Respiratory System Flashcards
In a healthy young subject (blood Hb concentration of 15g/dl), what is the concentration in atmospheric air for O2 and CO2?
(Symbol and value)
Fi02= 0.209 (20.9%)
FiCO2= 0.0004 (0.04%)
NB. subscript 2
In a healthy young subject (blood Hb concentration of 15g/dl), what is the partial pressure in alveolar air for O2 and CO2?
(Symbol and value)
PAO2= 13.3 kPa (100 mmHg) PACO2= 5.3 kPa (40 mmHg)
NB. subscript A and 2
In a healthy young subject (blood Hb concentration of 15g/dl), what is the partial pressure in arterial blood for O2 and CO2?
(Symbol and value)
PaO2= 13.3 kPa (100 mmHg) PaCO2= 5.3 kPa (40 mmHg)
NB. subscript a and 2
In a healthy young subject (blood Hb concentration of 15g/dl), what is the partial pressure in mixed venous blood for O2 and CO2?
(Symbol and value)
PvO2= 5.3 kPa (40 mmHg) PvCO2= 6.1 kPa (46 mmHg)
NB. subscript v and 2
What percentage of deaths in the UK are due to respiratory diseases?
20%
What are the main causes of respiratory related deaths?
Cancer Pneumonia Chronic obstructive pulmonary disease (COPD) Pulmonary circulatory disease Pneumoconioses Asthma Other respiratory diseases
What is the UK’s biggest cancer killer?
Lung cancer
Very small 5 year survival rate
COPD is expected to be the (number) biggest cause of mortality by 2020
3rd
What fraction of people visit their GP at least once a year because of a respiratory condition?
1/3
How are lung diseases classified?
AIRWAY DISEASES
Local obstruction
Generalised obstruction
SMALL LUNG DISORDERS (RESTRICTIVE)
Disease within the lung
Disease outside the lung
INFECTIONS
PULMONARY VASCULAR DISORDERS
List examples of airway diseases (local and generalised obstruction)
LOCAL Sleep apnoea (6x risk RTA) Laryngeal carcinoma Thyroid enlargement Vocal cord dysfunction Relapsing Polychondritis Tumours Post tracheostomy stenosis Foreign bodies Bronchopulmonary dysplasia
CHRONIC Asthma COPD Bronchiectasis Cystic Fibrosis Obliterative Bronchiolitis
List examples of small lung (restrictive) diseases (disease within/outside the lung)
WITHIN Sarcoidosis Asbestosis Extrinsic Allergic Alveolitis Fibrosing Alveolitis Eosinophilic pneumonia Idiopathic pulmonary fibrosis (35% increase in diagnosis 2000-> 2008, 3 year median survival)
OUTSIDE Pleural effusions Pneumothorax Scoliosis Respiratory muscle weakness Obesity (increases resp workload, increases i) Mesothelioma (asbestos)
List examples of lung infections
Tuberculosis (infection rate rising in London)
Infective bronchitis
Pneumonia
Empyema
List examples of pulmonary vascular disorders
Pulmonary emboli= clots in the lung may complicate immobility and be fatal e.g. associated with child birth, (more common >40y)
Pulmonary hypertension
What is the most common symptom associated with lung disease?
Breathlessness – also known as DYSPNOEA; a sensation of difficult, laboured or uncomfortable breathing
Cough Sputum production Haemoptysis Chest discomfort Wheeze or musical breathing Stridor (harsh/grating sound) Hoarseness Snoring history /Daytime sleepiness Weight loss Anorexia Fever
To aid diagnosis, what should you ask about (regarding lung diseases)?
Onset (acute, gradual)
Circumstances (on exertion, at rest, at night, lying flat, associated symptoms)
Degree
What may cause breathlessness?
Lung Disease
Heart Disease
Pulmonary Vascular Disease
Neuromuscular disease (e.g. diaphragm weakness
Systemic Disorders (e.g. anaemia, hyperthyroidism, obesity)
{Psychogenic Factors}
What are the 5 stages for MRC dyspnoea grading?
- Normal
- Able to walk and keep up with people of similar age on the level, but not on hills or stairs
- Able to walk for 1.5Km on the level at own pace, but unable to keep up with people of similar age
- Able to walk 100m on the level
- Breathless at rest or on minimal effort
What are the 2 main processes impaired by lung disease?
Disturbed gas exchange
Damaged respiratory mucosa
Outline gas exchange in the lungs
Small organisms meet their oxygen demand via diffusion, whereas larger organisms e.g. a resting adult cannot meet their requirements via diffusion alone
Breathing delivers warmed humidified air to specialised gas exchange surfaces
The heart delivers deoxygenated blood to the pulmonary capillaries
Gas exchange between the air and blood occurs by diffusion
How much oxygen does a resting adult need per minute?
250ml oxygen
Outline how damage to respiratory mucosa can lead to lung disease
Cell walls of epithelial cells are broken down, damaging and destroying the cilia so patients may have a reduced number of cilia as well as ineffective cilia
Damaged cilia are less effective at removing mucus from airways
How do enzymes lead to damaged respiratory mucosa?
Activity of enzymes e.g. neutrophil elastase – released from neutrophils which are attracted into the airways by cigarette smoke, bacterial products etc.
How is the respiratory system examined clinically?
Chest X ray
MRI
Spirometer
(Observation, palpating)
What does spirometry do?
Tests how well you can breathe
Can help diagnosis of different lung diseases e.g. COPD
Deep breath in, blow out as fast as possible into spirometer (small machine attached by a cable to mouth piece)
Why are some symptoms of lung disease hard to diagnose?
Overlap with lung and cardio conditions
Describe the nasal cavities
Nearly triangular cross-section
Fairly smooth medial and inferior walls
Elaborate lateral wall (respiratory epithelium covers 3 scroll-like plates of bones called conchae)
Nasal mucus and hair present
High resistance to airflow (because need to conserve heat and water)
Paranasal air sinuses present
How is nasal resistance affected by exercise?
During exercise, nasal resistance to flow means the respiratory muscles cannot propel air through the nose fast enough
Open-mouth breathing takes over with an increased loss of water and exposure to airborne particles
What do nasal mucus and hairs do?
Nasal mucus and hairs help exclude a range of airborne particles from flying insects to quite fine dust and particulate pollutants
Describe how nasal cavities are involved in inspiration and expiration
‘Conditioning the air’
Inspired air passes through these warm, moist plates-> become warmed and humidified
This protects lower parts of the respiratory tract from cold shock and drying
Nasal lining becomes cooled in this process so, during expiration, nasal lining cools the expired air and also retrieves water by condensation
Describe the paranasal air sinuses
Four sets of blind-ended ‘out-pocketings’ of the lateral walls of the nasal vaities
Slow air turnover
Little role in heat and water transfer
Probably function to:
- Reduce weight of facial bones
- Provide a ‘crumple zone’ in facial trauma
- Act as resonators for the voice
- Insulate sensitive structures from rapid temperature fluctuations
Why is infection of the maxillary sinus common?
Opening is high up
What are the lower airways?
Trachea
Bronchi
Bronchioles (initially surrounded by smooth muscle, but end as respiratory bronchioles from which alveoli are direct or indirect buds)
What are the walls of the larynx, trachea and bronchi held open by?
Plates or crescents of cartilage
Non-mineralised, supporting but flexible
What are the nasal cavities and pharynx held open by?
Attachments to nearby bones
What do alveoli and bronchioles contain to prevent collapse?
Microscopic air spaces (alveoli and bronchioles) contain a surfactant phospholipid
Prevents collapse caused by surface tension forces
What is the role of the pharynx?
After air is conditioned, passes down back of nasal cavity
Final part of airway before oesophagus
What are the 3 parts of the pharynx?
Nasopharynx= posterior to nasal cavity (Eustachian tube opening)
Oropharynx= posterior to tongue, consists of lymphoid tissue
Laryngopharynx= after epiglottis
How is food channeled to the oesphagus?
Posteriorly along the oropharynx
What is the anatomy of the larynx?
Cartillagenous structure
Supported from roof of mouth by hyoid bone
Associated with lateral carotids
Superior and posterior to thyroid gland, superior to trachea
Entire structure is membrane lined (forms complete sheath inside trachea)
Arytenoid cartilage to control entry to larynx
Allows air into lower airways but excludes liquids and solids
What respiratory structure develops differently in men and women?
Larynx
What is the arytenoid cartilage?
Attached to vocal ligaments
Open and close entry to larynx
Act as sphincter (prevent entry to lower airways)
When is the arytenoid cartilage open and closed?
Open= during inspiration
Closed= during phonation
Vocal folds partially open and air is passed through= sound is made (mechanism of vocalisation in the mouth)
What is the role of the larynx?
Modulation of sound
Without larynx, voice would be monotonous and low pitch
What effect does the closure of the larynx vocal folds have on the thorax and abdomen?
Closure-> increased pressure in thorax and abdomen
Can lead to expulsive force (during sneezing, childbirth and vomiting)
What is the structure of the trachea?
Regular cartilage arrangement
Approx 20 horseshoe shaped cartilage rings (keep trachea open)
Rings= not continuous at posterior surface
Anterior surface lined with epithelium
Posterior surface consists of trachealis muscle (anterior to oesophageal muscle, needed for swallowing)
What is the tracheobronchial tree?
Bronchi held open by cartilage horseshoes and plates
Bronchiolar and alveolar surface tension reduced by surfactant
What is the surface marker for where the trachea branches?
Sternal angle at T4
What is the dimorphism between the primary bronchi?
Right side is larger and more vertical
-> More things inhaled into right lung
What do the secondary and tertiary bronchi do?
Secondary bronchi supply each lung lobe
Within each lobe, tertiary bronchi then supply each pulmonary segment
With branching of the bronchi, number of cartilage rings …… and amount of smooth muscle ……
With branching of the bronchi, number of cartilage rings DECREASE and amount of smooth muscle INCREASES
What separates the two pleural cavities?
Mediastinum
Central partition of tissue
What does the mediastinum contain?
Trachea Oesophagus Heart Great arteries and veins Various important nerves and lymph vessels
What is the pleura?
Thin, shiny, moist layer of tissue
Covers each lung and inside of pleural cavities
Allows each lung to slide smoothly within its pleural cavity during breathing
Describe the surfaces of each lung
Costal surface= convex, facing the ribs
Mediastinal surface= moulded to mediastinum
Diaphragmatic surface= inferior, concave
What is the diaphragm?
Sheet-like dome-shaped muscle
- Centre of dome bulges up because of pressure difference between pleural and abdominal cavities
Separates thoracic and abdominal cavities
Margin attached to costal margin
Highest in expiration
Where is the highest part of each lung?
Apex
2-3cm above clavicle in adult (in root of neck)
How do the chest wall muscles, diaphragm, ribs, pleural cavities, pleura and lungs have a role in breathing?
Contraction of diaphragm-> pulls domed centred down-> increases height of pleural cavities
Contraction of the intercostal muscles-> pulls ribs upwards towards relatively fixed first rib-> ribs slope down towards their anterior ends
Lifting movement-> expansion of pleural cavities (depth and width) -> decreased pleural pressure
Decreased pleural pressure means air flows through airways into lungs (which expand with increase in pleural cavity)
Lower part of each lung expands downwards to occupy much of the costo-diaphragmatic recess
Breathing normally passive
What is the costo-diaphragmatic recess?
Lowest region of each pleural cavity
In expiration, contains no lung because margin of diaphragm is pressed closely against lower part of rib cage
What are the diaphragm’s motor nerves?
C3, 4, 5
‘Keep the diaphragm alive’
What are airways?
Air-filled spaces/tubes which take air from outside to alveoli
What are alveoli?
Microscopic spaces lined by very thin simple squamous epithelium through which O2 and CO2 exchange takes place
What are alveolar capillaries?
On the pulmonary circuit
Bring deoxygenated blood from the right ventricle of the heart via the pulmonary trunk and pulmonary arteries
What are the upper airways?
Nasal cavities
Nasopharynx
Laryngopharynx
Larynx
What are the cellular layers separating alveolar air from blood?
Air Alveolar wall Epithelial basement membrane (Interstitial space) Capillary basement membrane Endothelial cells of capillary Blood
How thick is the alveolar-capillary membrane?
What does the interstitial space between the basement membranes between alveolar air and blood contain?
Pulmonary capillaries
Elastin
Collagen
How is the respiratory tract protected against drying, cold and inhaled particles?
Inspired air passes through the conchae are warmed and humidified on route
Protects lower parts of respiratory tract from cold, shock and drying
This process cools nasal cavities, so during expiration the expelled air is cooled and water is retrieved by condensation
Nasal mucus and hairs exclude airborne particles
During exercise, nasal resistance to air flow becomes too great and open mouthed breathing takes over (less protection)
How do alveoli resist collapse?
Trachea and bronchi are held open by cartilage
Bronchi are held open by cartilage horseshoes and plates
Bronchiolar and alveolar surfce tension reduced by surfactant
How is blood circulated through the lungs?
Double circulation in body (pulmonary for deoxy, systemic for oxy)
PULMONARY
Deoxygenated blood enters the right atrium via the inferior and superior vena cava
Atrial systole forces the blood into the right ventricle (through tricuspid valve)
Ventricular systole ejects the blood into the pulmonary trunk (through pulmonary valve) which branches in pulmonary arteries
Pulmonary arteries branch further into arterioles and capillaries within each lung-> carries blood close to alveolar so gas exchange can occur
Oxygenated blood returns to heart via venules and pulmonary veins which enter the heart at the left atrium
What is minute ventilation?
Volume of air expired in 1 minute (VE)
NB. E in subscript
What is respiratory rate?
Frequency of breathing per minute (RF)
NB. F in subscript
What is alveolar ventilation?
Volume of air reaching the respiratory zone (Valv)
NB. alv in subscript
What is respiration?
The process of generating ATP either with an excess (aerobic) and a shortfall (anaerobic) of oxygen
What is anatomical dead space?
Capacity of the airways incapable of undertaking gas exchange
What is alveolar dead space?
Capacity of the airways that should be able to undertake gas exchange but cannot (e.g. hypoperfused alveoli)
What is physiological dead space?
Equivalent to the sum of alveolar and anatomical dead space
What is hypoventilation?
Deficient ventilation of the lungs
Unable to meet metabolic demand
Results in increased PO2- acidosis
What is hyperventilation?
Excessive ventilation of the lungs atop of metabolic demand
Results in reduced PCO2- alkalosis
What is hyperpnoea?
Increased depth of breathing (to meet metabolic demand)
What is hypopnoea?
Decreased depth of breathing (inadequate to meet metabolic demand)
What is apnoea?
Cessation of breathing (no air movement)
What is dyspnoea?
Difficulty in breathing/shortness of breath
What is bradypnoea?
Abnormally slow breathing rate
What is tachypnoea?
Abnormally fast breathing rate
What is orthopnoea?
Positional difficulty in breathing (when lying down)
What type of structure is the chest wall?
Chest wall= a rigid support structure composed mostly of the ribcage, sternum and intercostal muscles that naturally recoils outwards
What type of structures are the lungs?
Lungs= soft tissue structures are very elastic that naturally recoil inward (large SA for gas exchange)
What is the mechanical relationship between the chest wall, pleural membranes and the lung?
The chest wall has a tendency to spring outwards, and the lung has a tendency to recoil inwards
These forces are in equilibrium at end-tidal expiration (at functional residual capacity; FRC), which is the ‘neutral’ position of the intact chest
To further inspire (or expire), requires the equilibrium to be temporarily imbalanced
The lungs are surrounded by a visceral pleural membrane
The inner surface of chest wall is covered by a parietal pleural membrane
The pleural cavity is between the visceral and parietal pleura
The chest wall and lungs have their own physical properties that in combination dictate the position, characteristics and behaviour of the intact chest wall
What is the pleural cavity?
Between the visceral and parietal pleura
The gap between pleural membranes is a fixed volume and contains protein-rich pleural fluid
How can chest and lung recoil be expressed in equations considering inspiratory and expiratory muscle effort?
Chest recoil = lung recoil
Inspiratory muscle effort + chest recoil > lung recoil
Chest recoil
Why is the pleural cavity being breached a serious problem?
E.g. perforated or punctured
Bad because lung relies on the pleural fluid to operate normal lung mechanics
Thoracic wall-lung relationship is delicate (imbalance-> dysfunction)
E.g. haemothorax or pneumothorax
What is a haemothorax?
Accumulation of blood in the pleural cavity-> impedes lung function
Blood can’t enter pleural cavity as fast as air-> slow accumulation of fluid
Gradually reduces the space the lung has to inflate into, increases the effort required to inhaled to a given volume-> limits the overall volume achievable
Requires draining
What is pneumothorax?
Puncture in thoracic cavity that breaches the pleural cavity
‘Tension’ caused by normally negative pressure caused by constant inward recoil of the lung tissue
Outward recoil of the chest wall is suddenly compromised
This means the resistance (or link) between the two forces disappears
Allows lung to recoil and chest wall to expand
What is functional residual capacity (FRC)?
Lung volume at end of quiet expiration
RV+ERV = FRC
What is residual volume (RV)?
Lung volume at end of forced expiration
What is inspiratory reserve volume (IRV)?
Maximum amount of air that can be inhaled after normal inspiration
From TV to TLC
What is expiratory reserve volume (ERV)?
Maximum amount of air that can be exhaled after normal expiration
From TV to RV
What is tidal volume (TV)?
Volume of air breathed in or out during normal respiration
NB. T is subscript
What is total lung capacity (TLC)?
When taking maximum inspiration
TV+RV+IRV+ERV= TLC
What is vital capacity (VC)?
Amount of air that can be forced out of the lungs after maximal inspiration
IRV+VT+ERV= VC
NB. T (in VT) is subscript
What does peak flow test?
Tests airway resistance (how fast can air be expired)
What does time-volume curve test?
Tests airway resistance and FVC
What does flow volume loop test?
Tests airway resistance, flow rates, TV, IRV, ERV and FVC
What is transmural pressure?
Pressure inside - pressure outside = transmural pressures
-ve= leads to inspiration \+ve= leads to expiration
What is negative pressure breathing?
Palv is reduced below Patm
-> Healthy breathing
What is positive pressure breathing?
Patm is increased above Palv
-> Ventilation CPR
What is ventilation?
Quiet breathing
What is tidal breathing?
Predominantly diaphragm-induced (syringe movement)
What muscles are involved in maximum ventilation?
Full inspiratory muscle recruitment involved
Syringe and bucket handle movement
How does ventilation happen?
At FRC, mechanical forces of the lung are in equilibrium
Equilibrium needs to be imbalanced to generate airflow (and stimulate ventilation)
So atmospheric/intrapulmonary pressure is increased (positive pressure) or intrapleural pressure is decreased(negative pressure)
The respiratory musculature decrease intrathoracic pressure (diaphragm contracts downward towards the abdomen and the external intercostals pull the ribcage outwards and upwards) by creating a partial vacuum
Lung is elastic and expandable tissue stretches to fill the space (while maintaining intrapleural volume) assuming airway is clear
Which 3 pressures fluctuate and are important to determine whether inspiration or expiration?
Atmospheric pressure (Patm)
Intrapleural pressure (Ppl or PIP)
Intraalveolar pressure (PAlv)
(NB. After P, letters are subscript)
What is transmural pressure?
Pressure across tissues
Refers to the pressure inside relative to the pressure outside
What is transpulmonary pressure?
Difference in pressure between the alveolar sacs and the pleural cavity
PTP= Ppl-Palv
What is transthoracic pressure?
Difference between the pleural cavity and the atmosphere
PTT= Patm - Ppl
What is the transrespiratory system pressure?
Difference between the alveolar sacs and the atmosphere
PRS= Patm-Palv
At rest, when the lung capacity is at FRC, what is the PRS?
Transrespiratory system pressure
PRS= 0
Recoil forces of the lung tissue and chest wall are balanced
Volume can increase (inspiration > FRC) or decrease (expiration
How do you initiate inspiration in negative pressure breathing?
Inspiratory muscles contract (principally diaphragm and other deeper muscles)
Ppl (intrapleural pressure) decreases as the thoracic pleura expands
To prevent this decrease, in pressure the visceral pleura is pulled outwards which inflates the lungs (negative pressure breathing)
How do you initiate inspiration in positive pressure breathing?
Increase in alveolar pressure
Stimulates an expansion of lung tissue against the resistance of the thoracic wall
Leads to increased increased pleural pressure which causes an expansion of the chest wall (prevent Palv rising too high)
NB.
- Intrapleural volume fixed and resistant to change (because its a fluid and not a gas)
- Intrapleural pressure not equal from base to apex (base pressure is -3 cmH20, apex is -7 cmH20)…. So average is -5 cmH20
What factors affect lung volumes and capacities?
Body size (height affects more than weight)
Sex (male larger than female)
Age (older= more diseased)
Disease (pulmonary, neurological)
Fitness (innate e.g. born in Andes, training)
What effect does obstructive disease have on RV, TV, IRV, ERV, TLV, FRC, VC?
↔↑RV ↔↑TV ↓↔IRV ↓↔ERV ↔↑ TLC ↔↑FRC ↓↔VC
What effect does restructive disease have on RV, TV, IRV, ERV, TLV, FRC, VC?
↓ RV ↔↓TV ↓IRV ↔↓ERV ↓TLC ↓FRC ↓VC
Describe the respiratory tree
Airway network of progressively bifurcating smaller tubes across 23 ‘generations’
Air is warmed, humidified, slowed and mixed as it passes down the respiratory tree
What is the conducting zone of the respiratory tree?
Where the velocity dramatically slows as the cross-sectional area increases
Functions= defence (mucus secreted), speech (vocal folds in larynx) and preparation of air for gas exchange (warming and humidifying)
16 generations
No gas exchange
150ml in adults at FRC
ANATOMICAL DEAD SPACE
What is the respiratory zone of the respiratory tree?
Respiratory bronchioles have occasional sacs off the sides that provide a surface for gas exchange
Further down the airway the concentration of these alveolar sacs increases dramatically
These respiratory sacs are called alveoli (parenchymal tissue of the airways)
7 generations
Gas exchange
350ml in adults
Air reaching here is equivalent to ALVEOLAR VENTILATION
What is non-perfused parenchyma?
Alveoli without a blood supply
No gas exchange
0ml in adults
ALVEOLAR DEAD SPACE
Parenchyma = functional subunit
What is dead space?
Generic term that describes parts of the airways that don’t participate in gas exchange
What is physiological dead space?
Anatomical + alveolar dead space
What is anatomical dead space?
Entirety of the conducting airways and upper respiratory tract
Can’t be measured using standard spirometry, use dilution test
How is a dilution test carried out?
Known volume of inert gas (e.g. helium) that is inspired and expired into a closed circuit
After enough breathing to equilibrate it with the air already in airway-> measure sample of the original volume for concentration of inert gas
To calculate VD use:
Ratio of inert gas to original concentration
Spirometry data
NB. Tubing connected to the airway increases the volume of anatomical dead space
What is alveolar dead space?
Includes respiratory tissues unable to participate in gas exchange, usually due to absent or inadequate blood flow
Healthy individuals, volume is effectively 0
What is physiological dead space?
Sum of anatomical and alveolar dead space volumes
How does alveolar ventilation happen?
Primary function of breathing (or mechanical ventilation)
Increasing depth of breathing is more effective at increasing alveolar ventilation
What is the value of alveolar ventilation during tidal (subconscious) breathing?
Equal to the difference between tidal volume and dead space
Valv= VT - VD
For every generation further down the airway, what happens to pressure and velocity of airflow?
Divergence in path associated with 50% decrease in pressure and velocity of airflow
Why you can’t get a longer snorkel to swim deeper?
More dead space (snorkel functions as extension of lung)
This means more times greater than resting TV and typical TLC
Poiseuille’s law:
Resistance= 8nl/πr4 (n with arrow down)
Boyle’s= P gas is proportional to 1/(v gas)
What does there need to be to ensure effective and sustainable gas exchange?
Ventilation= fresh sample of atmospheric air (alveolar ventilation) in the alveolar sac
Perfusion= Adequate perfusion (pulmonary capillary)
Need to be in close proximity (shorter diffusion distance)
What happens when there is a proportional imbalance between ventilation and perfusion ?
Compromise pulmonary gas exchange
Ventilated alveoli with no blood supply= wasted ventilation
Pulmonary capillaries that perfuse non-ventilated alveoli= wasted perfusion
Where in the lung is ventilated more readily and why?
Ventilation (V)in healthy upright individual…
Base ventilates more readily
Because of effect of gravity on the transpulmonary pressure
Makes the basal lung tissue more compliant (distensible)
Explain the difference between transpulmonary pressure in the apex, base and middle of the lung
APEX
PA > Pa > Pv
MIDDLE
Pa > PA > Pv
BASE
Pa > Pv > PA
How does perfusion (Q) vary in the lung?
Gravity affects distribution of blood flow
As pulmonary circulation flows at a low pressure, the vessels perfusing the base of the lung receive a greater proportion of blood flow (least resistant)
At rest, apex receives very little perfusion
How can the ratio of ventilation to perfusion be interpreted?
Ideally, blood would only flow to ventilated parts of the lung
Ratio shows ventilation volume per litre of perfusion
High V/Q associated with poorly perfused regions
Low V/Q associated with poorly ventilation regions
What factors alter the V/Q ratio?
Exercise stimulates increased cardiopulmonary effort to increase oxygen supply to meet escalating demand in the skeletal musculature
So RF, VE and Q increase proportionately
Increased force of ventilation-> improves apical ventilation-> increased pressure in the pulmonary circulation-> increases perfusion of apical capillary beds
Slight discrepancy between the base and apex of the lung, more subtle than at rest
What role does gravity have on ventilation and perfusion?
Favours V and Q of the basal lung versus the apical lung
Where in the lung is more likely to have ‘wasted perfusion’ and ‘wasted ventilation’?
Basal lung has ‘wasted perfusion’
Apical lung has ‘wasted ventilation’
What are common lung function tests?
Volume-time curve
Peak expiratory flow
Flow-volume loop
How does the volume-time curve work?
PROTOCOL
- Patient wears nose clip
- Patient inhales to TLC
- Patient wraps lips round mouthpiece
- Patient exhales as hard and fast as possible
- Exhalation continues until RV is reached or six seconds have passed
- Visually inspect performance and volume time curve- repeat if necessary
- Look out for:
a. Slow starts
b. Early stops
c. Intramanouever variability
How does peak expiratory flow work?
PROTOCOL
- Patient wears nose clip
- Patient inhales to TLC
- Patient wraps lips round mouthpiece
- Patient exhales as hard and fast as possible
- Exhalation doesn’t have to reach RV
- Repeat at least twice (take highest measurement)
How does flow-volume loop work?
- Patient wears noseclip
- Patient wraps lips round mouthpiece
- Patient completes at least one tidal breath
- Patient inhales steadily to TLC
- Patient exhales as hard and fast as possible
- Exhalation continues until RV reached
- Patient immediately inhales to TLC
- Visually inspect performance and volume time curve and repeat if necessary
Look out for:
a. Inconsistencies with clinical picture
b. Interrupted flow data
List common airway problems
Mild obstructive disease Severe obstructive disease Restrictive disease Variable extrathoracic obstruction Variable intrathoracic obstruction Fixed airway obstruction
What is the shape of the curve for mild obstructive disease?
Displaced to the left (indented exhalation curve)
RV and TLC are higher than normal
Because of mild breakdown in lung parenchymal tissue and hyperinflation of lungs
More air retained in lungs at RV (can’t be emptied)
Mild ‘coving’ (indentation) on the expiratory loop that suggests obstruction of the smaller airways
What is the shape of the curve for severe obstructive disease?
Shorter curve
Displaced to the left
Indented exhalation curve
Like mild, except the features of the loop are more pronounced
The RV is larger (more hyperinflation) and the ‘coving’ is deeper
Also, the height of the curve is lower, showing a lower peak expiratory flow rate (due to obstruction)
What is the shape of the curve for restrictive disease?
Displaced to the right
Narrower curve
Overall shape of the curve is preserved, however it is narrower on the x-axis (indicating a smaller TLC) and shorter on the y-axis (indicating impaired flow rates for inspiration and expiration)
What is the shape of the curve for the variable extrathoracic curve?
Blunted inspiratory curve (bottom too short)
Otherwise normal
This curve shows a complete normal expiratory curve, but an impeded (flattened) inspiratory curve
This is due to an obstruction outside thorax (perhaps the upper airway)
What is the shape of the curve for the variable intrathoracic curve?
Blunted expiratory curve (top too short)
Otherwise normal
This curve shows a complete normal inspiratory curve, but an impeded (flattened) expiratory curve
This is due to an obstruction within the thorax (perhaps the trachea)
What is the shape of the curve for the fixed airway obstruction?
Loop shows mixed characteristics of variable intra and extra obstruction
Blunted inspiratory and expiratory curves
Otherwise normal
What part of the lung/chest is in a partial vacuum?
Pleural cavity
What are the different mechanical forces involved in tidal and maximal ventilation?
Tidal breathing is predominantly diaphragm-induced (syringe movement)
Maximum ventilation involves full inspiratory muscle recruitment (syringe and bucket handle movement)
In gas transport/exchange, how are descriptions denoted?
I.e. how would you say volume of carbon monoxide bound to haemoglobin in the alveolar blood?
Prefix e.g. P, F, S, C, Hb
Middle (subscript) e.g. I, E, A, a, v (with line across top), P, D
Suffix e.g. O2, CO2, N2, Ar, CO, H20
SO…..
HbACO (A subscript)
In gas transport/exchange, what are these prefixes; P, F, S, C, Hb?
P= partial pressure (kPa or mmHg)
F= fraction (% or decimal)
S= Hb saturation (%)
C= content (mL)
Hb= volume bound to Hb (mL)
In gas transport/exchange, what are these middle (subscript) initials; e.g. I, E, A, a, v (with line across top), P, D
I= inspired
E= expired
A= alveolar
a= arterial
v (with line across top)= mixed venous
P= peripheral
D= dissolved
In gas transport/exchange, what are these suffixes; e.g. O2, CO2, N2, Ar, CO, H20?
O2= oxygen
CO2= carbon dioxide
N2= nitrogen
Ar= argon
CO= carbon monoxide
H20= water
List the key gas laws relevant in gas transport
Henry Fick Dalton Boyle Charles
‘Charles found Henry drinking beer’
What is Dalton’s law?
The pressure of a gas mixture is equal to the sum of partial pressures of gases in that mixture
Describes the pressure composition of the atmosphere
What is Fick’s law?
Molecules diffuse from regions of high conc to low conc at a rate
PROPORTIONAL TO:
P1-P2= the conc gradient
A= surface area for exchange
D= diffusibility of the gas
INVERSELY PROPORTIONAL TO:
T= thickness of the exchange surface
Describes factors affecting diffusion of molecules across a membrane
What is Henry’s law?
At a constant temperature, the amount of given gas that dissolves in a given type and volume of liquid is:
DIRECTLY PROPORTIONAL TO:
a= solubility of the gas
P= partial pressure of gas in equilibrium with that liquid
Describes how gas solubility in blood is proportional to pressure
What is Boyle’s law?
At a constant temperature, the volume (V) of a gas is indirectly proportional to the pressure (P) of the gas
Describes how gas volume decreases with increasing pressure
What is Charles’ law?
At a constant pressure, the volume (V) of a gas is proportional to the temperature (T) of that gas
Describes how gas volume increases with increasing temperature
What is atmospheric gas made up of?
- 2% nitrogen
- 9 % oxygen
- 9% argon
- 04% carbon dioxide
- 01% neon, xenon, helium and hydrogen
What is the barometric pressure (PB) at sea level?
101.3 kPa (760 mmHg)
How can the partial pressure of a gas (PGas) be calculated within a mixture?
Barometric pressure x gas proportion (as decimal) = kPa
E.g. 101.3 kPa x 0.209 = 21.2 kPa
= PO2 at sea level
What percentage of oxygen is in supplemental/therapeutical oxygen and how is it administered?
Up to 100%
Nasal cannula or full face mask
Depending on the concentration and flow rate of therapeutical oxygen, how much could the fraction of inspired oxygen (FI02) be increased to?
Above 60%
So amount of oxygen that will dissolve in the blood increases
What happens when noxious or polluted air is inspired?
Dangerous
Low oxygen in the mixture or chemicals that interrupt normal physiology (e.g. CO)
What happens to barometric pressure as altitude increases?
Ambient PB reduces
Fractions in inspired air are unchanged but reduced overall pressure
So PBIO2 at sea level= 21.2 kPa
PBIO2 at 4000m= 61.3 kPa
BUT still 20.9% oxygen
I.e. 20.9% of a smaller cake
What PO2, PCO2 and PH20 are found at sea level, in the conducting airways and in the respiratory airways
DRY AIR AT SEA LEVEL
PO2= 21.3
PCO2= 0
PH20= 0
CONDUCTING AIRWAYS
PO2= 20
PCO2= 0
PH20= 6.3
RESPIRATORY AIRWAYS
PO2= 13.5
PCO2= 5.3
PH20= 6.3
All in kPa
Air is warmed, humidified, slowed and mixed down respiratory tree
What is the total oxygen delivery at rest?
16ml/min
What is resting VO2?
Approx 250ml/min
Why is there a need for a more effective transport mechanism for oxygen than just relying on dissolved oxygen?
Total oxygen delivery at rest=16ml/min
Resting VO2= approx 250ml/min
Dissolved oxygen alone is not enough
Describe a monomer of haemoglobin
Ferrous iron ion (Fe 2+, haem-) at the centre of a tetrapyrrole porphyrin ring
Connected to a protein chain (-globin)
Covalently bonded at the proximal histamine residue
What are the 4 variants of haemoglobin
Alpha chain + haem = Hbα
Beta chain + haem = Hbβ
Delta chain + haem = Hbδ
Gamma chain + haem = Hbγ
How many monomers of haemoglobin form a haemoglobin molecule?
4-> tetramer
So can carry 4 oxygen molecules
What are the 3 most common variants of haemoglobin tetramer molecules?
HbA (2 Hbα & 2 Hbβ)= Adult Hb; 98%
HbA2 (2 Hbα & 2 Hbδ)= Adult Hb normal variant; ~2%
HbF (2 Hbα & 2 Hbγ)= Foetal Hb; trace amounts
What does it mean that haemoglobin is an allosteric protein?
As more molecules of oxygen bind, there is a greater attraction for other oxygens to bind
Cooperativity-> high affinity
What is methahaemoglobin?
If the ferrous iron (Fe 2+) is further oxidised by nitrites (-> Fe 3+, ferric form) then the haemoglobin becomes methaemoglobin (MetHb)
MetHb doesn’t bind oxygen so can cause functional anaemia
- Normal Hct
- Normal PCV
- Impaired O2 capacity
Describe the oxygen dissociation curve
Relationship between PO2 and oxygen in solution is simple and linear BUT Hb is more efficient than this
Across the physiological range of the lungs, Hb remains almost fully saturated (very shallow relationship)
At respiring tissues, there is a steep relationship (between PO2 and Hb saturation)
Why is haemoglobin very efficient at loading oxygen in the lungs and unloading oxygen at respiring tissues?
Lungs: LARGE change in PO2 = SMALL change in HbO2
Tissues: SMALL change in PO2 = LARGE change in HbO2
What causes a rightward shift in the oxygen dissociation curve?
Increased temperature
Acidosis (Bohr effect)
Hypercapnia
Increased 2,3- DPG
What causes a leftward shift in the haemoglobin oxygen dissociation curve?
Decreased temperature
Alkalosis
Hypocapnia
Decreased 2,3- DPG
What is the PO2 on the oxygen dissociation curve that corresponds to 50% binding called?
P50
Used as an index of oxygen affinity
Found on one of the steepest parts of the ODC (so highly susceptible to changes)
What is the normal P50 for adult Hb?
3.3 kPa
What haemoglobin concentration does the oxygen dissociation curve assume?
15g/dL
What causes the haemoglobin concentration to change?
Polycythaemia= condition where concentration of RBCs in the blood is much higher than normal, usually when the Hct/PCV is >55%
Anaemia
NB. severely anaemic patient may still have a normal pulse oximetry because can still fully saturate their Hb
.
Carbon monoxide= colourless, odourless poisonous gas (usually due to incomplete fuel combustion)
Why does CO affect haemoglobin concentration?
Hb has a greater affinity for CO than oxygen (250 times greater)
Hb will preferentially bind CO in the lungs, which reduces the number of binding sites for oxygen-> reducing oxygen content in the blood (causing a functional anaemia)
Also, binding CO pushes Hb into the tense state, reducing its ability to unbind any oxygen it is carrying
NB. Inhaling gas solution of 0.2% CO will occupy 80% haem binding sites
What does the HbCO dissociation curve look like?
HbCO ODC is displaced downwards (less capacity to bind O2) and leftwards (greater affinity for bound oxygen)
How does polycythaemia affect haemoglobin concentration?
RBC conc is much higher than normal
This stretches the ODC upwards, meaning that for a given PO2 there is no change in HbO2 saturation but a marked increase in blood oxygen content
How does anaemia affect haemoglobin concentration?
ODC pushed downwards as there is a lower concentration of haemoglobin, markedly reducing the overall oxygen-carrying capacity of the blood
Pulse oximetry may be same (can fully saturate their Hb)
What is the principal factor controlling the haemoglobin-oxygen relationship?
The partial pressure of dissolved oxygen
Although small by proportion (1.5%) it is pivotal in O2 transport
What does the ODC of foetal haemoglobin look like?
Greater affinity than adult HbA to ‘extract’ oxygen from mothers blood in placenta
So ODC shits to left
What does the ODC of myoglobin look like?
Much greater affinity than adult HbA to ‘extract’ oxygen from circulating blood and store it
So ODC shifts very far to left (almost vertical by Y axis), more left than foetal haemoglobin
What does foetal haemoglobin (HbF) consist of?
2 alpha chains
2 gamma chains
Greater affinity for oxygen than adult haemoglobin
In utero, HbF proportion is dominant (switches to HbA post-partum)
What is the P50 for HbF?
2.4 kPa
Why does methaemoglobin only occur in low quantities in healthy people?
Redox reactions constantly liberating or binding electrons
What is methaemoglobinaemia?
MetHb concentration is >1%
Functional anaemia (Hct and PCV normal, oxygen carrying capacity impaired)
100% MetHb would result in death (dissolved oxygen can’t support metabolic demands)
Familial methaemoglobinaemia is genetically recessive medical condition-> blue tinge of skin
What is myoglobin (Mb)?
Not a haemoglobin variant
Another oxygen-binding molecule
Consists of a haem molecule bound to a protein chain
What are the main differences between Mb and Hb?
Mb is a monomeric molecule (i.e. one haem group, one protein chain and one molecule of bound O2
Mb is a principally a storage molecule (Hb is a transport molecule) found in myocytes (myoglobin)
Why is meat fresh red/pink in colour?
High concentration of myoglobin
What is the P50 for Mb?
Very low
Approx 0.37 kPa
In respiratory gas transport, how is mixed venous blood involved in oxygen loading?
Blood in the venous circulation is often referred to as deoxygenated, despite the blood still containing 75% of the oxygen that arterial blood has
So known as mixed venous, and by using the symbol v̄
Blood retains 75% of its oxygen because metabolic demand for oxygen is low at rest
Using the ODC, this gives a PVO2 of 5.3 kPa (40 mmHg)
PAO2 is 13.5 kPa, and when deoxygenated blood reaches the respiratory exchanges surface it rapidly equilibrates with alveolar gas (0.25 s)
Oxygen passively diffuses down a concentration gradient (Fick’s Law)
During oxygenation, it passes from the alveolar space, into the pulmonary epithelial cells, into the interstitial space, into vascular endothelial cells, into the plasma, into red blood cells, and then binds to molecules of Hb that are not fully saturated
After equilibration, post-alveolar PaO2 is equal to PAO2 (which is 13.5 kPa) and SaO2 will be 100%
Post-alveolar venules converge into pulmonary veins but some deoxy blood enters circulation from bronchial venous drainage (before draining into the left atrium and being pumped into the systemic circulation)
This deoxygenated blood dilutes the PaO2 to 12.7 kPa (95 mmHg) and the SaO2 to 97%
In total, oxygen content (CaO2) is still slightly more than 20 mL/dL which is a delivery rate of about 1000 mL/min (assuming a cardiac output (Q̇) of 5 L/min)
In respiratory gas transport, how is mixed venous blood involved in oxygen unloading?
Arterial blood leaving heart remains unchanged (after oxygen loading) until it reaches systemic capillary beds, where tissue PO2 is considerably lower than PaO2
This gradient promotes diffusion of oxygen from the plasma into the endothelial cells, into interstitium, respiring cells, and mitochondria
As soon as the PaO2 starts to decrease, oxygen unloads from Hb (according to the ODC) and follows the dissolved oxygen down the concentration gradient and out of the circulation
Once the blood enters the venous circulation the PO2 has been reduced 5.3 kPa and SV̄O2 to 75%
CaO2 is reduced to 15 mL/dL, which is a 5 mL/d reduction from the pre-capillary vessel
In respiratory gas transport, how is mixed venous blood involved in oxygen flux?
Assuming a 5 L/min cardiac output, this represents a 250 mL/min rate of oxygen utilization
This is termed the oxygen consumption and is denoted by V̇O2
Blood is then returned to the right side of the heart where it is pumped back to the lungs and the cycle restarts
In respiratory gas transport, how is mixed venous blood involved in carbon dioxide loading?
CO2 is much more soluble (about 20x greater) than oxygen and diffuses into plasma very quickly
But in an aqueous solution (like plasma) CO2 will combine with H2O to form carbonic acid (H2CO3)
H2CO2= a weak acid that dissociates into a proton (H+) and bicarbonate (HCO3-)
Although very slow, this can cause the pH to fall significantly below the tightly regulated set-point of 7.4
Like oxygen, CO2 diffuses down the concentration gradient, so when plasma PCO2 begins to rise, CO2 begins to diffuse into erythrocytes
Once inside, the conversion of CO2 and H2O to carbonic acid is accelerated by the enzyme carbonic anhydrase
Bicarbonate is pumped out of the erythrocyte by an AE1 exchanger, which imports chloride ions to maintain membrane electroneutrality
The influx of chloride is associated with an influx of H2O – keeps the cell hydrated (water pumped out cell in form of bicarbonate)
To prevent an intracellular decrease in pH, excess protons are buffered by globin chains of haemoglobin molecules– certain residues are active proton accepters (e.g. Histamine)
Some intraerythrocytic CO2 binds to haemoglobin, but not to the haem molecule like oxygen; instead it combines with the amine group and the N-terminal of globin chains (-NH2 to -NHCOOH) adding a carboxyl group
When this occurs the haemoglobin molecule becomes carbamino-haemoglobin (HbCO2)
In respiratory gas transport, how is mixed venous blood involved in carbon dioxide unloading?
Similar to oxygen, CO2 in solution will diffuse into the alveoli first, which will trigger the reversal of all of the other binding mechanisms
Bicarbonate will re-enter erythrocytes and be re-associate with H+ to form carbonic acid, which the carbonic anhydrase enzyme will convert back into CO2 and H2O
Less oxygen bound, the more carbon dioxide will bind (and vice versa)
How long are pulmonary transmit time and gas exchange time?
Pulmonary transmit time= 0.75s
Gas exchange time= 0.25s
Oxygen less soluble, takes slightly longer
What is the main difference between carbon dioxide and oxygen transport?
The major difference between oxygen and carbon dioxide transport is that CO2 is much more soluble (about 20x greater) and diffuses into plasma very quickly
BUT in an aqueous solution (like plasma) CO2 will combine with H2O to form carbonic acid (H2CO3); a weak acid that dissociates into a proton (H+) and bicarbonate (HCO3-)
Very slow reaction but can cause the pH to fall significantly below the tightly regulated set-point of 7.4
What enzyme catalyses the reaction from CO2 and H2O to carbonic acid?
Carbonic anhydrase
Catalyses the reaction by a factor of 5000x and subsequent H2CO3 dissociates into H+ and HCO3- ions
Summarise how respiratory gases are transported in the blood
O2 transported in solution (~2%) or bound to Hb (~98%)
CO2 transported in solution, as bicarbonate (HCO3-) and as carbamino compounds (e.g. HbCO2)
What is the basic structure of the airways?
Conduit pipes to:
Conduct oxygen to the alveoli
Conduct carbon dioxide out of the lung
Cartilaginous or alveolar
What facilitates the functions of the airways?
Mechanical stability (cartilage)
Control of calibre (smooth muscle)
Protection and ‘cleansing’
How many generations of branches are there from trachea to alveolar sacs?
23
Cartilage quantity decreases
Smooth muscle increases
NB. cartilage ring incomplete and slightly offset, smooth muscle and nervous innervation complete
Why are the C shaped cartilages not set?
If set and stacked, there would be less tensile strength
This means can’t see the whole C
What happens to mucus when muscle contracts?
Muscle contracts-> squeezes mucus onto airway surface
Unknown process
What type of airways cells are found in ….?
Lining Contractile Secretory Connective Neuroendocrine Vascular Immune
Lining= ciliated, intermediate, brush, basal
Contractile= smooth muscle (airways, vasculature)
Secretory= goblet, mucous, serous
Connective= fibroblast, interstitial cell (elastin, collagen, cartilage)
Neuroendocrine= nerves, ganglia, neuroendocrine cells, neuroepithelial bodies
Vascular= endothelial, pericyte, plasma cell (and smooth muscle)
Immune= mast cell, dendritic cell, lymphocyte, eosinophil, macrophage, neutrophil
What do goblet cells contain?
Mucin granules
What do ciliated cells contain?
Many mitochondria
What cells are in the submucosal glands in the airway?
Mucous and serous acini
What is secreted by mucous and serous cells?
Mucous cells secrete mucins (mucin granules contain mucin in highly condensed form)
Serous cells secrete antibacterials (e.g. lysozyme)
Glands also secrete salt and water (Na ions and Cl ions)
What is the function of epithelial cells?
Secretion of mucins, salt and water
(Mucus + plasma , mediators etc.)
Physical barrier
Production of inflammatory and regulatory mediators (NO, CO, chemokine, cytokines, proteases, prostaglandins)
What is the ciliary structure?
9 + 2 arrangements of microtubules
Metachronal rhythm (beats out of sync-> moves mucus in one direction instead of backwards and forwards)
Mucus flakes= could be artefact of imaging or just how it works in people without lung conditions
With conditions-> thick mat of mucus
Describe the response of the smooth muscle in airways to inflammation
Structure- hypertrophy, proliferation
Tone (airway calibre)- contraction, relaxation
Secretion (mediators, cytokines, chemokines)
What is the secretory response of smooth muscle cells to inflammation?
Inflammation-> bacterial products and cytokines which act on smooth muscle cell
NOS-> NO
COX-> prostaglandins
Inflammatory cells recruitment (chemokines
cytokines and adhesion molecules)
What is the humoral control of the function of the airway cells?
Regulatory and inflammatory mediators:
- Histamine
- Arachidonic acid metabolites (e.g. prostaglandins, leukotrienes)
- Cytokines
- Chemokines
Reactive gas species
- Proteinases
Describe the tracheo-bronchial circulation (of the airway circulation)
1-5% of cardiac output
High blood flow (100-150 ml/min/100g tissue)
Bronchial arteries arise from sites on:
Aorta, intercostal arteries and others
Blood returns from tracheal circulation via systemic veins
Blood returns from bronchial circulation to both sides of heart via bronchial and pulmonary veins
Contributes to warming and humidification of inspired air
Clears inflammatory mediators and inhaled drugs
Provides airway tissue and lumen with inflammatory cells
Supplies airway tissue with proteinaceous plasma
Describe the 3 types of nerve that control the function of airway cells
Parasympathetic- cholinergic (ACh)
Sympathetic- adrenergic (adrenaline and noradreanline)
Sensory
What do cholinergic neurons do to control airways?
Principle motor control of airway (constriction)
Cholinergic nerves-> ACh onto muscarinic receptors on:
- Blood vessels
- Smooth muscle cells
- Submucosal glands
Why do the airways rely on the adrenal gland?
Little/no adrenergic nerves
List cells in regulatory-inflammatory cells in airways
Eosinophil Neutrophil Macrophage Mast cell T lymphocyte Structural cells e.g. smooth muscle, may also be regulatory-inflammatory cells
List mediators in regulatory-inflammatory cells in airways
Histamine Serotonin Adenosine Prostaglandins Leukotrienes Thromboxane PAF Endothelin Cytokines Chemokines Growth factors Proteinases Reactive gas species
What functions do the mediators have on on regulatory-inflammatory cells in airways?
Smooth muscle (airway, vascular: contraction, relaxation)
Secretion (mucins, water etc.)
Plasma exudation
Neural modulation
Chemotaxis
Remodelling
What respiratory diseases are associated with loss of airway control?
Loss of control-> respiratory disease
Asthma, COPD, cystic fibrosis
Airway inflammation, airway obstruction
Airway remodelling
What is the prevalence of asthma, COPD and CF?
Asthma – 5% of population
COPD – 4th cause of death in UK/USA
CF – 1:2000 Caucasians
What is asthma?
Increased airway responsiveness to a variety of stimuli -> airway inflammation and obstruction
Airway obstruction varies over short periods of time, is reversible
Dyspnea, wheezing, coughing
Varying degrees (mild to severe)
Airway inflammation-> re-modelling
Bronchoconstriction
What is bronchoconstriction?
Airway wall is thrown into folds, mucus plug in lumen
What is the mucosa in the lung?
Epithelium and underlying matrix
What is the structure of the mucosa?
From the large conducting airway to the alveoli
The structure is optimised for gas exchange (s.a. approximately size of tennis court)
Gas exchange units form a sponge-like structure which are intimately linked with the airways
The cross-sectional area of the lung increases peripherally
The gas exchange units are linked with surfactant
What lines the gas exchange units and why?
Surfactant
Phospholipid-rich surface active material that prevents lung collapse on expiration (immunological functions)
Secreted in the peripheral link and accounts for about 1 wine glass of fluid
Forms a very thin layer covering the respiratory units
Without it, the surface tension of the different gas exchange units will increase-> collapse of the lung
Describe the healthy lung?
HEALTHY LUNG
Epithelium forms a continuous barrier, isolating the external environment from the host
Produces secretions to facilitate mucociliary clearance
Protects underlying cells as well as maintain reduced surface tension
Metabolises foreign and host-derived compounds which may be carcinogenic – important for smokers
Releases mediators – controls number of inflammatory cells that reach the lung
Triggers lung repair processes
Describe the lung in COPD?
IN COPD
Increased number of goblet cells (known as hyperplasia) and increased mucus secretion
Between the goblet cells, ciliated cells push the mucus towards the throat
What proportion of epithalial cells are the goblet cells?
1/5
In large, central and small airways
What do goblet cells do?
Synthesise and secrete mucus
Mucus is complex, very ‘thin’ sol phase overlays cells, thick gel phase at air interphase
What happens to goblet cells in smokers?
Goblet cell number at least 2x
Secretions increase
More viscoelastic secretions
What does the modified gel phase do?
Traps cigarette smoke particles but always traps and harbours microorganisms
Enhances chance of infection
What does mucus contain?
Mucin proteins, proteoglycans and gycosaminoglycans, released from goblet cells and seromucous glands
Serum-derived proteins, such as albumin and alpha 1-antitrypsin, also called alpha 1-proteinase inhibitor, an inhibitor of polymorphonuclear neutrophil proteases
Antiproteases synthesised by epithelial cells e.g. secretory leucoprotease inhibitor
Antioxidants from the blood and synthesised by epithelial cells and phagocytes - uric acid and ascorbic acid (blood), glutathione (cells)
What is the purpose of mucin proteins, proteoglycans and glycosaminoglycans in mucus?
Gives mucus viscoelastcity
What is the purpose of serum-derived proteins e.g. albumin in mucus?
Combats microorganism and phagocyte proteases
What is the purpose of antiproteases in mucus?
Combats microogranism and phagocyte proteases
What is the purpose of antioxidants from the blood in mucus?
Combats inhaled oxidants e.g. cigarette smoke, ozone
Counteracts excessive oxidants released by activated phagocytes
What percentage of epithelial cells are ciliated cells?
80%
Found in large, central and small airways
How do cilia beat?
Metasynchronously
Push mucus forward engaging when vertical
Then circle around to original position in order to prevent the movement of the mucus backward as well as forward
Tips of cilia in sol phase of mucus pushes mucus towards epiglottis
Usually swallowed but expectorate
What happens to ciliated cells in smokers with bronchitis?
BRONCHIOLAR CILIATED CELLS
Depleted
Beat asynchronously
Reduced mucus clearance, bronchitis and respiratory infections occur
Airways obstructed by mucus secretions
Which lung condition associated with COPD is more easily reversed than other illnesses?
Bronchitis
Describe small airways
reduces peripheral gas exchange)
What are clara cells?
Club cells (non-ciliated, bronchiolar exocrine epithelial cells)
In large, central and small airways, bronchi and bronchioles
Found in most conducting and transitional airways (they increase proportionally distally)
What is the role of clara cells?
Metabolism, detoxification and repair
Contain phase I (incl. cytochrome P450 oxidases) and phase II enzymes
Major role of these enzymes is in xenobiotic metabolism (metabolism of foreign compounds deposited by inhalation)
Phase I enzymes are designed to metabolise foreign compounds into a format that enables phase II enzymes to react and neutralise the toxic agent
What is the problem with Phase I enzymes in clara cells?
Phase I enzymes are designed to metabolise foreign compounds into a format that enables phase II enzymes to react and neutralise the toxic agent; BUT they often activate a precarcinogen to a carcinogen
E.g: Benzopyrene (BP) is a precarcinogen in the particulate tar phase of cigarette smoke
One cytochrome P450, labelled CYPIA1 (also called aryl hydrocarbon hydroxylase), oxidases BP to benzopyrene diol epoxide (BPDE) which is a potent carcinogen
Phase II enzymes include glutathione S-transferase, which enables conjugation of BPDE to a small molecule that neutralises its activity
Why is CYPIA1 (one cytochrome P450) dangerous for smokers?
Smokers with lung cancer have a polymorphism of CYPIA1 that results in high levels (extensive metabolism -> extensive production of potent carcinogen)
Why is not having glutathione S-transferase likely to cause problems?
Some individuals are “null” for glutathione S-transferase i.e. they do not synthesise glutathione transferase and cannot neutralise BPDE
What happens if an individual who smokes has the CYPIA1 extensive metaboliser gene and the null glutathione gene?
40 times more likely to get lung cancer
These cells also make and release high levels of antiproteases e.g. secretory leukoproteinase inhibitor (SLPI)
They also synthesise and secrete lysosyme - enzyme that can lyse microorganisms
They synthesis and release antioxidants e.g. glutathione, superoxide dismutase
What can happen to alveoli in susceptible subject smokers?
Holes may develop
Alveoli may become larger
-> Reduction in surface area available for gas exchange
Seen as elastic tissue loss (so expansion during breathing is reduced-> exacerbates dead space)
Also fibrotic regions form in emphysema
What does the alveolar wall consist of and how are they susceptible to damage?
2 types of epithelial cells= type II and type II
Type II cells are more susceptible to damage than type I (but type I will be damaged more often)
Epithelial type II cells are only found in alveoli (cover 5% of alveolar surface)
What do Type II cells contain?
Lamellar bodies which store surfactant prior to release onto the air-liquid interface
-> Secrete surfactant
Synthesises and secretes antiproteases
Where are type I and type II cells positioned?
In the corners of the alveoli
Embedded in interstitium with apical membranes facing the air
Type II very close to capillaries
What cell is a precursor to alveolar type I cells?
Type II cells
They divide and differentiate to replace damaged type I cells
What percentage of the alveolar surface is type I cells?
95%
What is the ratio of type I and type II cells?
I:II = 1:2
What are stromal cells (myo) fibroblasts?
Make EC matrix
Collagen, elastin to give elasticity and compliance
Divide to repair
What is in an alveolar unit?
Type I epithelial cells Type II epithelial cells Stromal cells fibroblasts Macrophages Capillary endothelium
What is the difference between type I and type II epithelial cells?
TYPE I
Large (80um)
Very thin to allow gas exchange
TYPE II Cuboidal (10um) Secrete surfactant Repair/progenitor cells Precursor of type I cells
What is the difference between fibroblasts in normal repair and in abnormal repair?
NORMAL
Growth factors help normal repair
Type I cell death (and GFs)-> fibroblasts at capillary endothelium
ABNORMAL (e.g. emphysema)
Necrosis of EP1 cells-> abnormal repair->
-Type II cell proliferation
-Stromal/fibroblast cell proliferation (elevated GFs)
- Connective tissue synthesis
Summarise the functions of secretory epithelium
Goblet cell, Clara cells, Type II cells
Secrete protective lining layer to trap deposited particles (surfactant and mucus)
Synthesise and release antioxidants (glutathione, superoxide dismutase)
Synthesise and secrete antiproteinases (secretory leukoproteinase inhibitor (SLPI))
Release lysosyme
Carry out xenobiotic metabolism (e.g. process and detoxify foreign compounds such as carcinogens in cigarette smoke)
Contain cytochrome P450, phase I and II enzymes etc.
What are polymorphonuclear neutrophils and where are they found?
Usually only about 5% of lower respiratory tract phagocytes
Higher proportion in conducting/large airways
Store high levels of potent proteases in granules
These are released on activation
Smoker’s lungs contain high levels of these released proteases
Release very potent oxidative molecules such as hydroxyl anions during activation
What happens to number of neutrophils and macrophages in smokers?
Increase significantly in number, 5-10-fold and proportionally (up to 30% of total phagocytes) in smokers and more so during infection
Phagocytosis, antimicrobial defence, synthesis antioxidants (e.g. glutathione), xenobiotic metabolism
(Smokers lungs also contain high levels of the released proteases)
What proteases are secreted by macrophages and neutrophils?
Neutrophil= serine proteinases e.g. neutrophil elastase (NE) Macrophage= metalloproteinases e.g. MMP-9
Substrates: proteins, connective tissue, elastin, collagen
Activate other proteases (e.g. NE degrades and activates MMP)
Inactivate other proteases (e.g. MMP degrades and inactivates alpha-1-antitrypsin)
Activate cytokines/chemokines and other pro-inflammatory mediators
What do oxidants secreted by macrophages and neutrophils do?
Neutrophil and macrophage-> oxidants-> antimicrobial
Generate highly reactive peroxides
Interact with proteins and lipids
Inactivate alpha-1 antitrypsin
Fragment connective tissue
What do chemokines secreted by macrophages and neutrophils do?
Neutrophil and macrophage-> secrete mediators
Chemokines- IL-8 (neutrophil), MCP-1 (monocytes)
Cytokines- IL-1B, TNFa (inflammation)
Growth factors- VEGF, FGF, TFGB (cell survival, repair and remodelling)
What happens to neutrophils and macrophages in a COPD lung?
Neutrophils predominate in the large airways
Macrophages predominate in the alveolar region
What do neutrophils and macrophages release/generate?
Proteases
Cytokines and chemokines
Growth factors
Oxidants
Outline the histopathology of emphysema?
Classic emphysema is centre-lobular (centre of each lobule marks the site of initial infection)
Fibroblasts lie adjacent to epithelial cells lining the alveoli, and are available for proliferation following infection
Infection -> chronic damage (TI cell death)-> alveolar fibrosis (repair mechanism)
Increased type II epithelial cells
Increased number of fibroblasts – make lots of connective tissue
Communication between the type II cells and fibroblasts determines whether repair mechanisms proceed normally or abnormally (e.g. interstitial fibrosis)
Increased collagen deposition
ABNORMAL REPAIR–> irreversible damage
What effect does smoking have on TII and TI cells?
Blocks proliferation and differentiation of TII cells into TI cells, as well stimulating apoptosis/necrosis of both TI and TII cells
Also blocks communication between TII cells and fibroblasts, therefore blocking repair mechanisms
How do procarcinogens in smoking cause damage?
Contains procarcinogens which are activated by phase I enzymes
In normal metabolism, phase II enzymes then make these water soluble so that they can be metabolised and excreted
Smoking overloads the pathway, and may inactivate the enzyme, therefore the carcinogen may undergo DNA binding, adduct formation, no repair and mutation
What are the main causes of lung cancer?
Tobacco (carcinogens, 75% attributable, 25% non-smokers)
Radon (radiation)
Asbestos
NB. Asbestos + smoking -> 50x increased risk
What percentage of lung cancer patients die within 1 year of diagnosis?
80%
How many deaths per year in the UK are caused by lung cancer?
40,000 deaths per annum in UK
3rd most common cause
(Quarter of all cancer deaths)
What are the trends in mortality from lung cancer in smokers/ex-smokers?
Trends in mortality from lung cancer match trends in smoking
Passive smoking also leads to lung cancer
Not ‘too late’ to stop-> whenever you stop lower risk
What is the genetic basis of lung cancer?
Increasingly recognised that polymorphisms in certain genes affect the risk of developing lung cancer and may help explain why some smokers do not develop lung cancer
FAMILIAL LUNG CANCERS
Rare, but epidemiological evidence of increased risk for first degree relatives of young age, non-smoking cases
SUSCEPTIBILITY GENES
Nicotine addiction, chemical modification of carcinogens-> polymorphisms in cytochrome p450 enzymes and glutathione S transferases which play a role in eliminating carcinogens
What are clinical features of lung cancer?
Haemoptysis
Unexplained or persistent (more than 3 weeks)
- Cough
- Chest/shoulder pain
- Chest signs
- Dyspnoea
- Hoarseness
- Finger clubbing
- Cachexia
Clubbing of finger nails (should be acute but becomes obtuse)
Fingers also likely to be nicotine stained (if rolling)
What is a bronchoscopy?
Bronchoscopy= video used to see tumour and collect samples/biopsies
What STOP genes are often affected in lung cancer?
pRB
p53
bax
Describe the pathway for squamous cell carcinoma?
25% of pulmonary carcinoma (closely associated with smoking)
Normal epithelium-> hyperplasia-> squamous metaplasia-> dysplasia-> carcinoma in situ-> invasive carcinoma
Normally from bronchial epithelium (but sometimes peripheral because low tar cigarettes-> breathe in deeper-> get further)
Cells have a propensity to become cancer, what do they commonly affect?
Affect STOP genes and oncogenic fusion protein
Affect genes which regulate cell proliferation, invasion, angiogenesis and senescence
Summarize how lung cancer is staged
TNM classification
T= Primary tumour (T1-4)
N= Nodal involvement (N0-N3)
M= Metastasis (MO-M1)
How is the ‘T’ in TNM classification determined?
T1
Tumour =3cm diameter w/o invasion more proximal than lobar bronchus
T2
Tumour >3cm diameter
OR
Tumour of any size with the following:
- Invades visceral pleura, atelectasis of less than entire lung
-Proximal extent at least 2cm from carina (last cartilage ring before trachea divides into bronchi)
T3
Tumour of any size with any of the following:
- Invasion of chest wall
-Involvement of diaphragm, mediastinal pleura, or pericardium
- Atelectasis involving entire lung
- Proximal entent within 2cm of carina
T4
Tumour of any size with any of the following:
- Invasion of the mediastinum
- Invasion of heart or great vessels
- Invasion of trachea or oesophagus
- Invasion of vertebral body or carina
- Presence of malignant pleural or pericardial effusion (excess fluid accumulation)
- Satellite tumour nodule(s) within same lobe as primary tumour
How is the ‘N’ in TNM classification determined?
N0= no regional node involvement
N1= metastasis to ipsilateral hilar and/or ipsilateral peribronchial nodes
N2 = metastasis to ipsilateral mediastinal and/or subcarinal nodes
N3= metastasis to contralateral mediastinal or hilar nodes OR ipsilateral or contralateral scalene or supraclavicular nodes
Lymph nodes include: anterior carinal, posterior carinal, right paratracheal, left paratracheal, right main bronchus, left main bronchus, right upper hilar, subcarinal, right lower hilar, sub-sub carinal, left hilar
How is the ‘M’ in TNM classification determined?
M0= distant metastasis absent
M1= distant metastasis present (includes metastatic tumour nodules in a different lobe from the primary tumour)
Metastasis may include: brain, bone, hepatic, superior vena cava obstruction
What are the stage groups of TNM subsets?
IA – T1 N0 M0
IB – T2 N0 M0
IIA – T1 N1 M0
IIB – T2 N1 M0 or T3 N0 MO
IIIA – T3 N1 M0 or T1-3 N2 M0
IIIB – Any T N3 M0 or T4 Any N M0
1V – Any T Any N M1
What are the main types of lung cancer?
Non small cell cancer (more treatable) Small cell lung cancer (more dangerous, no known precursors) Benign Malignant Squamous Adenocarcinoma
BAMS S N-S
What is a known precursor of adenocarcinoma?
Atypical adenomatous hyperplasia= precursor of adenocarcinoma
Precursor legions of some major lung cancer types are recognized
What are benign lung tumours?
Don’t metastasise
Can cause local complications e.g. airways obstruction e.g. chrondroma
What are malignant lung tumours?
Potential to metastasise, but variable clinical behaviour from relatively indolent to aggressive
Commonest are epithelial tumours
What is squamous cell carcinoma? (+ Histology)
25-40% of lung cancer
Strong association with smoking
Mainly central arising from bronchial epithelium
Distant spread is later than seen in adenocarcinoma
Histology – shows evidence of squamous differentiation (keratinisation, desmosomes), variety of sub-types
What is adenocarcinoma? (+ Cytology and Histology)
Atypical adenomatous hyperplasia – proliferation of atypical cells lining the alveolar walls seen
They increase in size and eventually can become invasive
Molecular pathways
- Precursor may be type 2 pneumocyte/clara cell
- In non-smoker, EGFR mutation/amplification
In smoker, K ras mutation with DNA methylation of p53 occurs
Cytology – mucin vacuoles seen
Histology – extrathoracic metastases common and seen early, evidence of glandular differentiation seen with mucin secretion
What is large cell carcinoma?
Poorly differentiated tumour composed of large cells with no histological evidence of glandular or squamous differentiation
Electron microscopy shows evidence of some differentiation, suggesting they are probably very poorly differentiated adeno/squamous cell carcinoma
Poor prognosis
What is small cell carcinoma?
20-25% of lung cancer, very strong association with smoking, very aggressive behaviour
80% present with advanced disease and paraneoplastic syndromes
Outline some cytological and histological ways of investigation lung cancer
CYTOLOGY- looking at cells Sputum Bronchial washings and brushings Pleural fluid Endoscopic fine needle aspiration of tumour/enlarged lymph nodes
HISTOLOGY- looking at tissues
Biopsy at bronchoscopy- central tumours
Percutaneous CT guided biopsy- peripheral tumours
Mediastinoscopy and lymph node biopsy- for staging
Open biopsy at time of surgery if lesion isn’t accessible (frozen section)
Resection specimen- confirm excision and staging
How is survival related to stage?
Survival related to suitability for surgery
Considered in patients with Stage I, II and some with IIIa disease
Need to detect tumour early
Histologically-determining tumour type (small or non-small) is important for treatment, why?
SMALL CELL LUNG CARCINOMA
Survival 2-4 months untreated
10-20 months with current therapy
Chemoradiotherapy (surgery very rarely undertaken as most have spread at time of diagnosis)
NON SMALL CELL LUNG CARCINOMA Early Stage 1: 60% 5 yr survival Late Stage 4: 5% 5 yr survival 20-30% have early stage tumours suitable for surgical resection Less chemosensitive
Molecular studies of lung cancer allow what data to be generated?
Prognostic data
Therapeutic data (e.g. response to chemo, targets for novel drugs) E.g. Advanced NSCLC ERCC1 (excision repair cross-complimentation group 1 protein) has poor response to cisplatin based chemo
What are key targets of treatment in lung cancer (EGFR)?
Membrane receptor tyrosine kinase (regulates angiogenesis, proliferation, apoptosis and migration)
Mutation/amplification in NSCLC (non-smokers, females, asian ethnicity, adeno 46% vs squam 5%, target of TK inhibitor)
What are the LOCAL effects of bronchogenic carcinomas?
BRONCHIAL OBSTRUCTION
Collapse of distal lung-> shortness of breath
Impaired drainage of bronchus-> chest infection (pneumonia abscess)
INVASION OF LOCAL STRUCTURES
Invasion of local airways and vessels (haemoptysis, cough)
Invasion around large vessels (superior vena cava syndrome- venous congestion of head and arm oedema and ultimately circulatory collapse)
Oesophagus (dysphagia)
Chest wall (pain)
Nerves (Horners syndrome)
EXTENSION THROUGH PLEURA OR PERICARDIUM
Pleuritis or pericarditis with effusions
Breathlessness
Cardiac compromise
DIFFUSE LYMPHATIC SPRERAD WITHIN LUNG
Shortness of breath, very poor prognostic features
Lymphangitis carcinomatosa
What are the SYSTEMIC effects of bronchogenic carcinomas?
Physical effects of metastatic spread Brain (fits) Skin (lumps) Liver (liver pain, deranged LFTs) Bones (bone pain, fracture)
What is paraneoplastic syndrome?
Paraneoplastic syndrome= systemic effect of tumour due to abnormal expression by tumour cells of factors (e.g. hormones and other factors) not normally expressed by the tissue from which the tumour arose
Endocrine or non-endocrine
What are the endocrine and non-endocrine causes of paraneoplastic syndromes?
ENDOCRINE
Antidiuretic hormone (ADH)
- “Syndrome of inappropriate antidiuretic hormone” causing hyponatremia (especially small cell carcinoma)
Adrenocorticotropic hormone (ACTH) - Cushing’s syndrome (especially small cell carcinoma)
Parathyroid hormone-related peptides
- Hypercalcaemia (especially squamous carcinoma)
Other
- Calcitonin ->Hypocalcaemia
- Gonadotropins ->Gynecomastia
- Serotonin ->“Carcinoid syndrome” (especially carcinoid tumors; rarely small cell carcinoma)
NON-ENDOCRINE
Haematologic/coagulation defects, skin, muscular, miscellaneous disorders
What is mesothelioma?
Malignant tumour of pleura
Aetiology - asbestos exposure
What are common risk factors of mesothelioma?
Most patients have history of asbestos exposure
Long lag time: tumour develops decades after exposure
Males>females, approx 3:1
50-70 years of age
Present with shortness of breath, chest pain
Dismal prognosis
What is the 5 year survival or cure rate of lung cancer?
What are the functions of the respiratory muscles?
Maintenance of arterial PO2, PCO2 and pH (H+ ion) but pH probably most important
Defence of airways and lung: cough, sneeze, yawn
Exercise- fight and flight
Speech, sing, blow
Laugh, cry, express emotions
Control of intrathoracic and intra-abdominal pressures e.g. defecation, belch, vomiting
What controls breathing?
Metabolic controller in the medulla
Behavioural controller in the cortex
Reflex control
What is the respiratory frequency per second?
1/Ttot (so 60/Ttot per min)
What is minute ventilation?
Total air moved in and out per minute
Ve= Vt x f
Ve= minute ventilation Vt= tidal volume f= frequency
What proportion of minute ventilation is dead space ventilation?
1/3
What happens to inspiratory flow when there is a greater force of inspiration (controlled by brain)?
Greater force-> faster contraction-> greater inspiratory flow
What is the speed of expiration controlled by?
Passive
Braked so it occurs smoothly
When measuring tidal volume, what needs to be considered (regarding respiratory tube)?
Tidal volume for normal subjects is larger than results because of dead space between mouth and respiratory valve
How is the slope of VT/TI altered in chronic bronchitis and emphysema?
Normal= peak tidal volume (0.8) at 2.2 seconds, back to 0 at 4.6 seconds
Emphysema= peak tidal volume (0.7) at 1.8 seconds, back to 0 at 3.6 seconds
Chronic bronchitis= peak tidal volume (0.5) at 1 second, back to 0 at 2.8 seconds
THIS MEANS TTOT IS LONGEST IN NORMAL SUBJECTS AND SHORTEST IN CHRONIC BRONCHITIS
What does a shorter Ttot mean?
Faster
What parts of the CNS are involved in controlling breathing?
Voluntary (behavioural) centre in motor area of cerebral cortex
Involuntary (metabolic) centre in the medulla (bulbo-pontine brain)
- Other parts of cortex not under voluntary control influence metabolic centre
- Sleep via the reticular formation also influences the metabolic centre
Outline metabolic control of breathing (from the CNS)
Involuntary (metabolic) centre in the medulla (bulbo-pontine brain)
- Responds to metabolic demands for and production of CO2 and determines, in part, the set point for C02 (generally monitored as PaCO2)
May be influenced by:
- Limbic system (survival responses- suffocation, hunger, thirst)
- Frontal cortex (emotions)
- Sensory inputs (pain, startle)
Metabolic will always override behavioural
Outline behavioural control of breathing (from the CNS)
Voluntary (behavioural) centre in motor area of cerebral cortex
Behavioural centre controls acts e.g. breath holding, singing
What role do the phrenic nerve and chest wall have in metabolic control of breathing?
Phrenic nerve-> respiratory spinal motor neurons
Metabolic controller H+ R sets impulse frequency
Chest wall and lung feedback to the metabolic centre
SEE DIAGRAM
How does the carotid body (peripheral) chemoreceptor contribute to changes in arterial blood gases?
Well perfused carotid body ‘tastes’ arterial blood
Lies at the junction of the internal and external carotid arteries in the neck
Rapid response system for detecting changes in arterial PCO2 and PO2
What ‘pacemakers’ control central breathing?
Unlike heart (which has single pacemaker)
‘Group pacemaker’ activity coming from about 10 groups of neurons in the medulla (near nuclei of IX and X cranial nerves)
E.g. 1 group= pre-Botzinger complex
What is the pre-Botzinger complex?
A pacemaker that controls central breathing
Gasping centre
In ventro-cranial medulla, near 4th ventricle
Essential for generating the respiratory rhythm
Coordinates with other ‘controllers’ (i.e. to convert gasping into orderly/responsive respiratory rhythm)
Discrete groups of neurons in the medulla discharge at difference phases of the respiratory cycle, what functions do these have?
Early inspiratory initiates inspiratory flow via resp muscles
Inspiratory augmenting may also dilate pharynx larynx and airways
Late inspiratory may signal end of inspiration and ‘brake’ the start of expiration
Expiratory decrementing may ‘brake’ passive expiration by adduction larynx and pharynx
Expiratory augmenting may activate expiratory muscles when ventilation increases on exercise
Late expiratory may signal end of expiration and onset of inspiration and may dilate the pharynx in prep for inspiration
List the nerves involved in reflex control of breathing
Vth nerve= afferents from nose and face (irritant)
IXth nerve= from pharynx and larynx (irritant)
Xth nerve= from bronchi and bronchioles (irritant and stretch)
- Hering=Breuer reflex from pulmonary stretch Rs senses lengthening and shortening and terminates inspiration and expiration
- Weak in humans (ventilator responses in denervated lungs post-transplantation are normal)
Irritant Rs-> cough, sneezing etc. are defensive
Thoracic SC= from chest wall and respiratory muscles (spindles~ stretch)
Why does monitoring H+ changes allow PC02 changes to be seen?
CO2 is very diffusible and H+ changes mirrors Pco2 changes
Very rapidly for the hyperperfused carotid body
But more slowly in ECF bathing medulla
Fast and slow responses exist
What are the 2 parts of the metabolic controller?
Central in medulla responding to H+ ion of ECF
Peripheral part at carotid bifurcation, H+ Rs of carotid body
What potentiates CO2 responses?
Acidosis (lowers threshold, doesn’t change store)
Hypoxia
What role does CO2 have in ventilatory responses to hypoxia?
Ventilatory responses to hypoxia are amplified by CO2
Always an interaction between PO2 and PaC02
What needs to be controlled by breathing?
PaCO2
H+
PaO2 is not as tightly controlled as PaCO2 and H+
SaO2 rather than PaO2 appears to be defended
What happens to PaO2 and PaCO2 when ventilation falls?
Fall in PaO2 and rise in PaCO2
PaO2 fall-> increased sensitivity of carotid body to PaCO2 and H+
Ventilation and PaO2 increases
PaCO2 falls by –ve fb
What happens when PaO2 and PaCO2 fall together (e.g. climbing)?
Fall in inspired PO2 rather than minute ventilation is the primary event
What are the neural responses to loaded breathing?
Respiratory acidosis
Metabolic acidosis
Metabolic alkalosis
What is respiratory acidosis?
Acute: hypoventilation-> PaO2 to decrease, PaCO2 and H+ increase
-> Stimulates metabolic centre (and carotid body) to increase minute ventilation and restore blood gas and H+ levels
Chronic: ventilator compensation may be inadequate for PaCO2 homeostasis but renal excretion of weak acids (lactate and keto) returns H+ to normal (even though PaCO2 remains high)
What is metabolic acidosis?
Acidosis= excess production of H+
Compensatory mechanisms
Ventilatory stimulation lowers
PaCO2 and H+
Renal excretion of weak (lactate and keto) acids
Renal retention of chloride to reduce strong ion difference
What is metabolic alkalosis?
Alkalosis: excess HCO3- lowers H+
Compensatory mechanisms
Hypoventilation raises PaCO2 and H+
Renal retention of weak (lactate and keto) acids
Renal excretion of chloride to increase strong ion difference
What are hypoventilation conditions?
PaCO2 increases
Central (acute or chronic)
Peripheral (acute or chronic)
COPD (mixture of peripheral and central)
What causes central ‘won’t breathe hypoventilation?
ACUTE
Metabolic centre poisoning (drugs especially opioids, anaesthetics)
CHRONIC
Vascular/neoplastic disease of metabolic centre
Congenital central hypoventilation syndrome (decreased VE and PaCO2)
Obesity hypoventilation syndrome
Chronic mountain sickness
What causes peripheral ‘can’t breathe’ hypoventilation?
ACUTE
Muscle relaxant drugs, myasthenia gravis
CHRONIC
Neuromuscular with respiratory muscle weakness
What conditions lead to hyperventilation?
PaCO2 decreases Chronic hypoxaemia Excess H+ (metabolic causes) Pulmonary vascular disease Chronic anxiety (psychogenic)
How can breathlessness arise?
With excitement or anticipation
- > Suspending breathing with an emotional cause
- > WITHOUT BREATH
Out of breath
- > Normal experience when exercise exceeds a threshold of comfort
- > TOO MUCH BREATHING
What is dyspnea?
Medical term for breathlessness but with connotation of discomfort or difficulty
Tightness (due to narrowing airway, feels like chest isn’t expanding normally)
Increased work and effort
- High minute ventilation
- OR normal minute ventilation with high lung volume
- OR against an inspiratory or expiratory resistance
What is air hunger?
Sensation of a powerful urge to breath, e.g. breath hold during exercise
Mismatch between VE demanded/VE achieved (output)
Cerebral cortex compares 2 afferent inputs
1) Demand= copy (corollary) of signal sent by metabolic controller to spinal motorneurones
2) Output= Afferents from lung, chest wall and chemoreceptors (carotid body)
How can air hunger be replicated experimentally?
Experimentally, produced by driving breathing with added CO2 while restricting tidal volume (breathing from bag of fixed volume)
What scales are used to measure breathlessness during an exercise test?
Borg CR 10 scale (0 nothing at all, 10 maximal)
Visual analogue scale (0 not at all breathless, 10 extremely breathless)
What is BHT?
Breath holding time
Tests strength of behavioural vs metabolic controller
Break point prolonged by increasing lung volume, lowering PaCO2 or by taking an isoxic/isocapnic breath near the break point
Acute thoracic muscle paralysis with curare does not prolong BHT
Break point is an expression of air hunger
BHT~ product of stretch receptor drive x metabolic drive
What test is used to test arterial blood gases (ABG)?
Cornerstone blood test
What is alkalaemia?
Raised pH of blood
What is acidaemia?
Lowered pH of blood
What is alkalosis?
Describes circumstances that will decrease proton concentration and increase pH
What is acidosis?
Describes circumstances that will increase proton concentration and decrease pH
What is an acid?
Any molecule that has a loosely bound H+ ion it can donate
Why does the acidity of the blood need to be tightly regulated?
Changes-> alter 3D structure of proteins -> altered enzymes, hormones, channels
What is a base?
Anionic (negatively charged ion) molecule capable of reversibly binding protons
-> Reduce amount of free H+
H+A- H+ and A-
Relationship is in equilbrium
When a relationship is in equilibrium, what happens when you increase something on one side?
Push the equation in the opposite direction
H2O + CO2 H2CO3 H+ + HCO3-
How do the blood react to pH imbalances?
Blood has enormous buffering capacity
Can react almost immediately to imbalances
(Pitts and Swan experiment)
Describe the pH scale?
Log 10 transformation using number of H+ ions (was too tiny to use easily) Made negative (-log10[H+]) to make positive values
Inverse log (10 to the power of x) can be used to calculate H+ concentration from pH [H+] = 10 to the power of -pH
What is the Sorensen equation?
pH= -log10[H+]
What is the Henderson equation?
K= ([H+][HCO3-]) / [CO2]
What is the Henderson-Hasselbalch equation?
pH= pK + log10 ([HCO3-] / [CO2])
Uses Sorensen and Henderson
pH= -log10[H+] AND K= ([H+][HCO3-]) / [CO2]
How do you assess the respiratory component of arterial blood gases (ABG)?
PaCO2 (high or low)
How do you assess the metabolic component of arterial blood gases (ABG)?
BE (high or low)
How do you assess hypoaxaemia using arterial blood gases (ABG)?
PaO2
> 10 kPa= normal
8-10= mild
6-8 moderate
How do you assess acidosis/ alkalosis using arterial blood gases (ABG)?
pH
How do compensatory mechanisms (renal and respiratory) correct acid-base imbalances?
Changes in ventilation can stimulate a RAPID compensatory response to change CO2 elimination and therefore alter pH
Changes in HCO3- and H+ retention/secretion in the kidneys can stimulate a SLOW compensatory response to increase/decrease pH
An acidosis will need an alkalosis to correct
An alkalosis will need an acidosis to correct
How is compensation described in ABG?
Uncompensated
Partially compensated
Fully compensated (pH is normal )
How is oxygenation described in ABG?
Hypoxaemia
Normoxaemia
Hyperoxaemia
How can pH be distorted?
RESPIRATION
Hypoventilation
Hyperventilation
METABOLISM
Lose bicarbonate= Diarrhoea (Proton gaining e.g. lactic acid production increase)
Bicarbonate gaining (losing HCL) and proton losing= Vomiting
How does hypoventilation distort pH?
Less breathing than normal
Reduction in minute ventilation
Less fresh air reaching alveolar
Amount of CO2 in alveolar sacs steadily increases
Reduces diffusion gradient
Less CO2 moves out of the blood
Amount of CO2 in post-alveolar blood increases
Favours forward reaction (carbonic acid-> increased H+ and HCO3-)
Excess accumulation of protons
SO.... Decreased pH Increased PCO2 BE (Bicarbonate concentration is correct for PCO2 'proportionally normal')
UNCOMPENSATED RESPIRATORY ACIDOSIS
Why is CO2 called a respiratory acid?
CO2 is a respiratory acid
Combines with water to form carbonic acid-> dissociates to H+ and HCO3-
How does the body attempt to correct the imbalance caused by lower pH (proton accumulation) (RESPIRATORY) ?
Body tries to reduce proton concentration (respiratory acidosis)
Increase bicarbonate to bind excess protons and normalise pH
ACUTE PHASE
CO2 moving into erythrocytes combines with H20 in presence of carbonic anhydrase-> bicarbonate
Bicarbonate moves out of cell via AE1 transporter
Increased plasma bicarbonate concentration pushes the carbonic acid equilibrium backwards-> increases pH
CHRONIC PHASE
Increases amount of bicarbonate reabsorbed in the kidneys
Once corrective mechanisms in action…
pH still low (closer)
PCO2 still increased
BE high (plasma bicarbonate higher than expected for the PCO2)
PARTIALLY COMPENSATED RESPIRATORY ACIDOSIS
What is fully compensated respiratory acidosis?
Compensation returns pH to within normal range
pH
High PCO2
High BE
FULLY COMPENSATED RESPIRATORY ACIDOSIS
How does hyperventilation distort pH?
More breathing than normal
Increase in minute ventilation
More fresh air reaching alveolar
Amount of CO2 in alveolar sacs steadily decreases
Increases diffusion gradient
More CO2 moves out of the blood
Amount of CO2 in post-capillary blood decreases
Favours backward reaction (more protons lost from solution)
Increasing pH
SO.... Increased pH Decreased PCO2 BE (Bicarbonate concentration is correct for PCO2 'proportionally normal')
UNCOMPENSATED RESPIRATORY ALKALOSIS
How does the body attempt to correct the imbalance caused by increased pH (RESPIRATORY)?
Body tries to increase proton concentration in the blood
CHRONIC PHASE
Reduces amount of bicarbonate reabsorbed in the kidneys (renal nephrons)
Increases bicarbonate secretion in collecting ducts
More carbonic acid will dissociate into proteons
Once corrective mechanisms in action…
pH still high (closer)
PCO2 still decreased
BE low (plasma bicarbonate lower than expected for the PCO2)
PARTIALLY COMPENSATED RESPIRATORY ALKALOSIS
What is fully compensated respiratory alkalosis?
Compensation returns pH to within normal range
pH
Low PCO2
Low BE
FULLY COMPENSATED RESPIRATORY ALKALOSIS
Why does diarrhoea affect acid/base balance?
Watery faeces
Bicarbonate lost in enteric secretions that can’t be replaced quickly enough
Means decreased bicarbonate and accumulation of protons
Decreased pH
Normal PCO2
Decreased BE
UNCOMPENSATED METABOLIC ACIDOSIS
How does the body attempt to correct the imbalance caused by decreased pH (METABOLIC)?
Plasma proton concentration needs to be increased
Manipulate ventilation
Increased ventilation
Reduces alveolar PCO2
Increases diffusion gradient
Reduces systemic arterial PCO2
Shifts carbonic acid reaction to left to correct PACO2
Decreased CO2
More protons and bicarbonate combine-> carbonic acid which is then converted into water and CO2
pH low
PCO2 low
BE low
PARTIALLY COMPENSATED METABOLIC ACIDOSIS
What is fully compensated metabolic acidosis?
Compensation returns pH to within normal range
pH
Low PCO2
Low BE
FULLY COMPENSATED METABOLIC ACIDOSIS
Why does vomiting affect acid/base balance?
Vomiting
Lose HCL from stomach
Generalised loss of protons from EC environment
Bicarbonate concentration increases (less protons to bind to)
Increased pH
Normal PCO2
Increased BE (disproportionately high)
UNCOMPENSATED METABOLIC ALKALOSIS
How does the body attempt to correct the imbalance caused by increased pH (METABOLIC)?
Plasma proton concentration needs to be reduced
Manipulate ventilation
Reduced ventilation
Increases PCO2 of arterial blood
Shifts carbonic acid reaction to right to correct increased PACO2
Produces more protons and further increases bicarbonate
pH high
PCO2 high
BE high
PARTIALLY COMPENSATED METABOLIC ALKALOSIS
What is fully compensated metabolic alkalosis?
Compensation returns pH to within normal range
pH
High PCO2
High BE
FULLY COMPENSATED METABOLIC ALKALOSIS
Regarding pH, PCO2 and BE, what is characteristic of:
Uncompensated respiratory acidosis
Partially compensated respiratory acidosis
Fully compensated respiratory acidosis
Uncompensated respiratory alkalosis
Partially compensated respiratory alkalosis
Fully compensated respiratory alkalosis
Uncompensated metabolic acidosis
Partially compensated metabolic acidosis
Fully compensated metabolic acidosis
Uncompensated metabolic alkalosis
Partially compensated metabolic alkalosis
Fully compensated metabolic alkalosis
pH PCO2 BE (ARROW DIRECTION) SAME means no change
Uncompensated respiratory acidosis= DOWN UP SAME
Partially compensated respiratory acidosis= DOWN UP UP
Fully compensated respiratory acidosis= SAME UP UP
Uncompensated respiratory alkalosis= UP DOWN SAME
Partially compensated respiratory alkalosis= UP DOWN DOWN
Fully compensated respiratory alkalosis= SAME DOWN DOWN
Uncompensated metabolic acidosis= DOWN SAME DOWN
Partially compensated metabolic acidosis= DOWN DOWN DOWN
Fully compensated metabolic acidosis= SAME DOWN DOWN
Uncompensated metabolic alkalosis= UP SAME UP
Partially compensated metabolic alkalosis= UP UP UP
Fully compensated metabolic alkalosis= SAME UP UP
If BE is normal and there has been a respiratory disturbance, what compensation has occurred?
Uncompensated
If CO2 is normal and there has been a metabolic disturbance, what compensation has occurred?
Uncompensated
If pH is normal and BE and CO2 are both 1) UP? 2) DOWN? What has happened?
1) Fully compensated respiratory acidosis OR Fully compensated metabolic alkalosis
2) Fully compensated respiratory alkalosis OR Fully compensated metabolic acidosis
If pH, BE and CO2 are all 1) UP? 2) DOWN? What has happened?
1) Partially compensated metabolic alkalosis
2) Partially compensated metabolic acidosis
If pH is in a different direction to BE and CO2, what happened?
pH DOWN, BE & CO2 UP= partially compensated respiratory acidosis
pH UP, BE & CO2 DOWN= partially compensated respiratory alkalosis
Describe the neurophysiological pathway of respiratory symptoms being generated and perceived?
Sensory stimulus-> transducer-> excitation of sensory nerve-> integrated into CNS-> sensory impression
Describe the behavioural psychology pathway of respiratory symptoms being generated and perceived?
Sensory impression-> perception-> evoked sensation
What are the symptoms and signs of respiratory disease?
SYMPTOMS
An abnormal or worrying sensation that leads the person to seek medical attention e.g. cough, chest pain, shortness of breath (SOB), haemoptysis
SIGNS
An observable feature on physical examination e.g. hyperinflation of chest wall, dullness on percussion of chest wall, increased respiratory rate, reduced movement of chest wall
What is the prevalence of coughs, chest pain and dyspnea in patients?
COUGH
3rd most common complaint heard by GP
10-38% of patients in respiratory outpatients complain of cough
CHEST PAIN
Most common pain for which patient seeks medical attention (35%), including acute chest pain
DYSPNEA (shortness of breath)
6-27% of general population
3% of visits to A&E
Define: cough
A crucial defence mechanism protecting the lower respiratory tract from inhaled foreign material and excessive secretion, secondary to mucociliary clearance
What is the most prevalent cough?
Chronic cough correlated to smoking, but also associated with current asthma, environmental tobacco smoke exposure
Prevalence 7.2-18%, with reduced prevalence involving sputum production
What does the expulsive phase of a cough do?
Generates a high velocity of airflow
Facilitated by bronchoconstriction and mucus secretion
How much fluid is removed from the airways each day?
30-100ml of fluid
What is the ‘cough receptor’?
Nerve profile situated between a goblet cell and a columnar epithelial cell
When stimulated-> cough
Where are irritant receptors found?
Within airway epithelium
Mostly on posterior wall of trachea
Rapidly adapting
Less numerous at main carina (last cartilage before trachea bifurcation) and large branching points
less numerous in more distal airways
Also in pharynx
Possibly elsewhere
What do laryngeal and tracheobronchial receptors respond do?
Chemical and mechanical stimuli
What sensory receptors give rise to a cough?
Slowly adapting stretch receptors
= Myelinated nerve fibres
Rapidly adapting stretch receptors
= Small myelinated nerve fibres, respond to mech/chem stimuli and inflamm mediators
C fibre receptors
= Free nerve endings, small unmyelinated fibres
Respond to chemical irritants and inflamm mediators
Release neuropeptide inflammatory mediators (substance B, neurokinin A, calcitonin gene related peptide)
Where are sensory receptors involved in coughing?
In lungs and airways
SA stretch= airway smooth muscle, predominantly in trachea and main bronchi
RA stretch= naso-pharynx, larynx, trachea, bronchi
List examples of chemical and mechanical irritants that can lead to coughs
Mechanical= dust, mucous, food, drink
Chemical= noxious, intrinsic inflammatory agents
Outline the nerve pathways/neural activity involved in coughing
AFFERENT
From lungs via vagus (X) nerve (relay impulses to near the nucleus tractus solitarius to medulla cough centre)
From throat via superior laryngeal nerve (also stimulates cough centre in medulla-> cerebral cortex)
CENTRAL
Cough centre in brainstem probably diffusely located
EFFERENT
Cerebral cortex-> cough centre-> glottis, diaphragm and expiratory muscles
I.e. motor neurones to respiratory muscles
What is the bulbopontine controller?
The respiratory centre
Different from cough centre in medulla oblongato
What neurotransmitters may be involved in coughing?
5-HT, GABA
Opiates suppress cough
Describe how coughing produces a sound?
Inspiratory phase= negative airflow occurs
Glottic closure= subglottic pressure increases (while glottis is closed)
Expiratory phase= explosure, airflow increases rapidly-> sound
What are causes of chronic coughs?
Acute infections– tracheobronchitis, bronchopneumonia, viral pneumonia, acute-on-chronic bronchitis, bordetella pertussis
Chronic infections– bronchiectasis, tuberculosis, cystic fibrosis
Airway diseases– asthma, chronic bronchitis, chronic post-nasal drip
Parenchymal diseases– interstitial fibrosis, emphysema
Tumours– bronchogenic carcinoma, alveolar cell carcinoma, benign airway tumours
Foreign body
Cardiovascular– left ventricular failure, pulmonary infarction, aortic aneurysm
Other diseases– reflux oesophagitis, recurrent aspiration
Drugs– angiotensin converting enzyme
What types of cough are there?
ACUTE 3 weeks on presentation to respiratory clinic Asthma + eosinophil associated Gastro-oesophageal associated Rhinosinusitis (post-nasal drip) Chronic bronchitis (“smokers cough”) Bronchiectasis, Drugs, Post-viral, Idiopathic and other causes
How are unnecessary coughs controlled?
Oesophageal bronchial reflex
Direct action of protons on cough receptors
Activation of brainstem cough centres
What is the oesophageal bronchial reflex?
Activation of cough receptors occurs due to interconnecting neurones between the trachea and oesophagus
What is the direct action of protons on cough receptors?
Protons travel to the pharynx and stimulate cough receptors
What is the activation of brainstem cough centres?
Neural mechanism (plastic i.e. can be increased by chemical mediators)
Chemical mediators (e.g. prostaglandin E2) increase the excitability of afferent nerves
The number of receptors and voltage-gated channels increases, e.g. TRPV-1 (transient receptor potential vanniloid-1: calcium-permeable, non-selective cation channel)
Neurotransmitter levels increase e.g. neurokinins in brain stem
What are the indications of a chronic cough?
Increased cough reflex
Irritation in the throat or upper chest
Cough paroxysms are difficult to control
Triggers of chronic cough include: deep inhalation; laughing; talking too much; vigorous exercise; smells; cigarette smoke; eating crumbles; cold air; lying flat
What are possible complications of coughs?
Pneumothorax with subcutaneous emphysema
Loss of conciousness (cough syncope)
Cardiac dysrythmias
Headaches
Intercostal muscle pain
Rupture of rectus abdominis juscle
Social embarrassment
Depression
Urinary incontinence
Wound dehiscence
How can coughs be treated?
Inhaled corticosteroids and inhaled beta-adrenergic agonists (for asthma, cough-variant asthma and eosinophilic bronchitis)
Topical steroids, topical vasoconstrictors for rhinosinusitis (post-nasal drip)
Proton-pump inhibitors, medical therapies - for gastro-oesophageal reflux
Stop ACE inhibitor – for ACE inhibitor cough
Antitussives:
- Opiates – codeine, pholcodeine, dextromethorphan
- Demulcents
- Aromatics
What do bronchodilators target in coughs?
E.g. Beta 2 agonists and anticholinergics
Target airway smooth muscle
What do anti-inflammatories target in coughs?
Blood vessel eosinophil communication
What do opioids target in coughs?
CNS and Vagus nerve
What do acid pH inhibitors target in coughs?
Airway epithelium
Periciliary fluid
What is the sensory input involved in chest pain?
Nose: trigeminal nerve (V)
Pharynx: glossopharyngeal nerve (IX); vagus nerve (X)
Larynx: vagus nerve (X)
Lungs: vagus nerve (X)
Chest wall: spinal nerves
What nerve pathways are involved in chest pain?
PAIN PATHWAY
Pain receptors: Aδ and C-fibres
Nerve fibres cross at the spinal level and synapse in the thalamus
Nerves travel to the primary somatosensory cortex
Pain consciously sensed (neurophysiology and behavioural psychology)
TOUCH PATHWAY
Touch receptors: Aα and Aß
Nerve fibres cross at the medullary level and synapse in the thalamus
Nerves travel to the primary somatosensory cortex
What are the main types of pain?
ACUTE
Somatic
Visceral (less well understood)
CHRONIC
More complications than acute, neural basis
What kind of chest pain can occur in respiratory disorders?
Chest wall- muscular or rib fracture
Pleural pain
Deep-seated, poorly-localised pain
Nerve-root pain/intercostal nerve pain
Referred pain: shoulder-tip pain of diaphragmatic irritation
What kind of chest pain can occur in non-respiratory disorders?
CVD – myocardial ischaemia/infarction, pericarditis, dissecting aneurysm
Gastrointestinal disorders – oesophageal rupture, gastrooesophageal ferlux
Psychiatric disorders – panic
What is dyspnea?
Shortness of breath
Symptom reported by patient - occurs at inappropriately low levels of exertion and limits exercise tolerance
Unpleasant and frightening experience
Can be associated with feelings of impending suffocation
Poor perception of respiratory symptoms and dyspnoea may be life-threatening
What is used to assess dyspnoea?
1. COMMENTS Respiratory descriptors (different terms fit into different clusters* of phrases)
- SUBJECTIVE RATING SCALES
(Modified Borg scale
or visual analogue) - QUESTIONNAIRES
Exercise tolerance related
Quality of life related - EXERCISE TESTING
6 in walk
Shuttle test
Clusters
Air hunger e.g. starved for air
Work/effort e.g. breathing requires work
Tightness e.g. heaviness in chest
What disorders present with chronic dyspnoea?
Impaired pulmonary function
Impaired cardiovascular function
Altered central ventilatory drive or perception
Physiologic processes e.g. deconditioning, hypoxic high altitude, pregnancy, severe exercise
Idiopathic hyperventilation
How does impaired pulmonary function lead to SOB?
Airflow obstruction e.g. Asthma, COPD, tracheal stenosis
Restriction of lung mechanics e.g. idiopathicpulmonary fibrosis
Extrathoracic pulmonary restriction e.g. Kyphoscoliosis, pleural effusion
Neuromuscular weakness e.g. Phrenic nerve paralysis
Gas exchange abnormalities e.g. Right to left shunts
How does impaired CV function lead to SOB?
Myocardial disease leading to heart failure Valvular disease Pericardial disease Pulmonary vascular disease Congenital vascular disease
How does altered central ventilatory drive/perception lead to SOB?
Systemic or metabolic disease
Metabolic acidosis
Anaemia
How is dyspnoea treated?
Treat the cause, e.g. lung/cardiac
Therapeutic options include:
- Add bronchodilators e.g. anticholinergics or b-adrenergic agonists
- Drugs affecting brain e.g. morphine, diazepam
- Lung resection (e.g. lung volume reduction surgery)
- Pulmonary rehabilitation (improve general fitness, general health, psychological well-being)
How common is pneumonia in GPs?
Most have lower respiratory tract illnesses which don’t require treatment
Large clinical iceberg of lower respiratory tract infections
Most who go to hospital have pneumonia
Many with pneumonia still in community
Why are lung infections so common?
Breathing in -> constantly exposed to potential infectious agents
What is the multi-layered defence mechanism of the respiratory tract?
Mechanical= URT filtration, mucociliary clearance, cough, surfactant, epithelial barrier
Local= BALT, slgA, lysozyme, transferrin, antiproteinases, alveolar macrophages
Systemic= polymorphonuclear leucocytes, complement, immunoglobulins
BALT (bronchiole-associated lymphoid tissue)
Describe how mucociliary clearance works
Cilia are an example of mechanical defence – they are part of the mucociliary system which protects the
upper and lower airways all the way distally to the respiratory bronchioles
Ciliated layer lies beneath the sticky mucus layer, surrounding by a watery fluid (periciliary fluid)
Each epithelial cell has 200 cilia, with tight junctions sealing the gaps between the cells acting as a barrier protecting the airways
Each cilium has a coordinated beating movement, consisting of a stiff downstroke which propels mucus forward, and a curved backstroke within the periciliary fluid underneath the fluid
This ensures mucus is propelled in one direction only
Each cilium beats about 14 times per second, and engages with the mucus with its claws only when at full vertical height
Each cilium and its surrounding neighbours beat in an ordered fashion, known as metchronal rhythm
Describe the structure of cilia
Each cilium also has an individual ultra-structure which can be examined under EM
Consist of 9 doublets + 2 central microtubules, which slide up and down each other to cause ciliary movement
(ATPase in the dynein arms provides the energy for movement)
How many cilia are there per epithelial cell?
200
How many times per second does each cilium beat?
14
Infectious agents overcome lung defences or defences are weakened by…
Inherited factors e.g. immunodeficiency
Acquired e.g. through smoking
Often a combo
What effect does smoking have on mucociliary clearance?
Cigarettes perturb mucociliary clearance
By destroying the cilia (seen by biopsy) and changing the nature of airways to stimulate increased mucus production (causing morning cough).
Also, makes the mucus produced more viscous and difficult to move by any remaining cilia
What effect do viruses have on mucociliary clearance?
Viruses perturb mucociliary clearance by destroying cilia, stimulating the production of more and more watery mucus (leading to a runny nose)
The cilia therefore do not have a grip on the mucus, making it difficult to get rid of
In addition viruses separate the tight junctions between airway epithelium and destroy epithelial cells
What symptoms/signs indicate that something is wrong with lung defences (i.e. respiratory infection syndromes)?
Incidence of virulent infections Recurrent infections (especially pneumonia) Chronic infections (body unable to get rid of infection
What causes respiratory infection syndromes?
Congenital abnormality-> weak defences
Hereditary
Viruses
Cigarette smoking
What is Primary Cilia Dyskinesia (PCD)?
Loss of some proteins in cilia
Cilia don’t beat properly so mucociliary clearance doesn’t work
Some men are infertile because sperm tails are cilia, so they do not move successfully to reach the
ovum
Cicila present with absent dynein arms, no energy, no movement
Other ultrastructural abnormalities involve the microtubules, which perform disorganised beating
How can abnormal cilia be diagnosed?
Painless nasal brushing
Nitric oxide levels (less painful)
What kind of bacterial pathogens of the lung are there?
Virulent species- cause pneumonia e.g. streptococcus pneumonia
Less virulent species- cause bronchitis (equipped to chronically infect airways in defences that have been compromised) e.g. unencapsulated haemophilus influenza
How does influenza bacteria infect airways?
Haemophilus influenza is the commonest cause of airway infections; (1/4 smokers have this bacterium chronically infecting their airways)
Bacteria has hair-like projections called fimbriae which anchor the bacterium to epithelial cells to stop the bacteria being moved away by ciliary beat
In an infected bronchial mucosa, the bacterial infection stimulates more mucus production, and the bacteria bind avidly to mucus
In an episode of bronchitis, the inflammatory response and antibiotics help clear the infection from the airways
However bacteria are equipped with ways of avoiding elimination by the body’s defences
What strategies do bacteria use to avoid being cleared from airways?
They either produce factors which impair the defences, or find ways of “hiding” from the defences
THESE INCLUDE:
Exoproducts which impair mucuciliary clearance – by slowing and disorganising ciliary beat, stimulating mucus production, affecting ion transport + damaging epithelium
Enzymes – break down local immunoglobulins
Exoproducts – impair neutrophil, macrophage + lymphocyte function
Adherence is increased by epithelial damage and tight junction separation
Avoid immune surveillance – using surface heterogeneity, biofilm formation, surrounding gel and endocytosis
How does pneumonia infect airways?
Infection of the alveoli, which is a much more serious illness than infection of the airways
Most common cause is streptococcus mneumoniae – this a virulent bacterium produces a toxin called pneumolysin which punches holes into cell membranes killing the cell
5% mortality rate from hospital admissions
Clinical features: cough, sputum, fever, dyspnoea, pleural pain, headache
Consolidation of lung seen on x-ray
What is the histology of pneumonia?
Histology: alveoli filled with inflammatory cells, fibrin, cell debris and bacteria
When studied under EM; dead cells seen with invading bacteria between them
What is bronchiectasis?
Dilated airways in which the structural proteins have been damaged-> chronic productive cough
Viscous cycle of infection and inflammation without microbial infection-> inflammation-> tissue damage-> impaired lung defences-> more infection
Chronic infection also involves a protease/antiprotease balance
E.g. case study with childhood suggests a problem with lung defences
Managed with physiotherapy (phlegm out of lungs) and many different medications
What are the causes of chronic bronchial sepsis?
Congenital – e.g. pulmonary sequestration, bronchial wall abnormalities
Mechanical obstruction – e.g. foreign body, tumour, lymph node
Inflammatory pneumonitis – e.g. gastric contents, caustic gas
Fibrosis – e.g. CFA, sarcoid
Postinfective – e.g. TB, pneumonia
Immunological – e.g. ABPA, post-transplant
Impaired mucociliary clearance – e.g. CF, PCD, Youngs
Immune deficiency e.g. hypogammaglobulinaemia
How does chronic infection involve a protease/antiprotease balance (in bronchiectasis)?
When phagocytes engulf bacteria they spill a little protease enzyme (normally inside the cell) to kill the bacteria
This is usually neutralised by antiproteases in the mucus
In chronic infection, so much protease is spilled it overwhelms the ability of the antiproteases to neutralise it
The proteases then digest the epithelial cells, damaging them
Structural protein elastin digested away by protease airways (released by neutrophils which are attracted into airway lumen by bacteria) in bronchiectatic airway wall
What are the possible outcomes of bacterial infection?
The host defences win: bacterial eradication
The bacterium wins: serious illness or death
Bacterial persistence: lung abscess or chronic airway infection
Chronic airway infection leads to chronic inflammation-> progressive damage to the airway wall leading to bronchiectasis
The vicious circle hypothesis proposes that bacteria stimulated host-mediated inflammation causes progressive lung damage
Summarise inspiration
For positive pressure breathing (mechanical ventilation):
Air flows from high pressure to neutral pressure
Air ‘pushed’ into lungs
For negative pressure breathing (regular ventilation):
Air flows from neutral pressure to low (negative) pressure
Air ‘drawn’ into lungs
What are the stages of resting inspiration?
- Diaphragm contracts-> compresses the abdominal cavity and decompresses the thoracic cavity
- Intrapleural pressure decreases from -5cm H20 to -8cm H20
- Lung expands to prevent further decreases in intrapleural pressure
- Alveolar pressure decreases (Boyle’s law) and air flows in until alveolar pressure returns to 0cm H20
- At end inspiration, Ppl is lower than before inspiration and Palv is the same as before inspiration
Summarise expiration
Diaphragm relaxes and the elastic recoil of lung increases Palv
Air flows out of lungs down the pressure gradient
Ventilation is controlled by pressure changes
NEGATIVE TRANSMURAL PRESSURE
A negative transmural pressure will cause air to flow into the lung (distending pressure)
POSITIVE TRANSMURAL PRESSURE
A positive transmural pressure will cause air to flow out of the lungs (recoil pressure)
How can the relationship between the lungs and chest be described?
Fixed
Functionally treated as one unit
What happens to inspiratory muscles in overweight people?
Muscles work harder
What happens to lung mechanics in obstructive diseases (and examples)?
Flow of air into and out of the lung is obstructed
Lungs are operating at higher volumes
CHRONIC CAUSES= COPD, emphysema, bronchitis
ACUTE CAUSES= Asthma
What happens to lung mechanics in restrictive diseases (and examples)?
Inflation/deflation of lung or chest wall is restricted
Lungs are operating at lower volumes
PULMONARY CAUSES= Lung fibrosis, interstitial lung disease
EXTRAPULMONARY CAUSES= Obesity, neuromuscular disease
What does the pressure volume curve look like?
Sigmoid shape
Large changes in volume per unit pressure occur at middle volumes
Small changes in volume per unit pressure towards RV and TLC
OBSTRUCTIVE-> operate at higher volumes so greater changes per unit change in pressure (more compliant)
RESTRICTIVE-> operate at lower volumes so involve considerably higher pressures to inflate lungs
What is compliance?
Voltage change / pressure change
Tendency to distort under pressure (i.e. expand on inflation)
Greater change in volume per unit of pressure reflects a higher degree of compliance
Compliance is most applicable to changing lung volume away from FRC (i.e. against the elastic properties of the intact lung)
Condom more compliant than balloon
What is elastance?
Pressure change / voltage change
Tendency to recoil to its original volume
Greater change in pressure per unit of volume reflects a higher degree of elastance
Elastance is most applicable to changing lung volume towards FRC (i.e. in tandem with the elastic properties of the intact lung).
Condom less elastic than balloon
What is more compliant: fluid or air filled lungs?
Fluid filled lungs
Air-water interface exhibits surface tension
Fluid-water interface does not
Why do inflation and deflation require less pressure in fluid-filled lungs?
Inflation and deflation require less pressure in fluid-filled lungs due to elimination of the air-water interfece
Why are alveoli described as interdependent?
Each alveolus doesn’t have its own wall (like ‘bunch’ of grapes metaphor)
Walls are shared between adjacent alveoli
Forces acting on 1 directly affect the others
(In diseased lungs, interrelationships between alveoli are impaired, diseased subunits can affect healthy ones)
What is surface tension?
The tendency for water molecules to attract each other
Tension changes proportionately to the radius
Surface tension of pulmonary fluid is a contributor to the recoil of the lung (and resistance to expansion)
What forces attract water molecules on the surface layer?
No forces attracting water molecules upwards
Plenty attracting downwards-> water molecules slowly pulled under to reduce this imbalance-> density gradient from the bottom to the top-> natural curvature at surface
What would happen if water was only fluid at the air-lung interface in the alveoli?
Surface tension would be so great the compliance of the lung tissue would be greatly reduced
What is pulmonary surfactant?
Secreted by Type II pneumocytes into alveolar spaces
80% polar phospholipids. 10% neutral lipids, 10% protein
Polar phospholipids migrate to the surface and arrange themselves with their hydrophilic heads in the fluid (hydrophobic tails protrude into the air)
Molecules interrupt the attraction between water molecules and reduce (not eliminate) the surface tension
What are the 4 main roles of surfactant?
Helps to reduce the surface tension
Prevents collapse of small alveoli
Increases compliance (by reducing surface tension)
Reduces the ‘work of breathing’
How are the surface tension reduction and concentration of surfactant related?
The amount of surface tension exerted is proportional to the volume of the alveolus (i.e. how much it is being stretched)
Because of the natural tendency for alveolar structures to shrink because of the surface tension, the exerted surface tension is proportional to lung volume
The reduction in surface tension is proportional to the concentration of surfactant at the fluid-air interface
What is the law of Laplace?
P= 2T/r
What is the difference between the surface tension of a lung at TLC and at the end of tidal expiration?
The surface tension of a lung at TLC is almost 40 times greater than at the end of a tidal expiration
How does pulmonary surfactant regulate alveolar size?
Larger alveoli have a larger air-fluid interface so surfactant is less concentrated
Alveolus requires greater pressure to increase its volume relative to a smaller alveolus
Also, large inter-alveolar variation (some expand faster than other due to elastic properties)
Because of the positive relationship between alveolar volume and surface tension, the increasing surface tension in ‘more compliant’ alveoli will hinder their expansion, allowing smaller, less compliant alveoli to increase in size
How does surfactant help prevent pulmonary oedema?
Decrease in alveolar size during expiration-> reduced pressure in the interstitial space
Negative pressure-> draws fluid out of the pulmonary circulation
BUT prevented by surfactant (limits decrease in alveolar size)
Where is airway resistance highest?
Medium-sized airways
Lower at higher volumes because the airways also dilate
What happens during airway closure?
As airway diameter decreases, radial tension force increases in the liquid lining (the force trying to tighten internal circumference of the airway)
This increases the propensity for the formation of a liquid plug from the fluid coating the airway
The hydrostatic attraction within the liquid lining narrows the lumen until it is occluded
Airway collapse is more prevalent towards the base of the lung
Temporary closure of the small airways can result in air trapping, and is associated with hyperinflation of the lungs in COPD
What is Poiseiulle’s law?
(8 x viscosity x length) / (pi x r^4)
Resistance is proportional to the viscosity of a fluid (including air) and the length of the tube, and inversely proportional to the fourth power of the radius according to (Poiseiulle’s Law)
Outline how airway resistance varies in the lungs
Based on Poiseiulle’s law, the resistance should increase as the cross-sectional area decreases BUT the constant generational divergence in the airways means that the cumulative cross-sectional area increase dramatically in the small airways
In fact, resistance is greatest in the fourth generation of the respiratory network, after which it decreases exponentially
Also, because the smaller airways do not have the rigid structure (cartilaginous support) of the larger airways, they are more prone to changing volume in response to pressure fluctuations
In principle, as the lungs inflate, the smaller airways also increase in diameter
This causes a progressive decrease in resistance from the fourth generation onwards
Explain how forced expiration relates to altered flow rate (L/s) per volume (L)?
MEFV (maximum expiratory flow volume)
There is ‘limiting envelope’ on the expiratory curve
Unable to break if air is not pushed out hard and fast
Flow-rate is effort dependent and determined by internal architecture of the lungs
SEE DIAGRAM
What happens to compliance and resistance in COPD?
Increased compliance and increased resistance
When is intra-alveolar pressure highest?
In mid-expiration
Define: hypersensitivity
An exaggerated response
May be immunological or non-immunological
Immunological (i.e. allergy)
- IgE-mediated e.g. hayfever, eczema, asthma
- Non- IgE-mediated e.g. farmers lung
Define: allergy
An exaggerated immunological response to a foreign substance (allergen) which is either inhaled, swallowed, injected, or comes in contact with the skin or eye
Mechanism (not a disease)
List some types of allergies
Atopic allergy (IgE mediated)
Non-atopic allergy (IgG mediated/T cell mediated)
Contact dermatitis (+ eczema, urticaria (hives), angioedema= swelling similar to hives, but not on surface of skin)
Extrinsic allergic alveolitis
Coeliac disease
Define: atopy
Hereditary predisposition to produce IgE antibodies against common environmental allergens
Atopic diseases= allergic rhinitis, asthma, atopic eczema
How are allergic tissue reactions in atopic subjects characterised?
Infiltration of Th2 cells and eosinophils
What is ‘allergic match’?
The term used to describe the common progression from atopic dermatitis to allergic asthma
How are allergic reactions in the upper and lower respiratory airways mediated by IgE?
Acute symptoms= from binding of allergen to IgE-coated mast cell (-> mast cell degranulation and histamine release)
Chronic symptoms= from interaction of the allergen with antigen-presenting cells (-> release of Th2 cytokines and chemokines)
What kinds of CD cell is Th2?
CD4+
What is released by Th2 cells (via interleukins)?
IL-4 -> IgE synthesis
IL-5 -> Eosinophil development -> IL-9
IL-9-> Mast cell development
IL-13-> IgE synthesis + airway hyper-responsiveness
Outline the responses of Th2
Involves the collaboration between innate and adaptive immune responses
PAMPs present on allergen interact with barrier cells e.g. epithelial cells lining airway - stimulates secretion of IL-33 and IL-25
Interleukins attract natural helper cells, nuocytes and MPPtype2 cells (which differentiate to form mast cells, basophils and macrophages)
These cells then secrete IL-4, IL-5 + IL-13, which induces Th2 cell differentiation, B1 cell proliferation and anti-allergen effector functions – this is where the adaptive immune response is involved
What interleukins induce Th2 cell differentiation?
IL-4
IL-5
IL-13
What are non-allergic hypersensitivity/intolerance responses?
Usually apply to food intolerance
Non-immunological mechanisms
E.g. include enzyme deficiency (Lactase DH), migraine (triggered by coffee, wine), IBS (exacerbated by various foods), bloating due to wheat intolerance
Also idiopathic environmental intolerance (also known as multiple chemical hypersensitivity – cause unknown)
What is allergic rhinitis?
Seasonal or perennial (indoor triggers)
Affects up to 17% of the population
Seasonal allergic rhinoconjuctivitis (hayfever) is caused by allergenic substances in pollen (usually grass, sometimes tree/weed)
High pollen counts can also lead to wheeziness with rhinitis (-> seasonal allergic asthma)
Why are hayfever symptoms worst in the height of summer?
Grass pollens become airborne
Now increasingly early in UK
What are non-allergic causes of perennial rhinitis?
ALLERGIC CAUSES
Indoor triggers e.g. dustmites or from animals
NON-ALLERGIC
Infection
Structural abnormalities
Define: asthma
Chronic disorder characterized by episodes of wheezy breathlessness, may also present as an isolated cough (especially in kids)
8-12% of population affected
What is the pathology of asthna?
Inflammation of the large and small airways (bronchi and bronchioles)
-> Irritable or twitchy airway in which airflow obstruction results from exposure to a variety of non-specific irritants (bronchial hyper-responsiveness)
What are common symptoms or asthma and how can they be controlled?
Mild occasional wheezing (controlled by occasional use of inhaled bronchiodilators)-> severe intractable disease (requires systemic corticosteroids)
How is allergy related to asthma?
Allergy can trigger an attack in around 75% asthmatics (commonly due to sensitivity to house dust mites or pollen)
However, even in patients who suffer from allergic asthma, there are usually other triggers such as viral infections, exercise, exposure to fumes and other irritants such as tobacco smoke, and certain drugs (especially aspirin and related compounds)
Food allergens and additives are rarely responsible
Some patients who wheeze when pollen count is high but not at other times of the year
25% asthmatics are not sensitised to common airborne allergens, and so are ‘non-atopic asthmatics’
(Their disorder often starts in later life and can be more severe than those who have asthma which begins in childhood)
TYPES OF ASTHMA
In intermittent, mild asthma – allergy frequently very important
In persistent but manageable asthma – allergy sometimes important
In chronic, severe asthma – allergy less important, but infection is important
What are some symptoms of anaphylaxis?
Dizziness, seizures
Loss of consciousness
Anxiety, sense of gloom
Arrhythmia
Vomiting, diarrhoea, pain
Urticaria/hives
Tingling in hands and feet
Bronchoconstriction
Laryngeal oedema
Lip, tongue swelling
What are common causes of anaphylaxis?
Drugs e.g. penicillin
Foods, e.g. peanuts, tree nuts, milk, eggs, fish, shellfish, sesame seeds, soybeans, celery, celeriac
Insect stings e.g. bees, wasps, hornets
Latex
How is anaphylaxis treated?
EpiPen
What is extrinsic allergic alveolitis (EAA)/ hypersensitivity pneumonitis (HP)?
A non-IgE T cell mediated inflammatory disease effecting the alveoli and interstitium
Affects 0.1% population
Occurs in susceptible people following repeated inhalation of certain antigens (typically bacteria or fungal microorganisms or bird antigens)
Cytokine gene polymorphisms in the TNF-alpha promoter region appear to eb a host susceptibility factor
What are some examples of EAA?
Farmer’s lung – mouldy hay
Bird fancier’s lung – bird droppings
Air conditioner lung – air conditioner moulds
Mushroom workers lung – mushroom compost
Malt works lung – mouldy malt or barley
Coffee works lung – unroasted coffee beans
Millers lung – infested flour
Hot tub lung – bacterial contamination
How is EAA diagnosed?
High index of suspicion necessary (good history needs to be taken)
Clinical exam
Complete pulmonary function tests and radiographic studies
Histology= lymphocytic infiltrate with predominance of CD8+ lymphocytes, ‘foamy’ alveolar macrophages and granulomas consistent with non-specific interstitial pneumonia
How is EAA treated?
Acute EAA- oxygen and oral corticosteroids
Steroids may not affect the long-term outcome
Intervention-> good prognosis if before pulmonary fibrosis
How common are allergic airway diseases?p
5.7 mil diagnosed with asthma at some point
1/15 people recorded diagnosis of allergic rhinitis
117% increase in number suffering from peanut allergy from 2001-2005
Number of hospital admissions due to anaphylactic shock increased 7x from 1990-2000 (also increased for urticaria and food allergy)
Decrease in infectious diseases (e.g. TB)
In UK, by 2004, the scale of the “allergy epidemic” was such that 39% of children and 30% of adults had been diagnosed with one or more of asthma, eczema and hayfever
38% of children and 45% of adults had experienced symptoms of these disorders in the preceding 12 months
Why have allergic disease trends risen?
Environmental influences must be increasing
Hygiene hypothesis= deprived immune system of microbial antigens that stimulate Th2 cells (vaccines, antibiotics and clean environments)
Genetic pre-disposition to asthma (Chr 5, 6, 11, 12 and 14)
Th2 phenotype also affected by date of birth around pollen season and how date/season affects what baby is fed
Atopic allergic diseases are less common in younger siblings
May be due to co-factors required to develop asthma attack (e.g. tobacco smoke and air pollutants)
How are allergic diseases treated?
Allergen avoidance, anti-allergic medication and immunotherapy (also called desensitisation/ hyposensitisation
Anti-allergic medication: antihistamines used to relief rhinitis symptoms, and topical corticosteroids (anti-inflammatory)
Histamine1-receptor antagonists less sedative + more selective than old antihistamines
Immunotherapy
Outline immunotherapy considering advantages and disadvantages
Administering increasing concentrations of allergenic extracts over long periods of time
Mode of action is complex, but central to its principle is down-regulation and up-regulation
-> Decreased Th2-type cytokines, IgE, eosinophils, mast cells, basophils
-> Increased Th1-type cytokines, IgG, interleukin 10, transforming GF beta
ADVANTAGES
Effective and produces long lasting immunity
DISADVANTAGES
Risk of developing anaphylaxis (particularly during induction), time consuming, standardisation problems
Attempts to minimize systemic reactions include pre-treatment of allergen extracts with agents like formaldehyde (-> allergoids)
However this results in reduced immunogenicity as well as a decrease in IgE binding
Indications for use: grass/tree pollen allergic rhino-conjunctivitis uncontrolled by medication, bee/wasp sting anaphylaxis at risk for repeats
What is hypoxia?
Describes a specific environment
Specifically the PO2 in the environment
What is hypoxaemia?
Describes the blood environment
Specifically the PaO2
What is ischaemia?
Describes tissues receiving inadequate oxygen
E.g. forearm ischaemia
What factors can put the body under hypoxic stress?
Altitude
Disease
Maybe exercise
Body can adapt and compensate for hypoxic circumstances to maintain oxygen delivery
Summarise the oxygen cascade
Oxygen cascade= the partial pressure of oxygen decreases from atmospheric air to respiring tissues
Atmosphere (21.3 kPa) -> Upper airways (20.0 kPa) -> Alveolus (13.5 kPa) -> Post-alveolar capillary (13.5 kPa) -> Pulmonary vein (13.3 kPa) -> Systemic artery (13.3 kPa) -> Cells (5.3 kPa)
Can be altered with supplemental O2, hyper/hypoventilation, diffusion defects, and increased tissue O2 utilisation
Fick’s law of diffusion states the flow rate is proportional to the pressure gradient
- Inspiring hypoxic gas reduces the gradient
- Structural disease reduces the area
- Fluid in the alveolar sacks increases thickness
Effectiveness determined by:
- Alveolar ventilation
- Ventilation-perfusion matching
- Diffusion capacity
- Cardiac output
How doe gas transport change during exercise?
Exercise stimulates an increase in energy demand that shifts the glucose metabolism equation to the right
This requires additional fuel substrates (carbohydrate, fat or protein) that are abundantly available in body and additional oxygen-> increased rate of cellular metabolism during exercise (-> more CO2 produced)
This causes an increase in the PCO2 and decrease in pH within tissues
This mild acidosis and hypercapnia shift the ODC to the right to improve oxygen unloading at the tissues
The increased PCO2 is detected by central chemoreceptors in the medulla that increase the ventilation rate to maintain oxygen delivery to tissues (and CO2 clearance)
If oxygen supply is inadequate (e.g. PaO2 lactic acid)
TO SUMMARISE Exercise increases the oxygen demand RF increases TV increases Q increases ODC curve shifts right
What is VO2 max?
The total capacity to deliver oxygen to tissues
What is aerobic respiration?
Energy production in a plentiful oxygen environment
What happens when there is low oxygen or the O2 supply
The body shifts to producing some of the energy needed through anaerobic mechanisms
This method of energy production is unsustainable as it produces lactic acid as a by-product – which dissociates into lactate- and H+ causing acidosis
This acidosis reduces the effectiveness of enzymes (especially those involved in aerobic energy production) and initiates a downward spiral of decreasing performance
What happens to tidal volume, respiratory frequency and depth of breathing with exercise?
Tidal volume increases early
Respiratory frequency stabilises at ~20 breaths/min and increases later
Increasing depth of breathing is more effective at increasing alveolar ventilation
What are the 5 main challenges of altitude?
Hypoxia (less O2 in ambient air)
Thermal stress (-7oC per 1000m, high wind-chill)
Solar radiation (less atmospheric screening, snow reflection)
Hydration (water lose humidifying inspired air, hypoxia induced diuresis)
Dangerous (windy, unstable terrain, confusion, mal-coordination)
What effect does altitude have on gas transport?
As altitude increases, the barometric pressure reduces (the air becomes thinner) and according to Dalton’s law, this means that the content of atmospheric gases is reduced (although proportions remain unchanged)
A reduced PIO2 -> reduced PaO2
A lower PaO2 -> reduced concentration gradient -> slows the rate of O2 diffusion from the alveoli to the capillaries (Fick’s law)
Low PaO2 stimulates ventilation (to increase PAO2 i and increase the concentration gradient) – termed hypobaric hypoxia
The ensuing hyperventilation causes CO2 to be “blown off” and PaCO2 to fall
This causes a decrease in plasma [H+] and a rise in pH that shifts the ODC to the left, increasing the affinity of Hb for O2 and reducing its ability to unload at systemic tissues
So actually this mechanism puts a “brake” on the main stimulus for breathing
Describe how acclimatisation occurs
Need to ascend slow to give the body time to adapt (acclimatise)
Climbers often follow the adage of ‘climb high sleep low’)
SHORT-TERM ADAPTATIONS
The initial physiological responses to hypobaric hypoxia are detrimental and there are two short-term adaptations:
1) Renal compensation = bicarbonate excretion-> helps pH to return to normal and shifts the ODC into its normal position
2) Increased production of 2,3-DPG to improve oxygen unloading at the tissues
*Also hyperventilation
LONG-TERM ADAPTATION
Secondary erythrocytosis
Chronic hypoxia is detected by cells in the kidneys and the hormone erythropoietin is secreted
Erythropoietin stimulates the bone marrow to produce RBCs at a higher rate
Over time, the conc of RBCs increases (associated with marked increase in Hct/PCV) and hence oxygen-carrying capacity of blood is also increased
How does acclimatisation vary in different people (NB. lowlanders)?
In lowlanders (residents at sea level) the ventilatory response to hypoxia at high altitudes is inadequate to restore the PaO2 to sea-level values
The lowlander therefore becomes hypoxaemic
The response to hypoxia is very variable between individuals and when the ventilatory response to hypoxia is poor and, at increasing levels of high altitude, the hypoxaemia may be severe leading to impaired cognitive function
Initially on arrival at high altitude lowlanders often feel unwell with poor physical and mental function (possible headache, nausea, vomiting, photophobia and poor sleep)
These symptoms are usually mild but if it becomes severe it is termed acute mountain sickness (AMS)
Acclimatisation occurs over the next 2 to 10 days with steady resolution of symptoms and improved performance
When at high altitude, what leads to increased ventilation and PaO2?
Fall in PaCO2
Why is it beneficial to increase ventilation and PaO2 at high altitude?
Renal compensation
Slow increase of ventilatory sensitivity to hypoxia (possibly due to chemoreceptors)
Why is slowing the ascent beenficial?
The adverse effects of moving to high altitudes can be ameliorated or avoided by slowing the ascent to two days, or longer for the higher altitudes
Rapid ascent over a few hours will usually lead to the unpleasant effects of acute mountain sickness and may be complicated by impaired cognitive function
What happens at altitudes above 5500m?
The ventilatory response is dominated by the strength of the hypoxic stimulus
So at this height-> severe respiratory alkalaemia, increased O2 affinity and increased O2 uptake of O2 in the lung
BUT increased O2 uptake in lungs-> reduced downloading of oxygen in the tissue (so limited exercise capacity-> hard to climb mountains)
What adaptations do native highlanders have?
‘Barrel chest’ – larger TLC, more alveoli and greater capillarisation
(More O2 in body)
Increased haematocrit – greater oxygen carrying-capacity of the blood
(More O2 carried)
Larger heart to pump through vasoconstricted pulmonary circulation
(Greater pulmonary perfusion)
Increased mitochondrial density – greater oxygen utilisation at cell level
(More O2 utilised)
What can rapid ascent lead to?
AMS
HAPE
HACE
What are the causes, pathophysiology, symptoms, consequences and treatment of AMS?
Acute mountain sickness
CAUSES
Maladaptation to high-altitude environment
Usually due to recent ascent (onset within 24 hours)
Can last >1 week
PATHOPHYSIOLOGY
Mild cerebral oedema
SYMPTOMS Nausea Vomiting Irritability Dizziness Insomnia Fatigue Dyspnoea
CONSEQUENCES
Develops into HAPE or HACE
TREATMENT Monitor symptoms Stop ascent Analgesia Fluids Medication (acetazolamide) Hyperbaric O2 therapy
What are the causes, pathophysiology, symptoms, consequences and treatment of CMS?
Chronic mountain sickness
Acclimatised individuals can spontaneous acquire CMS (Monge’s disease)
Long-term adaptations become problematic
CAUSES
Unknown
PATHOPHYSIOLOGY
Secondary polycythaemia-> increased blood viscosity (SLUDGES through systemic capillary beds impeding O2 delivery despite adequate oxygenation)
SYMPTOMS
Cyanosis
Fatigue
CONSEQUENCES
Ischaemic tissue damage
Heart failure
Eventual death
TREATMENT
No interventional medical treatment
Sufferers are exiled to lower altitudes
What are the causes, pathophysiology, symptoms, consequences and treatment of HACE?
High altitude cerebral oedema
CAUSES
Rapid ascent or inability to acclimatise
PATHOPHYSIOLOGY
Vasodilation of vessels in response to HYPOXAEMIA (to increase blood flow)
Cranium can’t expand so intracranial pressure increases
SYMPTOMS Confusion Ataxia Behavioural change Hallucinations Disorientation Occulomotor palsies Extensor plantar responses
CONSEQUENCES Irrational behaviour Irreversible neurological damage Coma Death
TREATMENT Immediate descent O2 therapy Hyperbaric O2 therapy Dexamethasone
What are the causes, pathophysiology, symptoms, consequences and treatment of HAPE?
High altitude pulmonary oedema
CAUSES
Rapid ascent or inability to acclimatise
PATHOPHYSIOLOGY
Vasoconstriction of pulmonary vessels in response to HYPOXIA
Increased pulmonary pressure, permeability and fluid leakage from capillaries
Fluid accumulates once production exceeds the maximum rate of lymph drainage
SYMPTOMS Dyspnoea Dry cough Bloody sputum Crackling chest sounds With AMS- severe breathlessness, chest pain, sometimes haemoptysis
CONSEQUENCES
Impaired gas exchange
Impaired ventilatory mechanics
TREATMENT Descend Hyperbaric O2 therapy Nifedipine Salmeterol Sildenafil
What percentage of lowlanders with mild AMS develop HAPE, HACE or both?
1%
What would a chest X-ray show in HAPE?
Patchy pulmonary oedema
What is acclimation?
Like acclimatisation but stimulated by an artificial environment (e.g. hypobaric chamber or breathing hypoxic gas)
What is acetazolamide?
Carbonic anhydrase inhibitor
Accelerates the slow renal compensation to hypoxia-induced hyperventilation
What is nifedipine?
Lowers pulmonary arterial pressure (used in HAPE)
Reduces pulmonary capillary leakage and right ventricular workload
What is the untreated mortality of HAPE and HACE?
50%
What is respiratory failure?
Failure of pulmonary gas exchange
Generally V/Q inequality (not necessarily disease severity)
Differentiate between different types of respiratory failure
Type I: hypoxic
PaO2 6.7 kPa
(Increased CO2 production, decreased CO2 elimination)
Mixed:
Hypoxic PaO2 6.7 kPa
What conditions lead to type 1 respiratory failure?
Pulmonary oedema
Pneumonia
Atelectasis
What conditions lead to type 2 respiratory failure?
Decreased CNS drive Increased work of breathing Pulmonary fibrosis Neuromuscular disease Increased physiological dead space Obesity
Who is most likely to suffer from hypoxia?
ACUTE
Myocardial infarction, pulmonary embolus, severe haemorrhage
CHRONIC
Diabetes, respiratory failure, anaemia, COPD
What is the timeline of lung development?
Most airway and circulation development during early fetal life
Alveoli appear before birth and grow into early childhood
Development relies on interaction between airways and pulmonary vessels
EMBRYONIC PHASE= 0-7 weeks
Lung buds
Main bronchi
PSEUDOGLANDULAR= 5-17 weeks
Conducting airways
Bronchi & bronchioli
CANALICULAR= 16-27 weeks
Respiratory airways
Blood gas barrier
SACCULAR/ALVEOLAR= 28-40 weeks
Alveoli appear
POSTNATAL= adolescence
Alveoli multiply and enlarge with chest cavity
What is Scimitar Syndrome?
Congenital lung defect
Anomalous pulmonary venous drainage of R lung to IVC (usually close to junction of R atrium)
Associated R lung and R pulmonary artery hypoplasia
Dextrocardia
Anomalous sytemic arterial supply
Most have classical subtype (to the R)
Means hemi-thorax is small (lung hasn’t developed properly because of abnormal blood flow)
What is Laryngomalacia?
‘Floppy’ airways in children
Can be severe enough to need tracheostomy
If epiglottis collapses-> airways blocked
Outline the branching morphogenesis and vasculogenesis during embryogenesis?
Bifurcation and then additional split
Lobes appear from 6 weeks
Adult-like formation by end of 7 weeks
Outline the branching morphogenesis and vasculogenesis during the pseudoglandular phase (5-17w)?
Branching morphogenesis of airways into mesenchyme
Pre-acinar airways all present by 17 weeks
Development of cartilage,gland and smooth muscle tissue (continues into canalicular phase)
Describe the bronchial cartilage
Incomplete rings posteriorly
Irregular plates
Increasingly calcify with age
Can be malacic:
- Generalised= laryngotracheomalcia
- Localised= malacic segment
What factors drive branching morphogenesis?
Lung buds- consistent appearance during airway formation (5-17wks)
Epithelial cells at tips of buds are highly proliferative multi-potent progenitor cells
Cells behind the tip divide and differentiate into the various cell types
Communication between epithelial cells in distal branching lung buds and surrounding mesenchyme
What control mechanisms influence branching morphogenesis?
Epithelial-mesenchymal interaction essential for branching morphogenesis
Genetic and Transcription factors [TTF-1] involved in early bud formation
Branching development in humans follows a bifurcation pattern
Later a variety of growth factors are important
What growth factors are involved in lung development?
INDUCTIVE
FGF- branching morphogenesis, subtypes found in epithelium and mesenchyme
EGF - epithelial proliferation and differentiation
INHIBITORY
TGFb - matrix synthesis, surfactant production, inhibits proliferation of epithelium and blood vessels
Retinoic acid - inhibits branching
Complex signalling between GF’s, cytokines, receptors in the regulation of lung growth and differentiation
When is circulation present in the lung?
By 5 weeks gestation
Vasculogenesis and angiogenesis
Pulmonary vessels develop alongside the airways
List some congenital thoracic malformations
Cystic Pulmonary Airway Malformation (CPAM)
Congenital Lobal Emphysema
Congenital Large Hyperlucent Lobe (CLHL)
Intralobar Sequestration
What is Cystic Pulmonary Airway Malformation (CPAM)?
1 per 8300 to 35000
Mostly diagnosed on antenatal USS
PATHOGENESIS
Defect in pulmonary mesenchyma, abnormal differentiation 5-7th week
Normal blood supply, but can be associated with sequestration
TYPE 2
Multiple small cysts
May be associated with renal agenesis, cardiovascular defects, diaphragmatic hernia and syryngomyelia
Histologically bronchiolar epithelium with overgrowth, separated by alveolar tissue which was underdeveloped
What is Congenital Large Hyperlucent Lobe (CLHL)?
Progressive lobar overexpansion
Caused by... Weak cartilage Extrinsic compression One way valve effect Alveoli expand (not disrupted)
LUL > RML >RUL
Males > females
CHD association
Neonatal presentation before 6 months of age
Mass effect: atelectasis of lungs, displacement of heart, mediastinum, diaphragm
What is Intralobar Sequestration?
75% of pulmonary sequestrations
Abnormal segment shares visceral pleural covering of normal lung
No communication to tracheobronchial tree
Lower lobe predominance and L > R
? Due to chronic bronchial obstruction and chronic postobstructive pneumonia
What types of lung growth anomalies are there?
Agenesis (very rare)– complete absence of lung and vessel (mediastinal shift towards an opaque hemi-thorax)
Aplasia – blind ending bronchus, no lung or vessel
Hypolasia – bronchus and rudimentary lung are present, all elements are reduced in size and number
What is hypoplasia in lung growth?
Common (relatively) and usually secondary
Reduced size and number of lung elements
LACK OF SPACE Intrathoracic or extrathoracic - Hernia (L = 75 – 90%) - Chest wall pathology - Oligohydramnios - Lymphatic or cardiac mass
LACK OF GROWTH
- CTM
How do endothelial cells develop?
CD31-> endothelial cells
These differentiate in the mesenchyme around the lung bud
They coalesce to form capillaries (vasculogenesis)
Airways act as structural template
Stimulated by VEGF (Vascular endothelial growth factor, produced by epithelial cells to stimulate endothelial differentiation)
How is early blood vessel growth controlled?
VEGF (produced by epithelial cells throughout gestation in humans)
VEGF at branching points and induces a vascular response
Enabled due to Flk-1 (VEGF receptor on endothelium)
IGF and IGFR (from 4 weeks) blocks prevents capillary development
eNOS stimulates proliferation and tube formation
Angiopoietin (receptor Tie) important in wall differentiation
As capillaries add on at the periphery, arteries and veins get longer
At the end of pseudoglandular period, what airways and blood vessels have been developed?
All airways and blood vessels to the level of the terminal bronchiolus are present
Enters canalicular stage
What happens during the canalicular stage (16-27 weeks)?
The airspaces at the periphery enlarge
Thinning of epithelium by underlying capillaries allows gas exchange
Blood gas barrier required in post-natal life
Epithelial differentiation into Type I and II cells
(Type 2= more cuboidal, can differentiate into 1 , surfactant producing)
Surfactant first detectable at 24-25 wks
24 weeks gestation-> babies become viable
What happens during the saccular/alveolar stage (28-40 weeks)?
Alveoli appear (multiply up to 3 years of age)
1/3-1/2 of adult number by term (100-150 million)
How are alveolar walls formed?
Myofibroblast and elastin fibres at intervals along the saccule wall (epithelium on both sides with double capillary network)
Secondary septa develop from wall led by elastin produced by myofibroblast
Capillary lines both sides with matrix between
Capillaries have coalesced to form one sheet alveolar wall, thinner and longer with less matrix
Muscle and elastin still at tip
What adult disease are pre-term babies BELIEVED to be more at risk of?
COPD
But may be more scope for alveolar recovery after preterm birth than previously believed
What is the volume and size of the lung at birth?
Volume small and related to body weight
All airways present and differentiated (cartilage, glands, muscle, nerves)
33-50% alveoli allow normal gas exchange
Blood gas barrier as in adult
Most arteries and veins present
How do blood vessels change at birth?
Decrease in pulmonary vascular resistance
10 fold rise in pulmonary blood flow
Arterial lumen increases and wall thins rapidly
Change in cell shape and cytoskeletal organisation not loss of cells
Once thinning occurred, arteries grow and maintain relatively thin wall
Low pressure, low resistance pulmonary vascular system
What does expansion of alveoli after birth lead to?
Dilates arteries directly
Stimulates release of vasodilator agents (nO, PGI2)
(Inhibits vasoconstrictors present during foetal life, ET)
How do airways grow in childhood and adolescence?
LUNG VOLUME
Lung volume increases x30
Maximum lung volume at 22years in males
AIRWAYS
Airways increase in length and width x 2-3 by symmetrical growth
ALVEOLI
Structural elements of the wall increase
Alveoli increase in number up to 2-3 years
Alveolar number and/or complexity may increase up to adulthood
Adult alveolar number (300-600 million)
ARTERIES, VEINS AND CAPILLARIES
Arteries, veins and capillaries increase alongside the alveoli (cap volume x35)
Dysanaptic growth during the early period - alveoli growing more than airways (airways relatively large in infants)
What circulations does the lung have?
BRONCHIAL
From thoracic aorta and provide lung tissue with oxygen and nutrition
Eliminate waste products (approx. 1% of Q)
Bronchial vein converge and drain into pulmonary veins
PULMONARY
Left ventricle pumps blood to lungs via pulmonary artery
Capillary beds converge into bronchial veins and drain into left atrium
What is the aim of the pulmonary circulation?
Perfusion of the respiratory airways for gas exchange
Which circuit is higher pressure, systemic or pulmonary?
Systemic= high pressure, thicker arterial wall, larger arterial lumen
Pulmonary=low pressure, thinner arterial wall, larger arterial lumen
Why is the wall of the left ventricle thicker?
Systemic-> more muscular as systemic circuit requires more pressure= further to pump (whole body)
Compare the systemic and pulmonary circulation considering the: Cardiac output Volume Mean arterial pressure Mean venous pressure Pressure gradient Resistance Velocity Compliance Arterial wall thickness
CARDIAC OUTPUT
S= 5L/min
P= 5L/min
VOLUME
S= 4.5L (90% of volume)
P=0.5L (10% of volume)
MEAN ARTERIAL PRESSURE
S= 93
P= 13
MEAN VENOUS PRESSURE
S= 1
P= 4
PRESSURE GRADIENT
S= 92
P= 9
RESISTANCE
S= 18.4
P= 1.8
VELOCITY
S= faster
P= slower
COMPLIANCE
S= lower
P= higher
ARTERIAL WALL THICKNESS
S= thicker
P= thinner
What are the main functions of the pulmonary circulation?
Gas exchange
Metabolism of vasoactive substances
Filtration of blood
How does pulmonary circulation-> metabolism of vasoactive substances?
The luminal surface of the pulmonary epithelium expresses some specialised enzymes that are critical for management of the intravascular environment
Angiotensin converting enzyme (ACE)
- > Converts angiotensin I to angiotensin II by cleaving X AAs from the chain
- > Angiotensin II stimulates vasoconstriction
- > Degradation of bradykinin (which stimulates vasodilation)
Clearance of other key compounds e.g. serotonin, noradrenaline, prostaglandins and leukotrienes
How does pulmonary circulation-> filtration of blood?
The abundant pulmonary microcirculation acts as a ‘filter’ for harmful emboli that have entered the circulation in systemic capillaries and veins.
Small air bubbles – trapped and eventually diffuse out of the circulation into the alveolar spaces
Fat emboli/thrombi – trapped in the microcirculation and degraded by the vascular endothelium
Cancerous cells – these can also be ‘filtered’ which can result in secondary metastasis (but prevent spread to the rest of the body)
Define: embolus
‘Mass’ within the circulation capable of causing obstruction
E.g. small air bubbles, fat emboli/thrombi, cancerous cells
Define: embolism
‘Event’ characterised by obstruction of a major artery
Define: pulmonary shunt
Method of blood bypassing the respiratory exchange surface
What shunts are present in the lungs?
Bronchial circulation (defined as a shunt but mixed venous blood combined with oxygenated arterial blood)
Foramen ovale
Ductus arteriosus
What is the foramen ovale?
A shunt linking the two atria of the heart
During foetal development a large proportion of blood bypasses the entire pulmonary circulation
At birth, this shunt closes in 90% of individuals
Other 10%- can still allow inter-atrial blood flow to varying degrees
What is the ductus arteriosus?
Shunt linking the pulmonary artery bifurcation to the proximal descending aorta
This shunt normally fuses in the first days of life
What is an atrial septal defect/ventricular septal defec?t
Congenital heart disease involving a defect in the septum separating the L and R heart
Depending on severity, they allow some of the deoxygenated blood to ‘bypass’ the lungs
Ofter require corrective surgery
What is pulmonary vascular resistance?
PVR= lower than systemic vascular resistance
Prone to change during dynamic conditions e.g. exercise
What happens to Q (perfusion) during intense exercise?
Q can increase by 5-6x (with a CO of 25-30L/min)
NB. At rest CO= 5L/min, pulmonary circulation is a low resistance high capacity circuit
What would happen to resistance if pulmonary circulation was rigid?
Increased flow (perfusion) Increased MAP Increased fluid leakage Increased pulmonary oedema Decreased pulmonary function
What actually happens if flow rate is increased (increased Q) in pulmonary circulation?
Increased flow (perfusion) Increased pulmonary artery distention AND increased perfusion of hypoperfused beds Negligible change in MAP Minimal fluid leakage No onset of pulmonary oedema No detriment to pulmonary function
What happens to accommodate a greater volume of blood without increasing pressure?
Greater recruitment of pulmonary capillary beds
Distension of patent vessels
How does distending patient vessels allow pulmonary circulation to accommodate a greater volume of blood without increasing pressure?
Vessels stretch to accommodate a larger blood flow
Reduced risk of oedema
Reduced stress on the right ventricle
Reduced velocity for effective gas exchange
Where is perfusion highest?
Path of least resistance, perfusion decreases from the base to the apex of the lung
3-zone model
How is the volume of the alveolar and extra-alveolar vessels affected by inspiration and expiration?
Inspiration compresses alveolar vessels,
Expiration compresses extra-alveolar vessels
When the volume of (and pressure within) the chest changes, it affects alveolar and extra-alveolar vessels differently
How do the systemic and pulmonary responses to hypoxia differ?
Systemic vascular response to hypoxia is vasodilation
Pulmonary response to hypoxia is vasoconstriction
How does hypoxia lead to vascular smooth muscle contraction?
Hypoxia
- > closure of O2-sensitive K channels
- > decreased K efflux
- > increased membrane potential
- > membrane depolarisation (opening of VGCCs)
- > vascular smooth muscle contraction
When is hypoxic vasoconstriction beneficial?
FOETAL DEVELOPMENT
Hypoxic pulmonary vasoconstriction facilitates blood flow through the cardiac shunts as the ‘path of least resistance’
High-resistance pulmonary circuit means increased flow through shunts
First breath increases alveolar PO2 and dilates pulmonary vessels
When is hypoxic vasoconstriction detrimental?
COPD
Chronic lung disease patients have high pulmonary circuit resistance; this can cause the right ventricle to work extra hard-> LVH, pulmonary hypertension and potentially heart failure
Reduced alveolar ventilation and air trapping
Increased resistance in pulmonary circuit
Pulmonary hypertension (Cor pulmonale)
Right ventricular hypertrophy
Congestive heart failure
What is vascular recruitment?
During increased cardiac output, a greater number of capillary beds are perfused
Vessels distend more than systemic arteries to accommodate extra flow
What is the difference in porousness between pulmonary and systemic capillaries/
Pulmonary capillaries are more porous (and therefore leaky) than their systemic counterparts
Means that fluid moves more easily between the capillaries, the interstitium and the alveoli
What key pressures affect fluid balance in the lungs?
CAPILLARY HYDROSTATIC PRESSURE
Force pushes water out of the vessel (varies along capillary (13 to 6 mmHg; mean 9 mmHg)
INTERSTITIAL HYDROSTATIC PRESSURE
Force tries to push water into the vessel (0 mmHg)
Very small
PLASMA PROTEIN ONCOTIC PRESSURE (colloid osmotic)
Forces tries to draw water into the vessel (25 mmHg)
INTERSTITIAL PROTEIN ONCOTIC PRESSURE
Force tries to draw water into the interstitium (17 kPa)
What is the net effect of the fluid-balance forces?
The net effect of these forces is a 1 mmHg force from the vessels to the interstitium
This steady fluid loss is small and is easily drained by the lymphatic system
What happens in the lymphatic drainage fails?
If the lymphatic drainage fails, or the fluid accumulates at a rate exceeding lymphatic clearance, then oedema may develop
This would initially be pulmonary interstitial oedema, which may develop into pulmonary alveolar oedema
Oedema results from imbalanced fluid accumulation and clearance
By what mechanisms can fluid accumulation be triggered?
Increasing the intravascular hydrostatic pressure
Reducing the oncotic pressure
Increasing the interstitial oncotic pressure
Blocking the lymphatic system (e.g. vessels blocked by caner-> lymphoedema)
How does increasing the intravascular hydrostatic pressure lead to oedema?
Increased plasma hydrostatic pressure-> more fluid forced into interstitium-> lymph clearance exceeded
E.g. Mitral valve stenosis, heart failure
How does reducing the oncotic pressure lead to oedema?
Reduced plasma oncotic pressure-> less fluid drawn into capillary-> fluid accumulates in interstitium > lymph clearance exceeded
E.g. Hypoproteinaemia, protein-losing nephropathies, liver cirrhosis, protein-losing enteropathies
How does increasing the interstitial oncotic pressure lead to oedema?
Increase interstitial oncotic pressure-> more fluid drawn out of capillaries-> large net fluid movement out of capillary-> lymphatic clearance exceeded
E.g. Pulmonary endothelial damage, infection
What re the main consequences of oedema?
Oedematous lungs are much less compliant (‘increased stiffness’)
-> requires more effort to ventilate-> dyspnoea (shortness of breath)
Excessive oedema can also cause the walls of the bronchioles to become swollen-> increased resistance and work of breathing further
Excessive oedema in the interstitial space can increase the diffusion distance and impede gas exchange (Fick’s law)
What system controls breathing while asleep?
Autonomic
No voluntary or emotional influences from the motor cortex or limbic system
What equipment is generally sued to study sleep?
Brain cortical EEG across the general cortical areas (where brainwaves are fast frequency and low voltage)
What does sleep consist of?
4 stages and REM
Each stage= increased amplification of the electrical activity coming from the brain
What happens in stage 1 of sleep?
Transitional, slow rolling eye movements, postural movements, auditory response present
What happens in stage 4 of sleep?
No auditory response present
What happens in REM?
Rapid eye movement, dreaming sleep, all muscles functionally paralysed except eyes and diaphragm
REM in-between each stage, circadian rhythm (purpose: consolidate memory)
How long is a sleep cycle?
90 minutes
What controls breathing when awake?
Reflex/automatic control (by the brainstem) Voluntary/behavioural control (by the motor cortex) Emotional control (by the limbic system)
What factors of respiratory control are affected by sleep:?
Respiratory muscles in the upper airway and pump muscles
Respiratory control centres
Blood gases and chemosensitivity (i.e. pCO2 and pO2)
What happens to minute ventilation in healthy people when they sleep?
Sleep-> reduction in minute ventilation
Even lower in REM
What is the Pre-Botzinger Complex?
The area in the brainstem which controls respiratory rhythm generation
It contains 2 types of rhythm-generating neurones:
1) Inspiratory neurones – DRG 2) Expiratory neurones - VRG
The inspiratory and expiratory neurones exhibit reciprocal inhibition
What is the difference in the following during breathing while asleep vs awake? Minute ventilation Alveolar ventilation Frequency Tidal volume Oxygen saturation
MINUTE VENTILATION
Awake=6.28L/min
Sleep= 5.67L/min
REM=5.44L/min
ALVEOLAR VENTILATION
Awake= 4.02L/min
Sleep= 3.38L/min
REM=3.21L/min
FREQUENCY
Awake=15.1
Sleep= 15.2
REM= 14.9
TIDAL VOLUME
Awake= 420
Sleep= 373
REM= 367
OXYGEN SATURATION (virtually constant) Awake= 97.3% Sleep= 96.5 REM= 96.2
Why does SaO2 stay the same during sleep in healthy people?
Tidal volume decreases -> pO2 decreases; therefore SaO2 remains virtually constant in healthy individuals
What happens to SaO2 stay the same during sleep in people with COPD?
COPD patients live on the steep part of the oxygen-dissociation curve
SaO2 decreases significantly when pO2 decreases
What happens to CO2 during sleep in healthy people?
TV decreases -> pCO2 increases by ~3-4 mmHg
Increase in pCO2 (detected by central chemoreceptors) stimulates respiratory centres to continue breathing
N.B. if pCO2 does not increase during sleep, this results in death (i.e. don’t breath continually)
What happens to ventilatory sensitivity to CO2 during sleep?
CO2 sensitivity decreases during sleep
Decreased ventilation-> increase in pCO2
Sleep-related changes in breathing increase PaCO2 by 0.5 kPa in healthy people
NEED HYPERCAPNIA TO BREATH DURING SLEEP
Define: apnoea
Cessation of breathing
Define: apnoeic threshold
The ‘level’ above which the PaCO2 has to raise to maintain breathing during sleep
What causes central sleep apnoea?
If the PaCO2 doesn’t raise above the apnoeic threshold-> breathing stops
What upper airway muscles reduce their activity during sleep?
Tongue (genioglossus)
Levator palatini
Tensor palatine
(These muscles stiffen the soft palate in the pharyngeal region at the back of the throat)
What do the muscles that stiffen the soft palate do when they are active/not active?
When they’re active: they prevent airway constriction and collapse
When they are not active: they airway is prone to collapse
Why is the airway at the back of the throat (the pharynx) distensible?
Doesn’t contain cartilage
What influences does sleep have on the airway?
The muscles of the upper airway relax and the airway constricts
Pharyngeal resistance increases; therefore ventilation becomes more difficult
Hence more effort is required to achieve the same amount of ventilation
N.B. in some people, turbulent airflow is setup over the vocal chords-> snoring
What causes obstructive sleep apnoea?
Reduced upper airway muscle activity during sleep
Plus extra luminal pressure (ELP) and negative intra luminal pressure (ILP)
What is obstructive sleep apnoea?
Occlusion of phalangeal airway during sleep Airflow stops (increased respiratory effort)
No impairment of respiratory control
Positive pressure-> airway collapse
Mainly affects middle-aged men
Outline the mechanism involved in obstructive apnoea
(LOOP)
Patent airway
Increased ventilation (induces next apnoea)
Sleep
Decreased upper airway muscle function
Apnoea (hypoxia/hypercapnia, increased effort)
Arousal (termination of apnoea)
… continues
What is the consequence of obstructive apnoea?
Paradoxical breathing
Pressure moves between the thorax and the abdomen during breathing
Air does not move, as patient tries to breathe, they expose the thorax to large negative pressures at a time when the O2 saturation has fallen – this is dangerous for the heart
What are main symptoms of obstructive apnoea?
Loud snoring
Partner witness lack of breathing
Profound sleepiness during the day
What is central sleep apnoea
pCO2 decreases and gets closer to apnoeic threshold
Airflow stops; no respiratory effort due to lack of brain control
Rare unless congenital: congenital hyperventilation syndrome
Most patients with this conditions have heart failure
What are the 2 types of apnoea?
Obstructive= occlusion of phalangeal airway during sleep
Central= pCO2 decreases and gets closer to apnoeic threshold
What is the difference in airflow and respiratory effort (intra-thoracic pressure) between central and obstructive sleep apnoea?
Airflow= same
Respiratory effort= more in obstructive sleep apnoea including thoracic and abdominal effort (even when no airflow unlike central)
What cardio-respiratory diseases are exacerbated by sleep-related changed in the control of breathing?
COPD
Heart failure
Why is sleep detrimental to COPD patients?
Exacerbated during sleep
Normal changes in breathing during sleep (e.g. reduced ventilation) compromise breathing since the patient is on the steep part of the oxygen-dissociation curve
Therefore the patient is more likely to encounter respiratory difficulty during sleep since SaO2 decreases with a decrease in pO2
Why is sleep detrimental to patients with heart failure?
Exacerbated by the sleep-related changes in breathing because about 50% patients with heart failure hyperventilate-> lower PaCO2
Associated with increased risk of suffering central sleep apnoea
Heart failure -> pulmonary congestion -> irritation of J-receptors in the lungs -> chronic hyperventilation -> hypocapnia -> patient gets closer to the apnoeic threshold
When awake: patients have volitional control of breathing; therefore they are sensitive to CO2
During sleep: patients lack volitional control of breathing; therefore they depend on blood gases
Heart failure patients that breathe poorly at night have a higher mortality than those who breathe normally
What indicates mixed acidosis?
PCO2 up
Bicarbonate conc down
(Bicarbonate reduction is more than it should be)
What indicates mixed alkalosis?
PCO2 down
Bicarbonate conc up
(Bicarbonate reduction is less than it should be)
