Suzie Rayner
Respiratory System 11 –
Control of breathing during sleep

Describe the effect of sleep on blood gases and the pattern of breathing in healthy
people
[Need to known
direction and
magnitude of
change, not
specific
numbers]
Summary




Sleep causes a 3-8mmHg increase in CO2 due to:
o Removal of wakefulness drive
o Reduction in hypercapnic ventilatory sensitivity
o Incomplete ventilatory compensation to increased upper airway resistance
Alveolar ventilation has the largest % decrease from awake to REM – due to only
using diaphragm and no accessory muscles to breathe during REM
Minute ventilation and Tidal volume also have a large % decrease
Frequency and Oxygen saturation remain fairly constant
Normally 3 systems control breathing – voluntary/behavioural, emotional,
reflex/automatic.
When asleep, only the reflex/automatic system (from the brainstem) controls breathing.

Specifically how sleep effects oxygen and carbon dioxide levels during sleep and
the mechanism that lead to these changes.
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3
6
9
12
15
PaO2 (KPa)

CO2 levels increase when asleep

This causes breathing to continue as become less sensitive to CO2 when asleep

Oxygen saturation decreases very slightly from awake to REM sleep.

Describe the apnoeic threshold which, in some people leads to central sleep
apnoea.
Patients will show a lack of ventilatory drive from the respiratory centres in the medulla
→ as become less responsive when asleep, there is less activity in muscles which leads to
sleep apnoea
Patients that breathe using accessory muscles as well as diaphragm have problems
breathing during REM as REM: paralysis except for diaphragm and eyelids.
Apnoeic threshold: level of CO2 that must be maintained, if the level drops below this
threshold then breathing will not be stimulated.
Central sleep apnoea:
No airflow and No effort.
Often affects stroke patients.
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
Describe the influences of sleep on the upper airway which, in some people leads
to obstructive sleep apnoea.
During sleep there is increased pharyngeal resistance, therefore more effort is required to
achieve the same amount of ventilation. There is also a reduction in muscle tone when
asleep.
Obstructive sleep apnoea:
 Generally occurs in obese people
 Occurs when the airway at the back of
the throat is sucked closed (due to
pressure drop during inspiration) when
breathing
No airflow, but continued effort to breathe
(obstructed so control systems are trying to
breathe, where as is central the control centres
are not receiving signals)

Know the other major cardio-respiratory diseases (one cardiac, one respiratory)
that are exacerbated by sleep-related changes in the control of breathing; briefly
explain why sleep is detrimental to these patients.
Congestive heart failure – some patients are very pCO2 sensitive, meaning they often
hyperventilate and have a low pCO2, leading to an increased likelihood of sleep-induced
central apnoea.
Stroke – damage occurred to brainstem (apneustic centre in lower pons), means that
input to the medullary inspiratory neurons (Pre-Botzinger C region) from the apneustic
centre does not get through → body does not respond to pCO2 dropping, once drops
below apnoeic threshold the inspiratory muscles are not stimulated and therefore do not
contract → stop breathing.
COPD – loss of elastic recoil in lungs, destruction of alveolar walls, therefore generally
more resistance to airflow and poorer gas exchange → patients are often hypoxic. As
ventilation decreases by 10-15% when asleep, the drop in pO2 can cause problems due to
already hypoxic state.
Respiratory system 12 –
Sensory aspects of respiratory disease
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General:

Understand how respiratory symptoms are generated and perceived
[Review of Neuro]

Discuss the importance of measuring respiratory symptoms are in clinical
medicine and clinical research
Cough – 3rd most common complaint to GP, 10-38% of resp outpatients complain of
cough
Chest pain – most common pain which people seek medical attention for (35%)
Dyspnea – 6-27% of general population, 3% of A and E visits
Important as respiratory symptoms are large proportion of symptoms which people seek
healthcare advice for.

Outline the clinical causes and the pathophysiological basis of the respiratory
symptoms: cough, chest pain and dyspnea. (Dyspnea will be covered in detail
in another presentation).
SEE FOLLOWING LEARNING OBJECTIVES
Cough:

Describe the mechanics of a cough with reference to inspiration, expiration
and closure of the glottis. Briefly explain how this manoeuvre serves to (i)
protect the lungs from inhaled noxious materials and (ii) clear excessive
secretions from the lower respiratory tract.
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


Crucial defence mechanism protecting lower resp tract from foreign material
and excessive mucous secretion
Usually secondary to mucociliary clearance but important if mucociliary
function is impaired or excess mucous is being produced
Expulsive phase of cough produces high velocity airflow which is facilitated by
bronchoconstriction and mucous secretion
Causes
Acute cough (% become chronic)
Acute infection :

Tracheobronchitis

Bronchopneumonia

Viral pneumonia

Acute-on-chronic bronchitis

Bordetella pertussis
Chronic infection:

Bronchiectasis (5%)

Tuberculosis

CF
Airway diseases:

Asthma (25%)

Chronic bronchitis (8%)

Chronic post-nasal drip
Parenchymal disease:

Interstitial fibrosis

Emphysema
Tumours:

Bronchogenic carcinoma

Alveolar cell carcinoma

Benign airway tumour
Foreign body
Cardiovascular:

LV failure

Pulmonary infarction

Aortic aneurysm
Other disease:

Reflux oesophagitis (25%)

Recurrent aspiration
Drugs:

Angiotensin converting enzyme (ACE) (1%)
Chronic – only mentioned in chronic
Post-viral (3%)
Idiopathic (10%)
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Other cause (3%)

Identify the type and location of sensory receptors with the airways indicating
how they are stimulated to give rise to cough. Identify the neural pathways
which transmit this afferent (sensory) neural information to the brain.
Sensory receptors in the airway:
Slow adapting irritant receptors (SASR):

located in airway smooth muscle

myelinated nerve fibres

predominantly in trachea and main bronchi

mechanoreceptors
C-fibre receptors:

free nerve endings

Larynx, trachea, bronchi, lungs

Small unmyelinated fibres

Chemoreceptors and inflammatory mediators stimulate

release neuropeptides inflammatory mediators
Rapidly adapting irritant receptors (RASR):

Naso-pharynx, larynx, trachea, bronchi

Small myelinated nerve fibred

Most numerous on posterior wall of trachea

Present at bifurcation of the trachea (carina) and branching points of main
airways → less numerous as become more distal (absent beyond bronchioles)

Mechano and chemoreceptors, also stimulated by inflammatory mediators
Afferent neural pathways for cough (involves rapidly adapting sensory receptors):



Stimulation of
RASR in
respiratory tract
Signals via Vagus
nerve and superior
laryngeal nerve
Signal to cough
centre and then to
cerebral
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


Describe in outline which regions in the brain are involved in generating the
co-ordinated neural activity that results in the act of cough. Identify the
efferent (motor) neural pathways and the main muscle groups which produce
cough.
Cerebral cortex and medulla are involved in generating the co-ordinated neural
activity

Main muscle
groups involved
are the
diaphragm,
external
intercostals,
accessory
inspiratory
muscles,
expiratory
muscles and
glottis.
Explain the concept of the sensitised cough reflex in disease as the basis for
chronic cough.
Plasticity of neural mechanisms

Excitability of afferent nerves increased by chemical mediators (prostaglandin
E2)

Increases the number of receptors and voltage-gated channels (TRPV-1)

Neurotransmitter increases (neurokinins)
e.g. higher number of TRPV-1 expressed in chronic cough than healthy control →
increased sensitivity

Irritation in throat or upper chest

Cough paroxysms difficult to control
Triggered by:

Deep breath, laughing, talking, vigorous exercise, smells, smoke, changing
temp, lying flat, eating crumbly food.
Complications of cough

Pneumothorax with subcutaneous emphysema

Loss of consciousness

Cardiac dysrythmias

Headache, pain, depression, incontinence
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
Discuss ways of controlling unnecessary cough.
Antitussives: drug that suppresses coughing, possibly by reducing the activity of the
cough centre in the brain and by depressing respiration.

Can be narcotic or non-narcotic
Narcotic
Non-narcotic
Codeine
Dextramethorphan
Dihydrocodeine
(synthetic derivative of morphine)
Pholcodeine
(causes drowsiness, nausea, constipation,
erythema multiforme)
Morphine
Levopropoxyphene
Diamorphine
Methadone
(causes sedation, constipation, respiratory
depression, physical dependance
Chest pain:


Identify the type and location of sensory receptors with the thoracic cavity that
when stimulated give rise to chest pain. Identify the neural pathways which
transmit this afferent neural information to the brain.
Describe in outline which regions in the brain are involved in the perception of
pain.
[Image in Learning Objective 7]
Chest wall gives sensory input via spinal nerves.
Chest pain in respiratory disease

Chest wall – muscular, rib fracture

Skin – Herpes zoster

Pleural pain (pulmonary infarction, pneumonia)

Deep seated, poorly-localised

Nerve root pain/Intercostal nerve pain
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
Referred pain (e.g. shoulder tip from diaphragmatic irritation)
Neural pathway: nerves to thalamus and somato-sensory cortex (is it secondary?)


Discuss the concept of referred pain in the chest.
Describe different typical patterns of chest pain that can help in diagnosing the
cause of pain.
Visceral pain:

Vague

Overlap of location and quality of pain

Possible difficulty in diagnosis
Chronic pain:

More complicated that acute pain

Depends on poorly defined neural mechanisms within the brain
Chest pain and non-respiratory disorders:

Musculoskeletal– injured rib/thoracic muscle

Cardiovascular – myocardial infarction, dissecting aortic aneurysm

Gastrointestinal – gastro-oesophageal reflux

Psychiatric – panic disorder
Treatment:

Treat cause

Analgesia for chronic pain to reduce symptoms
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
can be severe and refractory
Dyspnea:





Review the terms used by patients to describe the troublesome symptom of
shortness of breath and its measurement.
Occurs at low levels of exertion
Limits exercise tolerance
Unpleasant/frightening → suffocation
Poor perception of respiratory symptoms and dyspnoea may be life-threatening
Scales
Modified Borg scale
Clinical dyspnea scale (American Thoracic Society)
Grade
Description
0 None
Not troubled by breathlessness except with strenuous
exercise
1 Slight
Troubled by shortness of breath when hurrying on the level
or walking up a slight hill
2 Moderate
Walks slower than people of same age on the level because
of breathlessness or has to stop for breath when walking at
own pace on the level
3 Severe
Stops for breath after walking about 100 yards or after a few
minutes on the level
4 Very Severe
Too breathless to leave house or breathless when dressing or
undressing
Rating
0
0.5
1
2
3
4
5
6
7
8
9
10
Intensity of sensation
Nothing at all
Very, very slight (just noticeable)
Very slight
Slight
Moderate
Somewhat severe
Severe
Very severe
Very, very severe
Maximal
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
Causes



Discuss the main important causes of shortness of breath and approach to
management
Impaired pulmonary function
o airflow obstruction (asthma)
o restriction of lung mechanics (pulmonary fibrosis)
o Extrathoracic pulmonary restriction (pneumothorax)
o Neuromuscular weakness (phrenic nerve paralysis)
o Gas exchange abnormality (shunt)
Impaired cardiovascular function
o Myocardial disease
o valvular disease
o pericardial disease
o pulmonary vascular disease
o congenital vascular disease
Altered central ventilatory drive/perception
o systemic/metabolic disease
o metabolic acidosis
o anaemia
o physiological processes (pregnancy, high altitude)
o idiopathic hyperventilation
Assessment

Patients comments

Rating scales

Exercise testing

Questionnaires
Treatment

Treat cause
Treatment of dyspnoea itself is hard, use therapeutic options:

Drugs affecting brain (morphine)

Lung resection (reduce lung volume)

Pulmonary rehabilitation (improve fitness, health, psychological well-being)
Respiratory system 13 –
Acute Respiratory Medicine

Describe the integrated system of cardio- respiratory function for tissue
oxygenation
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
Efficient integrated
cardiorespiratory
function is essential
to provide sufficient
oxygen delivery to
tissues

Physiological
homeostasis is
maintained due to
oxygen consumption
normally being
independent of
supply.
Oxygen delivery is determined by:

Adequate oxygen supply from respiratory system – due to minute ventilation
and gas exchange

Cardiac output

Oxygen carrying capacity of the blood – Haemoglobin and oxygen saturating
capacity
DO2 = Q x C (a-v)
Delivery of oxygen = Oxygen content of blood x cardiac output (arterio-venous difference)
Q = Hb x SpO2 (a-v)
= Oxygen content of blood
= Haemoglobin concentration x O2 saturation
C = cardiac output = volume of blood pumped out of LV in one minute
Clinical relevance of integrated cardiorespiratory function

Failure of any one of these processes may lead to insufficient tissue
oxygenation
Examples

Low cardiac output states (heart failure, haemorrhage)

Severe anaemia (low Hb)

Low SaO2 (hypoxaemia)

Also provides strategies for restoring adequate oxygen to tissues
o Increase Q – fluid resuscitation, increase heart contractility (INOtrope) or
heart rate (CHRONOtrope)
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o Increase Hb – Blood transfusions
o Increase O2 supply – via oxygen mask

Understand the meaning, classification and causes of ‘respiratory failure’.
Respiratory failure: inability of the respiratory apparatus to provide adequate blood
oxygenation – due to inadequate ventilation and/or gaseous exchange
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Type 1
PaO2 < 8kPa
PaCO2 < 6.5kPa
Type 2
PaO2 < 8kPa
PaCO2 > 6.5 kPa
Clinical patterns
Failure
Pure ventilatory
failure
PaCO2
Increased
PaO2
Decreased
Hypoxaemic failure
Same or
decreased
Decreased
Mixed picture
Increased
Decreased

Normo/Hypocapnic Hypoxaemia

Severe pneumonia

Pulmonary embolism

Emphysema

Severe early asthma

Severe pulmonary oedema
Hypercapnic Hypoxaemia

COPD

Asthma

Neuromuscular disease
What can cause it
Resp centre depression,
Neuro/muscular depression, Alveolar
hypoventilation
PE, early asthma, pneumonia,
emphysema, ARDS, pulmonary
oedema
COPD
Appreciate different types of ventilatory support and mechanisms involved in
their beneficial effects.
Reasons for mechanical ventilation:

Inadequate oxygenation – inadequate ventilation, ARF, arrest

Inadequate CO2 clearance – respiratory acidosis

Inadequate airway maintenance – unconscious, bulbar palsy

Electively – post op until normal spontaneous ventilation
MECHANISMS: Ventilation and externally applied pressures

When tidal volume is inadequate in depth, the lung apparatus may not be
providing sufficient O2 or removing sufficient CO2

Providing externally supplied pressure support (PS on diagram), tidal volume is
augmented

Applying continuous positive airway pressure (CPAP), alveoli remain
‘splinted’ open, rather than collapsing down at the end of expiration.
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Oxygen therapy

monitoring arterial pressures of O2 and CO2

Delivered flow and inspiratory flow related O2 concentrations

Venturi mask/Hudson mask, high flow circuits
Positive pressure ventilation (see below to explain how it works)

NIPPV – non invasive, facemask

IPPV – invasive, endotracheal tube normally
Continuously positive airway pressure (CPAP)

maintains patency of alveoli at end of expiration (don’t collapse)

Useful post surgery:
o on patients who have retained secretions due to pain induced shallow
breaths and basal atelectasis (part of lung doesn’t expand properly)
o can be used in addition to analgesia and physiotherapy

Give a definition of ARDS, and understand its pathophysiological mechanisms.
Acute respiratory distress syndrome in adults (ARDS): ARDS I

Combines 3 features
o Refractory hypoxaemia
o CXR (chest Xray) – bilateral diffuse infiltrates
o Absence of cardiogenic pulmonary oedema

PaO2/FiO2 (fractionally inspired oxygen) < 200mmHg (27kPa)
Range of severity, mild = acute lung injury (ALI), severe ARDS
ARDS II
Causes
Direct vs indirect (e.g. pneumonia vs acute pancreatitis)
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Pathophysiology – mechanisms of refractory hypoxaemia

High permeability pulmonary oedema

V/Q mismatch [Loss of HPV, atelectasis (part of lung not expanding)]
ARDS III – increased permeability and plasma leak

Plasma leak from post capillary venules causes increase in distance between
alveoli and capillaries, causing a decrease in diffusion.

Vascular reactivity is deregulated which causes loss of hypoxic pulmonary
vasoconstriction → intrapulmonary microvascular shunt (some blood being
circulated without being oxygenated)

Dead space ventilation in other areas

Understand the meaning of ‘refractory hypoxemia’ in relation to ARDS.
Refractory hypoxaemia:

Presence of low PaO2 despite increasing the oxygen supply.

Implies there is more to hypoxaemia than a simple diffusion problem

Not specific to one disease

Suggests need to consider other ways to improve blood/tissue oxygenation

Result of V/Q mismatch.

Explain the terms: Ventilation-perfusion mismatch, Hypoxic pulmonary
vasoconstriction, Dead space ventilation, Microvascular shunt
Ventilation-perfusion mismatch (V/Q mismatch): air supply and blood supply to areas
of the lung do not correlate i.e. good blood supply, but lung not expanding sufficiently
would cause mismatch.
Hypoxic pulmonary vasoconstriction (HPV): Vasoconstriction in response to low
oxygen levels. Reduces perfusion in the area of inadequate oxygenation.
Microvascular shunt: when blood is not ‘diverted’ by HPV. Area of lung has good
blood supply but poor oxygen supply, therefore blood is not being oxygenated and is
returning to heart deoxygenated.
Dead space ventilation: occurs following loss of HPV. Area of lung has good oxygen
supply but poor blood supply, so oxygen is not being used.

Describe the principals of managing respiratory failure in ARDS.
ARDS I

Treat underlying cause

Low tidal volume ventilation
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
PEEP (positive end expiratory pressure) – maintain patency of reopened
‘collapsed’ alveoli, prevent ventilator induced lung injury
ARDS II
Reduce V/Q mismatch

Prone positioning – blood/ventilation redistribution, improve chest wall
compliance

Inhaled pulmonary vasodilators – selective pulmonary vasodilation. improves
blood flow to areas of ventilated lung, reducing dead space ventilation





Appreciate that Sepsis and ARDS are linked by a panendothelial insult.
Activation of the endothelial and vascular smooth muscle cells causes acute
inflammation, release of inflammatory mediators
Blood borne spread of mediators to remote organ/tissues
Causes endothelial activation
Sequential organ dysfunction and multiple organ failure.
Respiratory system 14 –
Blood gases in health and disease

Oxygen delivery to the body tissues. Relationship of oxygen delivery to tissues
and oxygen consumption. The development of tissue hypoxia when delivery
fails to meet demand with onset of anaerobic metabolism (lactic acid
production)

Oxygen consumed is
only 3/10 of the oxygen
delivered to the tissues.
[Note
R.Q.
=
respiratory
quotient, ratio of CO2 produced
to O2 consumed]
[If hypoxia occurs, lactic acid can accumulate in the brain and cannot cross the blood
brain barrier, therefore causing a drop in pH. If hypoxia is reversed, the lactic acid is
metabolised.]
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
Haemoglobin and blood gas transport.
Coupled O2 and CO2 transport occurs within the red blood cell.
Summary of diagram:
Transport of Carbon Dioxide:

CO2 is taken into the cell and has 2 routes it can take

Route 1: CO2 + H2O → H2CO3 → HCO3- + H+

From this, HCO3- is removed from the cell (Cl- moves into cell in exchange)
and H+ is used to release oxygen from haemoglobin by replacing O2 [Hb-O2 →
Hb-H+]

Route 2: CO2 replaces O2 by binding with haemoglobin, forming carbaminoHb, allowing O2 to move into the tissue
Haemoglobin:

Molecular weight 64,500

Made up of 2α and 2β chains

Each chain has a haem molecule comprised of a porphyrin and a ferrous ion
(Fe2+)

1 molecule can bind to 4 oxygen molecules

In deoxyhaemoglobin, tight electrostatic bonds between the globin chains are
present, with the haem molecule placed in places with low oxygen affinity.

Increased surround oxygen tension causes small increase in uptake of oxygen
by Hb.

After 1 oxygen has binded to the molecule, the alteration in the configuration
of the Hb molecule allows more oxygen to bind easily, steep increase in
oxygen content for small rise in oxygen tension (pO2) [leads to sigmoid curve]

Other factors that influence binding of O2 to haem group are: pH, PCO2,
temperature, concentration of 2-3diphosphoglycerate.
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
Definition and causes of hypoxaemia.
Hypoxia: lack of oxygen
Hypoxaemia (Hypoxic hypoxia):

Arterial PO2 <10.7kPa (80mmHg)[normal PO2 = 13.3kPa]

Arterial O2 saturation <93%

Arterial O2 content reduced
Causes of hypoxaemia:

Alveolar hypoventilation

Impaired gas exchange with the lung

High altitude (reduced barometric pressure)
Other causes of hypoxaemia occur when the arterial PO2, saturation and content are
normal:

Anaemia hypoxia (lack of Hb to carry oxygen)

Stagnant hypoxia

Histotoxic hypoxia
Compensatory mechanisms to deal with hypoxia (rapidly increase oxygen levels):

Alveolar hyperventilation

Increased cardiac output

Improved pulmonary perfusion

Changes in regional blood flow (i.e. not to gut to digest food)

Polycythaemia (increase in packed cell volume in the blood)

Anaerobic metabolism

The relationships between content and gas tension in blood for oxygen (O2)
and carbon dioxide (CO2) i.e. the O2 and CO2 dissociation curves. Factors
affecting these curves with particular reference to oxygen uptake in the lung
and the downloading of oxygen in the tissues.
[N.B. ---- line is Hb with high affinity to O2, solid line is low affinity]
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Oxygen dissociation curve:

Defined as the readiness with which Hb takes up O2 with changes in O2 tension

At same oxygen tension, Hb with high affinity will have higher content of
oxygen than blood with low affinity [Obvious]

Shifting the dissociation curve to the left increase O2 affinity, right
decreases

In hypoxia oxygen loading is decreased due to decreased PO2.

Loading is increased by hyperventilation.
Bohr Effect: When PCO2 decreases, pH increases - oxygen dissociation curve shifts left
[same other way round]
Carbon Dioxide dissociation curve:

Conversion in the lung deoxyhaemoglobin to oxyhaemoglobin → released
CO2.

The rise in PCO2 enhances movement of CO2 from pulmonary capillaries to
alveolus.
Haldane Effect: In tissue, the conversion of oxyhaemoglobin to deoxyhaemoglobin
enables the blood to carry CO2 at a lower PCO2, thus enhancing movement from tissue to
blood.
Factors affecting oxygen affinity:
Decreasing (shift to right)
Fall in pH, rise in PCO2, temperature
Anaemia
Pregnancy
Increase in 2,3-biphosphoglycerate
Increasing (shift to left)
Rise in pH, fall in PCO2, temperature
Store blood
Fetal blood
Decrease in 2,3-biphosphoglycreate
Exercise:

Increase in tissue PCO2, fall in pH.

Reduces oxygen affinity

Increases oxygen release

Leads to reduction in O2 uptake in the lung and fall in PaO2. However, offset by
increased ventilation
[Carbon monoxide has affinity for Hb 250x higher than O2. CO causes oxygen
dissociation curve to shift left]

Definition of respiratory failure and effect on arterial gas tensions.
Respiratory failure: [See previous lectures notes]

Respiratory apparatus’s function is as a gas exchange system maintaing the gas
tensions of carbon dioxide and oxygen.

This is dependent on alveolar ventilation and gas exchange within the lung

Respiratory failure occurs when 1 or both of these mechanisms fail
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Failure boundaries:
PaO2 < 8kPa (60mmHg), PaCO2 > 6.7kPa (50mmHg)
3 classifications of respiratory failure:
A. Ventilatory failure (Type II):

Low PaO2, high PaCO2

Alveolar hypoventilation

Causes: impairment of respiratory ‘bellows’- interference with central
respiratory controller or its connection with respiratory muscles, drugs, head
injury, stroke, tumour, poliomyelitis
B. Hypoxaemic failure (Type I):

Low PaO2, normal/low PaCO2.

Disturbance of ventilation to perfusion relationships

Overall alveolar ventilation remains normal

Causes: Asthma, emphysema, pneumonia, pulmonary fibrosis, pulmonary
oedema
C. Combined hypoxaemic and ventilatory failure

Low PaO2, high PaCO2

Features of both types are mixed

Both alveolar hypoventilation and V/Q mismatch

Develops in patients who have suffered hypoxaemic failure for some years and
patients with bronchitis and emphysema – may lead to cor pulmonale.

The relationship between CO2 tension (PCO2) and arterial oxygen tension
(PO2) within the lung. The effect on the relationship of changes in alveolar
ventilation and ventilation / perfusion relationships within the lung
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


There is a reciprocal relationship between PCO2 and PO2 within the lung –
shown by the oblique continuous line on the above diagram.
Addition of PCO2 and PO2 will give the same value at any point on the line –
approximately 16kPa
This rule is useful in identifying between Type I and II respiratory failure.
Type I - PCO2 = 3.5kPa, PO2 = 8.0 kPa
Type II - PCO2 = 10kPa, PO2 = 7.5kPa
Ventilation perfusion mismatch

Low PaO2, but fairly normal PaCO2

As the gradient between CO2 in venous and arterial is low, the rise in CO2 due
to poor gas exchange due to under-ventilated alveoli

CO2 is returned to normal by compensatory mechanisms due to virtually linear
dissociation curve

O2 cannot be returned to normal by compensatory mechanisms due to the
sigmoid shape of the dissociation curve

Areas of the lung with normal V/Q ratio are nearly fully saturating blood with
O2. Therefore, even increasing ventilation will have very little or no effect on
the saturation and so O2 content will remain constant.
CO2 dissociation curve (see above right):

N is the content of blood leaving a normal lung.

In diseased lungs there are areas with low V/Q and areas with high.

The resulting PCO2 is only slightly raised (within normal range) as high areas
compensate for low.

This is achieved due to CO2 dissociation curve being nearly linear and a rise in
PCO2 stimulates chemoreceptors leading to an increase of ventilation in high
V/Q areas.
Oxygen dissociation curve (above left):
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Suzie Rayner

Doesn’t balance out in the same way that CO2 does as sigmoid curve rather
than a straight line.
Respiratory system –
Hands on Blood gases in Health and Disease




Describe the qualitative changes in arterial blood pH. PCO2 and Base Excess
in the following acid-base disturbances: (i) Acute respiratory acidosis, (ii)
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: (i) Metabolic acidosis with
respiratory compensation, (ii) Metabolic alkalosis with 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.
Normal range of values:
Hb
pH
PCO2
PO2
Base Excess
13.3 – 17.7 g/dl
7.37 – 7.45 units
4.7 – 6.4 kPa (35-48mmHg)
> 10.7 kPa (80mmHg)
-2 - +2 mmol/l
Summary table of all acid-base disturbances
Acid-Base Disturbance
pH
Acute respiratory acidosis
Low
Acute respiratory alkalosis
High
Respiratory acidosis with renal
Low
compensation
Respiratory alkalosis with renal
High
compensation
Metabolic acidosis with respiratory
Low
compensation
Metabolic alkalosis with respiratory
High
compensation
Acid-Base disturbance
Type I respiratory failure
(hypoxaemia respiratory
failure) with FULL renal
pH
Normal
PCO2
Normal
pCO2
High
Low
High
Base Excess
Normal
Normal
High
Low
Low
Low
Low
High
High
PO2
Low (V/Q
mismatch)
Base Excess
Normal
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compensation
Type II respiratory failure
(ventilatory respiratory
failure) with FULL renal
compensation

Normal
High (due to Low
inadequate
alveolar
ventilation)
Normal
Comment on the mechanism whereby metabolic changes in acid-base status
lead to alteration in ventilation and hence respiratory compensation.
HCO3- levels in the blood affect acid-base status. These can be affected by:

Gaseous – rise and fall with CO2 level

Metabolic
o HCO3- level falls when metabolic acids are buffered in blood (bicarbonate
is formed)
o Regenerated in kidney, win conjunction with excretion of hydrogen ions
o HCO3- level will rise if sodium bicarbonate is administered
orally/intravenously.

Renal - HCO3- rises when acid excretion by kidneys increases (excretion
hydrogen ions) and falls when there is a reduction in acid excretion
CO2 transport
The equilibriums in the CO2 transport
will be affected by the amount of H+
present (i.e. the pH)
Example:
If the H+ level increases, the
equilibrium will shift to left, and so less
carbon dioxide will be taken in
(buffered). This will cause ventilation
rate to increase to remove CO2 as fast as
possible
Elevated hydrogen ion concentration
associated with metabolic acidosis reflexly
stimulates ventilation and lower PaCO2
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Respiratory system 15 – Lung Infection

To learn about the healthy lungs defences against infection. We are
continually exposed to infectious agents during breathing, but the healthy
lung is sterile from the first bronchial division.
Lungs have multilayered defence mechanisms against infection as they are
constantly exposed to potentially infectious agents:
Mechanical:

Mucociliary clearance, URT filtration, cough, surfactant, epithelial
barrier
Local:

BALT, sIgA, lysozyme, transferrin, antiproteinases, alveolar
macrophage
Systemic:

Polymorphonuclear leucocytes, complement, immunoglobulins
Mucociliary clearance [mentioned in detail in previous lecture]:

200 cilia per cell, intact epithelium with tight junctions sealing gaps
between cells

Cilia beat within periciliary fluid, mucus floats on top of periciliary
fluid.

Coordinated ciliary beating with curved backstroke so that mucus only
moves 1 direction

14 beats per second

ATPase in the dynein arms provide energy for microtubules to slide up
and down each other, causing ciliary movement.

To understand how the host defences can be compromised; congenital or
acquired. Three examples: primary ciliary dyskinesia, viral infection,
cigarette smoking.
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Broadly speaking, infections can either occur in airway (bronchitis) or alveoli
(pneumonia).
When infection occurs, either the pathogens overcome the lung defences or the
defences are weakened in some way, allowing the pathogen in.
Weakened host defences are either:

Primary – hereditary – Primary ciliary dyskinesia, CF

Secondary – acquired – Smoking, Viral infection
Hereditary: Primary ciliary dyskinesia:

Rare, thought to be autosomal recessive with incomplete penetrance.

Ultrastructural abnormalities in the cilia causing their movement to be
inhibited or disordered.

Most common abnormality is the absence of one or both dynein arms
(other abnormalities are in microtubules or radial spokes)

Cilia beating is disorientated

Impaired ciliary function in all sites present in body (nose, paranasal
sinuses, middle ear, Eustachian tube, bronchi to bronchioles and
spermatozoa tail) → causes bronchiectasis, chronic sinusitis, middle
ear disease, male infertility

Kartagener’s syndrome – primary ciliary dyskinesia with
bronchiectasis, dextrocardia (heart is mirror of what it would normally
be i.e. on right) and chronic sinusitis present.
Diagnose abnormal cilia by nasal brushing or nitrous oxide.
Acquired: Cigarettes:

disturb mucociliary clearance (destroy cilia, more mucus produced,
stickier mucus)

causes long standing weakened defences
Viruses:

also disturb mucociliary clearance (watery mucus, destroy cilia, more
mucus produced, break up epithelium and kill epithelial cells)

causes temporarily weakened defences
Respiratory infections should raise suspicion of disordered defences when:

Acute, overwhelming

Recurrent-acute, slow to resolve (with or without antibiotics)

Daily purulent sputum only temporarily responding to antibiotics
Bacterial pathogens of the lung fall into two groups:

Virulent species that cause pneumonia (streptococcus pneumoniae)
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
Less virulent species which cause bronchitis – equipped to
chronically infect airway when host defences have been compromised
(unencapsulated Haemophilus influenzae)
Bacteria methods of avoidance:
They either produce factors which impair defences or hide from the defences

Impairs mucociliary clearance

Enzymes break down local immunoglobulins

Exoproducts impair neutrophil, macrophage, lymphocytes

Adheres to epithelia

Surface heterogeneity

Endocytosis
Haemophilus influenzae:

Commonest cause of airway infection

¼ of smokers have this bacteria infecting their airway

Fimbriae reach out and anchor the bacteria to epithelial cells →
therefore not cleared by mucociliary action

Bacterial infection stimulates more mucus production and bacteria bind
to mucus.

To understand the differences in pathogenesis between acute and chronic
lung infections. Two examples: pneumococcal lobar pneumonia and
bronchiectasis.
Pneumonia:

Infection of the alveoli

Much more serious that airway infection

5% of those admitted to hospital with pneumonia die.

Streptococcus pneumoniae is most common cause – produces toxin canned
pneumolysin which makes holes in cell membranes killing the cell.
Clinical features:

Cough, Sputum, dyspnoea, Pleural Pain, Headache

More severe than symptoms of bronchitis
Bronchiectasis:

Dilated airways in which structural proteins have been damaged

Mucus is poorly cleared- pools in dilated airways, ciliated cells are lost, mucus
is less elastic.

Chronic productive cough

Daily physiotherapy to remove phlegm

Airways plugged with mucus

Bacteria that adhere to the mucus attract neutrophils from the bloodstream into
the bronchial lumen by chemotactic products and host cell mediators.

Inflammatory response fails to eradicate infection once it is established in
patients with bronchiectasis due to impaired host cell defence and high
bacterial number
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Causes of bronchiectasis:

Congenital

Damage (infection)

Something wrong with body’s ability to fight infection

Excessive inflammation
Clinical features:

Cough, sputum, SOB, fatigue, recurrent infection
Chronic infection:

Chronic inflammation causes more damage to lung

Normally protease/anti-protease balance works – phagocytes engulfing bacteria
‘spill’ protease enzyme which is normally inside cell to kill bacteria. Antiproteases in the mucus normally neutralize this.

In chronic infection, so much protease is ‘spilled’ that the anti-proteases are
overwhelmed and cannot neutralize it.

Proteases damage epithelium and elastin
Respiratory system 16 – Lung Mechanics

Explain what is meant by elastic recoil.
Elasticity: property of matter that causes it to return to its resting shape after deformation
by an external force.
Tissues of lung are chest are elastic as removing external force causes the tissues to recoil
to resting position.
Elastic recoil = change in pressure/unit of volume change
(reciprocal of compliance)
When a spring is EASY to distend
When a spring is HARD to distend
Elastic resistance
LOW
HIGH
Compliance
HIGH
LOW
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Opening thorax causes separation of visceral and parietal pleura (there is normally a
small amount of fluid in pleural cavity allowing the two layers of pleura to slide over
each other.
The tendency for the lung to recoil away from the chest wall can be measured as the
pleural pressure.

Define compliance.
Compliance: the expression of pressure-volume characteristics of the respiratory
apparatus (chest wall and/or lungs)
Compliance = unit of volume change/change in pressure



Gradient of pressure-volume curve
High compliance: large change in volume for given change in pressure
Noncompliant: Larger pressure required to achieve same volume

Explain how pulmonary versus chest wall compliances can vary in various
respiratory diseases.
Lung condition
Healthy lungs
Emphysema (loss of elastic recoil)
Pulmonary fibrosis (increased elastic recoil)
[N.B. lowest number – most elastic recoil]
Compliance
0.2 l/cm H20
0.4 l/cm H20
0.1 l/cm H20
To measure pleural pressure:

Insert a needle (direct)

Measure pressure in a thin walled balloon introduced to middle third of the
oesophagus (indirect) [N.B. can be used to measure pleural pressure as
oesophagus has thin walls with little tone and lies between lungs and chest
wall]
Relationships between lungs and chest wall at different lung volumes:
Functional residual capacity (FRC) is determined by the balancing of opposing elastic
forces in the lung and chest wall
At FRC

Above FRC


Forces are equal but pulling in
opposite directions
RP is 0 (atmospheric)
Force of lung tending to empty >
force of chest wall tending to fill
it
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Below FRC

RP is positive

Pull of chest in inspiratory
direction > pull of lungs in
expiratory direction
RP is negative


Explain the concept of surface tension and the Law of Laplace.
Hysteresis: for any given pressure, the volume during deflation is greater than in
inflation.
Surface tension:

manifestation of attracting forces between molecules

measured in dynes/cm (force/length)

may be lowered by certain substances when placed in liquid (exert lesser force
for other molecules) - surfactant
Law of LaPlace:
P = 2T/r
[P = pressure, T = surface tension, R = radius of alveolus]
Lungs recoil inward away from chest wall due to:

Connective tissues in the lung (elastin and collagen)

Surface tension generated at the air-liquid interface in the alveoli
Elastic recoil of lungs comes from:

Half from elastic properties of the lungs
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
Half from their structure - alveoli
Smaller alveoli have to work harder to expand due to larger pressure.

Explain how pulmonary surfactant affects lung volume and airway patency.
Factors which stabilize the lungs:

Surfactant:
o forms late in gestation (25 weeks)
o can be assessed in amniotic fluid
o Glucocorticoids stimulate Type II cells to produce surfactant
o Respiratory distress syndrome results from inadequate amount of
surfactant

Interdependence of lung units:
o Adjacent alveoli share a common wall, therefore tendency of one alveoli
or lung unit to collapse is opposed by support of surrounding units
Pulmonary surfactant:

In lungs of all air-breathing vertebrates

Formed in type II alveolar cells (stores surfactant in osmiophilic lamellar
bodies and secretes contents into alveolar lumen)

Phospholipids and specific apoproteins

Can markedly decrease the surface tension of air-liquid interface

Surfactant is necessary to keep surface tension constant throughout ventilation
cycle (without it, surface tension would increase with inspiratory expansion and
reduce with expiration)

Describe the relationship between alveolar and atmospheric gas pressures,
airway resistance and airflow. [READ AND CHECK UNDERSTANDING]
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

Getting air into the lungs relies on the change in intrathoracic pressure.
Increasing the size of the thorax, inspiratory muscles lower the intratoracic
pressure (relative to atmospheric pressure) causing air to flow into airways.

Once Vmax has been reached, the resistance to airflow must rise in direct
proportion to the driving pressure.
The rise in airflow resistance occurring at each lung volume is due to the
dynamic compression of the airways

Pressure in airway drops from
the alveolar pressure to the
atmospheric pressure at the
mouth.



Equal pressure point = point
at which intramural and
extramural pressure are equal.
Flow limitation occurs at ‘choke points’ along the airway – likely to form
where the transmural pressure becomes negative.
As lung volume decreases airways narrow, resistance increases and the flowlimiting site moves peripherally
Thus in late forced expiration, flow in increasingly determined by the
properties of the small peripheral airways
Transpulmonary pressure = pressure in alveolus –
pleural pressure
[Pressure difference between alveoli and pleural
space]

Main factor leading to a positive
transpulmonary pressure is high lung static
recoil pressure (volume) as this contributes
to a greater pressure within the airspaces
relative to pleural pressure.
Pressure in the alveolus = elastic recoil pressure of
lungs + pleural pressure
When dynamic compression occurs, the maximum
driving force becomes
Alveolar pressure – intrapleural pressure
(determined by the volume and compliance of the
lung)
Points on Dynamic compression

During forced expiration, pleural pressure can exceed airway pressure –
favouring airway compression
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
Increased pleural pressure results in greater airway compression with no
change in airflow

Compression starts at the equal pressure point in the cartilage-free airways
within the lung

In disease, the weakened airways can collapse, trapping air behind the blockade
[Lip pursing moves the EPP to the mouth providing psychological relief to the patient
– therefore symptom of lung disease]

Describe the factors that affect airway resistance centrally and peripherally.
Lung Volume

As lung volume increases, airway resistance decreases
Airway calibre

Flow depends on resistance from airway and driving pressure
Airway generation

Regional airway resistance deceases as a function of airway generation

Highest resistance is at generation 4 – medium bronchi of short length and
frequent branching in highly non-laminar air flow with extreme turbulence.
Airflow profile

Tube radius is deciding factor in resistance to flow

Laminar (air flows in straight lines) – small airways


Transitional (branching)
Turbulent (air flow isn’t in straight lines) – occurs in large airways (diameter
>2mm)
[As lower density gases will reduce Reynolds number they may be used in case of airway
obstruction]
Phase of respiration

Resistance is less in inspiration than expiration
Vagal and sympathetic tone

Cholinergic blockade

β-2 receptor stimulation

β-blockade
Respiratory gases

Hypocapnia – abnormally low concentration of CO2 in the blood

Hypercapnia – abnormally high concentration of CO2 in the blood
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



Name the two major components that contribute to the work of breathing and
explain how each may be altered in disease states.
Flow-resistive work
o In asthma, elastic energy stored during inspiration is not enough to
produce airflow during expiration – expiratory muscles must do extra
work
Elastic resistance
o In pulmonary fibrosis, work required to overcome flow resistance is little
altered, much more work is required to overcome high elastic resistance of
the ‘stiff’ lungs
Describe the relationship between mechanical work and oxygen cost of
breathing in normals and patients with respiratory insufficiency.
In diseases, small increases in ventilation are
associated with marked increases in oxygen
consumption – oxygen cost of breathing is
higher in disease than health.
Respiratory system 17 –
Altitude and acclimatization
Mostly a repeat of lecture 14
Bohr Effect:

In lung, PCO2 reduced, pH rises, oxygen dissociation curve moves left →
affinity increased and oxygen loading enhanced

In tissues, PCO2 increases, pH falls, oxygen dissociation curve moves right →
affinity decreased, unloading of oxygen enhanced
When living at high altitude (hypoxia), oxygen loading is impaired due to low PO2.
Increased loading by:

Hyperventilation → increasing PO2 and reducing PCO2 (increasing oxygen
affinity)
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Haldane Effect:

Conversion in the lung of deoxyhaemoglobin to oxyhaemoglobin shifts the
curve to the right, reducing affinity of Hb for CO2.

In tissues, conversion of oxyhaemoglobin to deoxyhaemoglobin shifts curve
left, increasing affinity for CO2.
Respiratory response to a fall in barometric pressure (high altitude)

Primary need is to ensure adequate oxygen uptake

Alveolar ventilation increases, giving increased PaO2 and decreased PaCO2.

Rise in pH puts a brake on the respiratory response to hypoxaemia

Over the next few days, renal compensation for alkalaemia leads to return of
normal pH, removing the inhibition of breathing.
Oxygen affinity returns to same level as at sea level due to:

Correction of the alkalaemia by renal compensation

increased production of 2-3, deoxyhaemoglobin bisphosphoglycerate
2-3, bisphosphoglycerate binds
to deoxyhaemoglobin in the
tissues leading to it’s increased
production via
bisphosphoglycerate synthase
and hence the accumulation in
the red cells.
35