elastic forces, the chest wall has a tendency to spring out,
and the lungs have a tendency to collapse. At FRC, these two forces are exactly balanced,
and intrapleural pressure is negative. Compliance of the lungs increases in emphysema and
with aging. Compliance decreases in fibrosis and when pulmonary surfactant is absent.
Surfactant, a mixture of phospholipids produced by type II alveolar cells, reduces surface
tension so that the alveoli can remain inflated despite their small radii. Neonatal respiratory
distress syndrome occurs when surfactant is absent.
Airflow into and out of the lungs is driven by the pressure gradient between the atmosphere
and the alveoli and is inversely proportional to the resistance of the airways. Stimulation of
b2-adrenergic receptors dilates the airways, and stimulation of cholinergic muscarinic
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receptors constricts the airways. Diffusion of O2 and CO2 across the alveolar/pulmonary
capillary barrier is governed by Fick’s law and driven by the partial pressure difference of the
gas. Mixed venous blood enters the pulmonary capillaries and is “arterialized” as O2 is
added to it and CO2 is removed from it. Blood leaving the pulmonary capillaries will become
systemic arterial blood.
Diffusion-limited gas exchange is illustrated by CO and by O2 in fibrosis or strenuous
exercise. Perfusion- limited gas exchange is illustrated by N2O, CO2, and O2 under normal
conditions.
O2 is transported in blood in dissolved form and bound to hemoglobin. One molecule of
haemoglobin can bind four molecules of O2. The sigmoidal shape of the O2-hemoglobin
dissociation curve reflects increased affinity for each successive molecule of O2 that is
bound. Shifts to the right of the O2-hemoglobin dissociation curve are associated with
decreased affinity, increased P50, and increased unloading of O2 in the tissues. Shifts to the
left are associated with increased affinity, decreased P50, and decreased unloading of O2 in
the tissues. CO decreases the O2-binding capacity of hemoglobin and causes a shift to the
left.
CO2 is transported in blood in dissolved form, as carbaminohemoglobin, and as HCO3. HCO3
is produced in red blood cells from CO2 and H2O, catalyzed by carbonic anhydrase. HCO3 is
transported in the plasma to the lungs where the reactions occur in reverse to regenerate
CO2, which then is expired.
Pulmonary blood flow is the cardiac output of the right heart, and it is equal to the cardiac
output of the left heart. Pulmonary blood flow is regulated primarily by PAO2, with alveolar
hypoxia producing vasoconstriction.
Pulmonary blood flow is unevenly distributed in the lungs of a person who is standing: Blood
flow is lowest at the apex of the lung and highest at the base. Ventilation is similarly
distributed, although regional variations in ventilatory rates are not as great as for blood
low. Thus, V/Q is highest at the apex of the lung and lowest at the base, with an average
value of 0.8. Where V_/Q_ is highest, PaO2 is highest and PaCO2 is lowest.
V/_Q defects impair gas exchange. If ventilation is decreased relative to perfusion, then
PaO2 and PaCO2 will approach their values in mixed venous blood. If perfusion is decreased
relative to ventilation, then PAO2 and PACO2 will approach their values in inspired air.
Breathing is controlled by the medullary respiratory center, which receives sensory
information from central chemoreceptors in the brain stem, from peripheral
chemoreceptors in the carotid and aortic bodies, and from mechanoreceptors in the lungs
and joints. Central chemoreceptors are sensitive primarily to changes in the pH of CSF, with
decreases in pH causing hyperventilation. Peripheral chemoreceptors are sensitive primarily
to O2, with hypoxemia causing hyperventilation.
During exercise, the ventilation rate and cardiac output increase to match the body’s needs
for O2 so that mean values for PaO2 and PaCO2 do not change. The O2-hemoglobin
dissociation curve shifts to the right as a result of increased tissue PCO2, increased
temperature, and decreased tissue pH.
At high altitude, hypoxemia results from the decreased PO2 of inspired air. Adaptive
responses to hypoxemia include hyperventilation, respiratory alkalosis, pulmonary
vasoconstriction, polycythemia, increased 2,3-DPG production, and a right shift of the O2hemoglobin dissociation curve.
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Hypoxemia, or decreased PaO2, is caused by high altitude, hypoventilation, diffusion
defects, _ V/_Q defects, and right-to-left shunts. Hypoxia, or decreased O2 delivery to
tissues, is caused by decreased cardiac output or decreased O2 content of blood.
DL / TL


First CO crosses the alveolar capillary membrane (represented by
) and then CO
combines with the hemoglobin in capillary red blood cells at a rate times the volume of
capillary blood present ( ).[13] Since the steps are in series, the conductances add as the
sum of the reciprocals:

.
The volume of blood in the lung capillaries, ,
o changes appreciably during ordinary activities such as exercise [inc thoracic pressure
o
o
and inc Cardiac output]. Thus
will appear to increase when the subject is not
at rest [nb in the case of CO in addition to the inc in blood vol to enter (and
therefore improved VQ matching) (ie by both diffusion and HB-binding in the case of
this measure for CO) there is also an increase to Dl due to improved flow (because
CO is diffusion limited – ie this component will not be reflected in a comparable
DlO2 measure
The lung blood volume is also reduced when blood flow is interrupted by blood clots
(pulmonary emboli) or reduced by bone deformities of the thorax, for
instance scoliosisand kyphosis.
In disease, hemorrhage into the lung will increase its hemoglobin content, and so
increase
o

.
Finally,
is increased in obesity and when the subject lies down, both of which
increase the blood in the lung by compression and by gravity and thus both
increase
The rate of CO uptake into the blood, ,
o depends on the concentration of hemoglobin in that blood, abbreviated Hb in the
CBC (Complete Blood Count). More hemoglobin is present in polycythemia, and
o
so
is elevated. In anemia, the opposite is true. In environments with high
levels of CO in the inhaled air (such as smoking), a fraction of the blood's
hemoglobin is rendered ineffective by its tight binding to CO, and so is analogous to
anemia.
Varying the ambient concentration of oxygen also alters . At high altitude, inspired
oxygen is low and more of the blood's hemoglobin is free to bind CO; thus is
increased and
appears to be increased. Conversely, supplemental oxygen
increases Hb saturation, decreasing
 Lung diseases that reduce
and
and
.
[edit]
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Diseases that alter lung tissue reduce both
and
to a variable extent, and so
decrease
.
o Loss of lung parenchyma in diseases like emphysema.
o Diseases that scar the lung (the interstitial lung disease), such as idiopathic
pulmonary fibrosis, or sarcoidosis
o Swelling of lung tissue (pulmonary edema) due to heart failure, or due to an acute
inflammatory response to allergens (acute interstitial pneumonitis).
o Diseases of the blood vessels in the lung, either inflammatory (pulmonary vasculitis)
or hypertrophic (pulmonary hypertension).
 Lung conditions that increase
o
o
.[edit]
[15]
Alveolar haemorrhage, polycythemia, left to right intracardiac shunts,[16] due
increase in volume of blood exposed to inspired gas.
Asthma due to better perfusion of apices of lung. This is caused by increase in
pulmonary arterial pressure and/or due to more negative pleural pressure
generated during inspiration due to bronchial narrowing.[17]
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BONUS:
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Asthma:
o Running out of breath before the end of a sentence, together with a PEFR 33-50%
of predicted and HR > 110/min is consistent with a severe attack of asthma.
o SaO2 < 75% on air suggests a life-threatening asthma attack which should prompt
immediate referral to ITU.
BP 90/60 mmHg and Inaudible air entry bilaterally indicate hypotension
Costochondritis = presents as severe, sharp pain radiating from anterior (typically ribs 2-5)
to posterior.
o A 21-year-old woman has had left-sided chest pain for a week, sharp in nature and
worse on inspiration. The left medial border of her sternum is tender but her chest is
otherwise clear.
Myocardial infarction = pain would be on exertion not inspiration and rare in the young
Pulmonary embolus = would present with tachycardia with possible hypoxia (cyanosis) and
breathlessness / tachypnea, chest pain (worsened by breathing), cough / hemoptysis.
The British Thoracic Society suggest that hospital admission should be seen as an ideal
opportunity to review patients’ self-management skills to improve long-term asthma
control: Write a plan of how and when to take the inhalers
Pneumothorax = is the most likely cause of sudden pain with breathlessness in young males.
The PO2 inside skeletal muscle cells during exercise is closest to 3mm Hg
Clara cells have microvilli, and secrete products that are protective to the bronchial
epithelium
In health, physiological deadspace should equal anatomical deadspace at approx. 150ml (ie
no alveolar deadspace)
The most important stimulus controlling the level of resting ventilation is pH of CSF on
central chemoreceptors [NOT: PCO2 on central chemoreceptors: ie PCO2 exerts its control
mainly by acting via pH changes]
Important subtleties of central chemosensors at medulla:
o detect the changes in pH of CSF but are not sensitive to change in plasma pH
because H+ are not able to diffuse across the blood–brain barrier into the CSF. Only
CO2 levels affect this as it can diffuse across, reacting with H2O to form carbonic
acid and thus decrease pH of CSF.
o Ie central chemosensors sensitive to pCO2 only but detect pH changes only
Hantaviruses are a class of viruses which famously cause Hanta Cardiopulmonary Syndrome
(HCPS) and Haemorrhagic fever and Renal syndrome (HFRS). In the case of HCPS most
patients present ARDS and pulmonary oedema.
Influenza can cause rapidly- progressive pneumonia ± ARDS
FiO2 stands for fraction (F) of inspired (i) oxygen (O2). It is expressed as a number without
unit from 0.0-1.0. The normal value in the atmosphere is 0.21 (21%). It does not vary with
altitude unlike partial pressure of inspired oxygen (PiO2).
o At the presence of right-to-left shunting (V/Q mismatch), SaO2 might not respond
to an increasing FiO2.
o It may cause lung injury when >0.50
ARDS = PaO2:FiO2 ratio < 26.6. eg PaO2 = 8.0, FiO2 = 0.40 means ARDS
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The basal regions of the upright human lung are normally better ventilated than the upper
regions because the lower regions have a small resting volume and a relatively large increase
in volume.
Pulmonary surfactant
o Increases lung compliance
o Helps to prevent transudation of fluid from the capillaries into the alveolar spaces.
o Contributes to innate immunity
Concerning normal expiration during resting conditions flow velocity of the gas (in cm/sec)
in the large airways exceeds that in the terminal bronchioles
The most important factor limiting flow rate during most (by time) of a forced expiration
from total lung capacity is compression of airways
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