Respiratory Flashcards
What is the most superior part of the respiratory tract?
Nose
Functions of the nose (4):
-Warm inspired air (0.25s contact)
-Humidify air (70-80% RH)
-Filter function
-Defence function (cilia take inhaled particles back for swallowing)
What does the anterior nares open into?
Enlarged vestibule
Characteristics of enlarged vestibule:
-Skin lined
-Stiff hairs
What doubles the surface area of the nose?
Turbinates
What do turbinates create?
-Superior meatus
-Middle meatus
-Inferior meatus
Components of superior meatus:
-Olfactory epithelium
-Cribriform plate
-Sphenoid sinus
Components of middle meatus:
Sinus openings (drainage)
Components of inferior meatus:
Nasolacrimal duct (drainage)
What are the 4 paranasal sinuses?
-Frontal
-Maxillary
-Ethmoid
-Sphenoid bones
What does pneumatised mean?
Bone that is hollow or contains many air cells
What are the paranasal sinuses arranged into?
Pairs
Where are the frontal sinuses?
-Within frontal bone
-Midline septum
-Over orbit
What is the innervation to the frontal sinuses?
Ophthalmic division (V1) trigeminal nerve (CNV)
Where are the maxillary sinuses?
Body of the maxilla:
-Base - lateral nose wall
-Apex - maxilla zygomatic process
-Roof - floor of orbit
-Floor - alveolar process
What is the innervation to the maxillary sinuses?
Maxillary division (V2) of trigeminal nerve (CNV)
What does the maxillary sinus open into?
Middle meatus
Where are the ethmoid sinuses?
Between the eyes
What is the shape of the ethmoid sinuses?
Labyrinth of air cells
Where do the ethmoid sinuses open into?
Semilunar hiatus of middle meatus
What is the innervation of the ethmoid sinuses?
Ophthalmic (V1) & Maxillary (V2) branches of trigeminal nerve (CNV)
Where are the sphenoid sinuses?
-Medial to the cavernous sinus
-Inferior to optic canal, dura & pituitary gland
What does the cavernous sinus contain?
-Internal carotid artery
-Oculomotor nerve (CNIII)
-Trochlear nerve (CNIV)
-Trigeminal (CNV)
-Abducens (CNVI)
Where do the sphenoid sinuses empty into?
Sphenoethmoidal recess, lateral to attachment of nasal septum
What is the innervation of the sphenoid sinuses?
Ophthalmic (V1) branch of trigeminal nerve (CNV)
What gland is the sphenoid sinus very close to?
Pituitary gland
What is the pharynx?
Fibromuscular tube which takes filtered air from the nose to larynx
What cells line the pharynx?
-Squamous and columnar ciliated epithelium
-Mucous glands
Where is the pharynx?
Extends from skull base to C6 where it becomes continuous with oesophagus
What does the pharynx consist of?
-Nasopharynx
-Oropharynx
-Laryngopharynx (hypopharynx)
What is the nasopharynx bound by (5)?
-Base of skull
-Sphenoid rostrum
-C Spine
-Posterior nose (choana)
-Inferiorly at soft palate
What are on the lateral and posterior walls of the nasopharynx?
Lateral - Eustachian tube orifices
Posterior - Pharyngeal tonsils
Where is the oropharynx?
-Posterior to soft palate
-Superior to hyoid bone
What is the function of the larynx?
Valvular function: Prevents liquids and food from entering lung
What is the composition of the larynx?
-Rigid structure
-9 cartilages
-Multiple muscles
How are vocal chords changed?
Arytenoid cartilages rotate on the cricoid cartilage
What are the 3 paired laryngeal cartilages?
-Cuneiform
-Corniculate
-Arytenoid
What are the 3 single laryngeal cartilages?
-Epiglottis
-Thyroid
-Cricoid
What is the larynx innervated by?
-Superior laryngeal nerve
-Recurrent laryngeal nerve
What does the superior laryngeal nerve divide into and what are their functions?
-Internal - Sensation
-External - Motor innervation of cricothyroid muscle
Where does the superior laryngeal nerve arise from?
Inferior ganglion of the vagus
Where does the superior laryngeal nerve descend?
Lateral pharyngeal wall
What does the recurrent laryngeal nerve innervate?
Provides motor innervation for all laryngeal muscles EXCEPT cricothyroid muscle
What is the path of the left recurrent laryngeal nerve?
-Lateral to arch of aorta
-Loops under aortic arch
-Ascends between trachea & oesophagus
What is the path of the right recurrent laryngeal nerve?
-Loops under right subclavian artery
-Ascends through plane between trachea & oesophagus
What can be a sign of ulcers/tumours around laryngeal nerves?
Hoarse voice
What is the main function of the lower respiratory tract?
Gas exchange
How much gas exchange area is there per lung?
20m2
What is the minute volume (ventilation) of the lungs?
5 litres/minute
What is the cardiac output to the lungs?
5 litres/minute
Are there regional differences in ventilation and perfusion in the lungs?
Yes
What is the pathway of main structures that compose the lower respiratory tract?
-Trachea
-Main bronchi
-Lobar bronchi
-Segmental branches
-Respiratory bronchiole
-Terminal bronchiole
-Alveolar ducts & Alveoli
Where does the trachea run from?
Larynx to carina (C6 - T5)
What shape is the cross-section of the trachea?
Oval
What cells line the trachea?
Pseudostratified, ciliated, columnar epithelium, goblet cells
What are the C-shaped structures on the trachea and what are their function?
Semi-circular hyaline cartilages: They increase the flexibility of the trachea
What is the mobility of the trachea?
-3cm superior
-1cm inferior
What is the name of the sharp division between the left and right main bronchi?
The carina
What level is the carina on?
T5
How long are the right and left main bronchi?
-Right - 1-2.5cm
-Left - 5cm
Why are things more likely to get stuck in the right main bronchus?
It is more vertically disposed, the left main bronchus comes off at more of an angle and is longer
What are the right and left main bronchi related to?
-Right - Right pulmonary artery
-Left - Aortic arch
What are the right and left lobar bronchi called?
-Right:
-Upper lobe
-Middle lobe
-Lower lobe
-Left:
-Upper lobe + lingula
-Lower lobe
How many divisions do the right and left main bronchi have?
-Right - 3
-Left - 2
How many segmental bronchi does the right lung have?
10
How many segmental bronchi does the left lung have?
8
What are the names of the segmental bronchi of the right upper lobe?
-Apical
-Anterior
-Posterior
What are the names of the segmental bronchi of the right middle lobe?
-Medial
-Lateral
What are the names of the segmental bronchi of the right lower lobe?
-Apical
-Anterior
-Posterior
-Medial
-Lateral
What are the names of the segmental bronchi of the left upper lobe?
-Apico-posterior
-Anterior
What are the names of the segmental bronchi of the left lingular?
-Superior
-Inferior
What are the names of the segmental bronchi of the left lower lobe?
-Apical
-Anterior
-Posterior
-Lateral
What is an alveolar duct?
Short tubes leading to multiple alveoli
What is an acinus?
The tissue supplied with air by one terminal bronchiole
What are pores of Kohn?
interconnection between alveoli
What happens to alveoli with each increasing generation of subdivision?
Become more profuse
What different components make up alveoli (7)?
-Type I pneumocytes
-Type II pneumocytes
-Alveolar macrophages
-Basement membrane
-interstitial tissue
-Capillary endothelial cells
-Surfactant
What type of cells secrete surfactant?
Type II pneumocytes
What are the two main layers of the the lung pleura and what do they line?
-Visceral - Lung surface
-Parietal - Internal chest wall
How many layers of cells make the visceral and parietal pleura?
Single layer
What is in between the two pleural layers?
Small amount of pleural fluid
Which pleura has pain sensation?
Parietal
Which pleura has autonomic innervation?
Visceral
Where do the two pleura become continuous with each other?
Lung root
What are the two circulations of the lungs?
Bronchial & Pulmonary circulations
Where do the left and right pulmonary arteries run from?
Right ventricle
How many orders of branching are there in the pulmonary circulation?
17
What do pulmonary arteries run alongside into the lung?
Bronchus - via the bronchovascular bundle
What do pulmonary veins run alongside coming out of the lung?
Nothing, they run on their own
What is the lumen size of elastic arteries, muscular arteries and arterioles of the lung?
-Elastic - >1mm
-Muscular - <1mm
-Arterioles - <0.1mm
What is the pathway of oxygen from air spaces of the lung?
-Alveolar epithelium
-Interstitial fluid
-Capillary endothelium
-Blood plasma layer
-Erythrocyte membrane
-Erythrocyte cytoplasm
-Hb binding forces
What is the respiratory pump?
The generation of negative intra-alveolar pressure
What is the requirement of inspired gas for the respiratory pump?
5 litres/minute
What are involved in the respiratory pump?
-Bones
-Muscles
-Pleura
-peripheral nerves
-Airways
What generates flow in the respiratory pump?
Active inspiration
What is the role of bony structures in the respiratory pump?
-Support respiratory muscles
-Protect lungs
What do rib movements in the respiratory pump represent?
Pump and water handle
What is transpulmonary pressure (Ptp)?
-Difference in pressure between the inside and outside of the lung
-Alveolar pressure - Intrapleural pressure
What is intrapleural pressure (Pip)?
-Pressure inside the pleural space
-Also known as the intrathoracic pressure
What is the alveolar pressure (Palv)?
Air pressure in pulmonary alveoli
What induces inspiration?
Neurally induced contraction of diaphragm and external intercostal muscles
What muscle/s are most important for insipration during normal quiet breathing?
Diaphragm
How are impulses that stimulated contraction transmitted to the diaphragm?
Via the phrenic nerve which arises from C3,4 &5 (C3,4 & 5 keeps the diaphragm alive!)
What are the 6 steps of inspiration?
- Diaphragm contracts causing it to dome downwards - increasing thoracic volume
- Simultaneously, motor neurones of intercostal nerves to the external intercostal muscles are activated. EIM contract pulling ribs upwards and outwards - increasing thoracic volume
- Thorax expansion means intrapleural pressure decreases and transpulmonary pressure increases. This results in lung expansion - transpulmonary pressure force is greater than elastic recoil
- Lung expansion means alveolar pressure is -ve
- Inward airflow
6.At the end of inspiration, chest wall is no longer expanding. Alveolar pressure = atmospheric pressure. elastic recoil = transpulmonary pressure. No airflow
What are the 3 steps of expiration?
- Motor neurones to diaphragm + EIM decrease firing so the muscles relax. Diaphragm descends, decreasing thoracic volume
- Lungs and chest walls passively collapse due to elastic recoil. intrapleural pressure has increased and therefore so has transpulmonary pressure. Elastic recoil > transpulmonary pressure
- As lungs become smaller, alveolar air is temporarily compressed leading to increased alveolar pressure which exceeds atmospheric pressure. Air flows out
What are the 3 extra steps of forced expiration?
- internal intercostal muscles and abdominal muscles contract
- Ribs move downwards and inwards, decreasing thoracic volume actively. Abdominal muscle contraction leads to increase of intra-abdominal pressure - forcing the relaxed diaphragm further up
- Greater volume of air expired
Where is the greatest resistance in the airway and why?
-Trachea
-Has a much smaller surface area than the bronchioles, providing more resistance
What property does the chest wall and lungs have?
Elastic properties
What layer plays an important part in linking the chest wall and lungs?
Pleura
What does bulk flow in the airways allow?
O2 and CO2 movement
What does bulk flow in the airways require?
-Large surface area
-Minimal distance for gases to move
-Adequate perfusion of blood
What is the total combined surface area for gas exchange in the lungs?
50-100m2
How many alveoli are there per lung?
300,000,000 per lung
What is dead space?
-Volume of air not contributing to ventilation
-150mls anatomically
-25mls in alveoli
-175mls total (physiological)
Where are respiratory bronchioles found?
Centre of the acinus
What supplies the lungs with blood (bronchial circulation)?
Branches of the bronchial arteries
Where do paired bronchial arteries branch and what do they supply?
-Arise laterally
-Supply bronchial + peribronchial tissue, visceral pleura
What is the venous drainage of the lungs (bronchial circulation)?
Bronchial veins drain ultimately into the superior vena cava
What are the two types of circulation in the lungs?
Bronchial & pulmonary
What pressures are in the bronchial circulation?
Systemic pressures (LV/aortic)
What arteries form the pulmonary circulation and where do they run from?
-Left and right pulmonary arteries
-Right ventricle
What pressures are in the pulmonary circulation?
Lower pressure system (RV/pulmonary artery)
How many orders of branching are there in the pulmonary circulation?
17
What is a broncho-vascular bundle?
Pulmonary artery and bronchus run in parallel
How many capillaries are there per alveolus?
1000
Does each erythrocyte come into contact with more than one alveoli?
Yes, each erythrocyte may come into contact with many alveoli
What is an important component of the distance a gas has to be moved?
Erythrocyte thickness
At rest, how far through a capillary is haemoglobin fully saturated?
25%
What is preferential perfusion?
Capillaries at the most dependant part of the lungs are more preferentially perfused with blood at rest
What 3 factors does perfusion of capillaries depend on?
-Pulmonary artery pressure
-Pulmonary venous pressure
-Alveolar pressure
What is important in terms of the relationship of ventilation and perfusion?
Matching ventilation and perfusion
What is hypoxic pulmonary constriction?
Diverting blood away from capillaries that perfuse alveoli with a low PO2 via vasoconstriction
What is unique to pulmonary artery vessels and why is it important?
-Hypoxic pulmonary constriction
-Ensures blood flow is diverted away from diseased lung areas to well-ventilated areas
Equation showing the partial pressure of arterial CO2 is inversely related to alveolar ventilation:
PaCO2 = kV̇CO2 / V̇A
What is the normal range of PaCO2
4-6 kPa
Three ways CO2 is carried:
-Bound to haemoglobin (23%)
-Plasma dissolved (10%)
-As carbonic acid (60-65%)
4 Physiological causes of high CO2
-V̇A reduced - reduce minute ventilation
-V̇A reduced - increased dead space ventilation by rapid shallow breathing
-V̇A reduced - increased dead space by V/Q mismatch
-Increased CO2 production
What is the alveolar gas equation?
PAO2 = PiO2 - PaCO2 / R
What is R and what is its assumed value?
-Respiratory quotient
-Ratio of vol CO2 released / vol CO2 absorbed
-Assumed at 0.8
4 causes of low PaO2 (hypoxemia):
-Alveolar hypoventilation
-Reduced PiO2
-V/Q mismatch
-Diffusion abnormalities
What shape is the oxygen dissociation curve?
Sigmoid
Why does the oxygen dissociation curve have its shape?
-As each O2 molecule binds, it alters the conformation of haemoglobin
-Makes subsequent binding of oxygen molecules easier
What things can influence the oxygen dissociation curve?
-2,3-disphosphoglyceric acid
-H+
-Temperature
-CO2
What factors cause the oxygen dissociation curve to shift to the right?
-Increased temperature
-Decreased pH
-Increased CO2 concentration
(These are all due to higher metabolic activity)
Why does the body maintain close control of the pH of extracellular fluids?
To ensure optimal function - e.g. enzymatic cellular reactions
What interfaces are vital for the maintenance of pH control?
-Dissolved CO2
-Carbonic acid
-Respiratory sytem
What is the normal pH of extracellular fluids?
7.40 (7.35-7.45)
What is the most important pH buffer?
The carbonic acid/bicarbonate buffer
What predominantly controls CO2 levels and what is its speed?
Respiratory system
What predominantly controls HCO3- levels and what is its speed?
Renal system
What is required for the elimination of fixed acids?
Functioning renal system
What is the carbonic acid equilibrium equation (bicarbonate buffer equation)?
CO2 + H2 ⇌ H2CO3 ⇌ H+ + HCO3-
What is the Henderson-Hasselbalch equation?
pH=6.1 + log10([HCO3-]/[0.03*PCO2])
Why must HCO3- increase with an increase in PaCO2?
-Follows Henderson-Hasselbach equation
-To maintain pH at 7.40, the log must equal 1.3
-Increasing the denominator means the numerator must also increase
-Also follows bicarbonate equation
What are the 4 main acid-base disorders?
-Respiratory acidosis
-Respiratory alkalosis
-Metabolic acidosis
-Metabolic alkalosis
What causes respiratory acidosis?
-Increased PaCO2
-Decreased pH
-Mild increase in HCO3-
What causes respiratory alkalosis?
-Decreased PaCO2
-Increased pH
-Mild decrease in HCO3-
What causes metabolic acidosis?
-Reduced bicarbonate
-Decreased pH
What causes metabolic alkalosis?
-Increased bicarbonate
-Increased pH
What do the following abbreviations mean?:
-VC
-TV
-TLC
-FRC
-RV
-Vital capacity
-Tidal volume
-Total lung capacity
-Functional residual capacity
-Residual volume
What values are measured to determine lung function?
-FEV1
-FVC
-Flow volume curve
-Lung volumes
-Transfer factor estimates
-Compliance
What is FEV1?
-Forced expiratory volume in 1 second
-Person takes a maximal inspiration to TLC then exhales maximally as fast as possible to RV
What is FVC?
-Amount of air that can be exhaled with maximum effort after a maximum inspiration
-Breathe into TLC then exhale as fast as possible to RV
What does a volume/time plot look like?
What does a flow/volume plot look like?
What does PEF represent?
Peak expiratory flow (rate)
What is FEF25?
Flow at the point when 25% of FVC has been exhaled
What is peak expiratory flow (rate) and how is it measured?
-Single measure of highest flow rate during expiration
-Spirometer - peak flow meter
-Reading in L/minute
-Effort dependant
Why are expiratory procedures not useful for calculating lung volumes?
-Only measure VC and not RV
-Other methods to measure RV and TLC are needed
What methods can be used to calculate TLC?
-Gas dilution
-Body box
What is gas dilution?
-Measurement of all air in the lungs that communicates with the airways
-Doesn’t measure the air in non-communicating bullae
-Closed circuit helium dilution or open circuit nitrogen wash out
What is the scientific name of the body box?
Total body plethysmography
What is Total body plethysmography?
-Alternative way of measuring lung volume
-Gas trapped in a bullae
-From Functional Residual Capacity, patient pants with an open glottis against closed shutter
-Produces changes in box pressure proportionate to volume of air in chest
-Volume measured (TGV) represents lung volume when shutter was closed
How do you calculate TLC from the values collected in Total body plethysmography?
TLC = VC + RV
What are transfer estimates?
-Use of CO to estimate TLCO
Why is CO used in transfer estimates?
-CO has a high affinity for haemoglobin
What is TLCO an overall measure of (5)?
-Alveolar surface area
-Alveolar capillary perfusion
-Physical properties of alveolar capillary interface
-Capillary volume
-Hb concentration (reaction rate of CO and Hb)
What is the composition of a transfer estimate and how long is it held in for?
-10% helium
-0.3% CO
-21% oxygen
-Remainder Nitrogen
-10 seconds
How is DLCO calculated?
-Total lung volume
-Breath-hold time
-Initial and final alveolar concentrations of CO
What is compliance?
-Change in volume per unit change in pressure gradient of pleura and alveoli (transpulmonary pressure)
What is static compliance?
-Compliance during breath hold
-Measure of distensibility
What does high lung compliance mean?
A lung of high compliance expands more than one of low compliance when exposed to same trans-pulmonary pressure
What is dynamic compliance?
-Compliance during tidal breathing at end of inspiration and expiration when lung is apparently stationary
What type of compliance is reduced during airway obstruction?
Dynamic is reduced compared to static
How are the normal ranges of each lung function value derived and what do they show?
-Normally from regression equations on normal populations
-Wide range of values that are considered normal
What % of lung function values are arbitrarily defined as abnormal?
-Lowest 5%
-Highest 5%
Which lung function value is a good overall assessment of lung health?
FEV1
How do you assess whether a patient’s FEV1 and FVC is normal?
-Compare to predicted values
-80% or greater = ‘normal’
-Above lower limit of normal for the patient (LLN)
-Above mean minus 1.645 SD
What does a low FVC value indicate?
Airways restriction
What is considered a low FVC?
80% of the predicted value
What ratio can be calculated to assess an individual’s lung health?
FEV1 / FVC
What is an abnormal FEV1 / FVC ratio and what does it suggest?
-Value < 0.70
-Airways obstruction
Does a change in pH need to be large to alter physiological function?
No, only a small variation is required
What are the requirements of respiration (3)?
-Ensure haemoglobin is as close to full O2 saturation as possible
-Efficient use of energy resource
-Regulate PaCO2 carefully
What type of control is breathing under?
Automatic - no conscious effort for basic rhythm
What features of breathing are under additional influences to automatic control?
-Rate
-Depth
What physiology does respiration rely on?
-Cyclical excitation and control of many muscles
-Upper airway, lower airway, diaphragm and chest wall
-Near linear activity
-Increase thoracic volume
What are the 2 respiratory control centres?
-Medulla Oblongata
-Pons
What are the 2 respiratory centres of the pons?
-Pneumotaxic
-Apneustic
What are the 2 main groups of the medulla oblongata?
-Dorsal respiratory group (DRG)
-Ventral respiratory group (VRG)
What is the medulla’s role in respiration?
Phasic discharge of action potentials
When is the DRG predominantly active?
During inspiration
When is the VRG active?
During both inspiration and expiration
What can be used to describe both the DRG and VRG?
Bilateral
Where do the VRG and DRG project and interconnect?
They project into the bulbo-spinal motor neuron pools and interconnect
Where is the Central Pattern Generator located?
DRG/VRG (medulla)
What is the function of the Central Pattern Generator?
Start, stop and resetting of an integrator of background ventilatory drive
What initiates inspiration?
A burst of action potentials in the spinal motor neurons to inspiratory muscles like the diaphragm
What causes expiration?
-Action potentials to inspiratory muscles cease
-Inspiratory muscles relax
-Elastic lungs recoil
Is the activation of inspiratory muscles instant or progressive?
Progressive
How do the lungs fill during inspiration?
Fill at a constant rate until tidal volume is achieved
What happens at the end of inspiration?
Rapid decrease in excitation of the respiratory muscles
Why is expiration largely passive?
Due to the elastic recoil of the thoracic wall
What happens at the first part of expiration?
Active slowing with some inspiratory muscle activity
What happens during expiration with increasing demands?
-Further muscle activity recruited
-Active with additional abdominal wall muscle activity
What are the two types of chemoreceptors involved in respiration?
-Central
-Peripheral
What is the % influence of PaCO2 on central and peripheral chemoreceptors?
-Central - 60%
-Peripheral - 40%
What are chemoreceptors stimulated by?
-H+ concentration
-Gas partial pressures of arterial blood
What is the significant influence on brainstem chemoreceptors?
PaCO2
What influences carotid and aorta chemoreceptors and how much interaction is there?
-PaCO2
-PaO2
-pH
-Significant interaction
Where are central chemoreceptors located?
-Brainstem
-Pontomedullary junction
-Not within the DRG/VRG complex
What are central chemoreceptors sensitive to?
PaCO2 of blood perfusing brain
What is the blood-brain barrier relatively permeable and impermeable to?
-Impermeable - H+, HCO3-
-Permeable - PaCO2 preferentially diffuses into CSF
Where are peripheral chemoreceptors located?
-Carotid bodies
-Aortic bodies
Where are the carotid body chemoreceptors located?
-Bifurcation of the common carotid artery
-(IX) cranial nerve afferents
Where are the aortic body chemoreceptors located?
-Ascending aorta
-Vagal (X) nerve afferents
What are peripheral chemoreceptors responsible for?
All ventilatory response to hypoxia (reduced PaO2)
When are peripheral chemoreceptors generally not sensitive?
Across normal PaO2 ranges
What do type I peripheral chemoreceptors do in response to hypoxia?
They release stored neurotransmitters that stimulate the cuplike endings of the carotid sinus nerve
What kind of response do peripheral chemoreceptors have to PaCO2?
-Linear response
-Interactions between responses (poison and blood pressure responsive)
What does the graph look like for the ventilatory response to PaCO2?
What does the graph look like for the ventilatory response to PaO2?
What are the 3 types of lung receptor?
-Stretch
-J
-Irritant
What is the afferent input for lung receptors?
Vagus (X)
What are lung receptors a combination of?
Slow and fast adapting receptors
What is the function of lung receptors?
-Assist with lung volumes
-Responses to noxious inhaled agents
Where are stretch lung receptors and what do they sense?
-Smooth muscle of conducting airways
-Sense lung volume, slowly adapting
Where are irritant lung receptors and what is one of their features?
-Larger conducting airways
-Rapidly adapting (cough,gasp)
Where are juxtapulmonary lung receptors?
Pulmonary and bronchial C fibres
What are the locations of airway receptors?
-Nose
-Nasophraynx
-Larynx
-Pharynx
What are the airway receptors of the nose, nasopharynx and larynx and what do they sense?
-Chemo and mechano receptors
Some appear to sense and monitor flow (stimulation inhibits central controller)
What activates airway receptors of the pharynx?
-Swallowing
-Respiratory activity stops during swallowing to prevent aspiration of food or drink
What are muscle proprioceptors and what are their roles?
lungs
-Joint, tendon and muscle spindle receptors
-Important roles in perception of breathing effort
What is the relationship between PaCO2 and alveolar ventilation?
-PaCO2 ∝ 1/alveolar ventilation
-PaCO2 = kV̇CO2 / V̇A
What is the definition of respiratory failure?
-Failure of gas exchange
-Inability to maintain normal blood gases
-Low PaO2 with or without a rise in PaCO2
Does respiratory failure only occur in abnormal lungs?
No, respiratory failure can occur in normal or abnormal lungs
What is the sea level PiO2?
At sea level PiO2 = 100KPa x 0.21 = 21KPa
What blood gas values show respiratory failure?
-PaO2 <8KPa <60mmHg
-PaCO2 >6.5KPa >49mmHg
What are the normal ranges of blood gas values?
-PaO2 10.5 - 13.5
-PaCO2 4.7-6.5
What are the two types of respiratory failure?
-Type I
-Type II
What are the blood gas traits of the two types of hypoxia?
-Type I:
- PaO2 = Low (hypoxia)
- PaCO2 = Low/Normal (hypocapnia/normal)
-Type II:
-PaO2 = Low (hypoxia)
-PaCO2 = High (hypercapnia)
What are 3 causes of acute (rapid) respiratory failure?
-Opiate overdose
-Trauma
-Pulmonary embolism
What are 2 causes of chronic (long time period) respiratory failure?
-COPD
-Fibrosing lung disease
What general system causes produce type I failure?
Most pulmonary and cardiac causes produce type I failure
What are 5 general causes of type I respiratory failure?
-Hypoxia
-V/Q mismatch
-Shunting
-Diffusion impairment
-Alveolar hypoventilation
What 3 things show similar effects on tissues to type I respiratory failure?
-Anaemia
-CO poisoning
-Methaemoglobinaemia
Name 2 infection causes of type I respiratory failure:
-Pneumonia
-Bronchiectasis
What are the main treatments for type I respiratory failure?
-Airway patency
-Oxygen delivery
-Many differing systems
-Increasing FiO2
-Treating primary cause (e.g. antibiotics for pneumonia)
What are the main 3 mechanisms of type II respiratory failure?
-Lack of respiratory drive
-Excess workload
-Bellows failure
Name a congenital cause of type I respiratory failure:
Cyanotic congenital heart disease
Name a neoplasm cause of type I respiratory failure:
Lymphangitis carcinomatosis
Name 2 airway causes of type I respiratory failure:
-COPD
-Asthma
Name 2 vasculature causes of type I respiratory failure:
-Pulmonary embolism
-Fat embolism
Name 4 parenchyma causes of type I respiratory failure:
-Pulmonary fibrosis
-Pulmonary oedema
-Pneumoconiosis
-Sarcoidosis
Name 4 airway causes of type I! respiratory failure:
-COPD
-Laryngeal oedema
-Asthma
-Sleep apnoea syndrome
Name a drugs cause of type I! respiratory failure:
Suxamethonium
Name 2 metabolic causes of type I! respiratory failure:
-Poisoning
-Overdose
Name 3 neurological causes of type I! respiratory failure:
-Central
-Primary hypoventilation
-Head and cervical spine injury
Name a muscle cause of type I! respiratory failure:
Myasthenia
Name 2 polyneuropathy causes of type I! respiratory failure:
-Poliomyelitis
-Primary muscle disorders
What are 4 clinical features of hypoxia?
-Central cyanosis - in oral cavity (may not be obvious in anaemic patients)
-Irritability
-reduced intellectual function
-Reduced consciousness
What are 3 things hypoxia can lead to?
-Convulsions
-Coma
-Death
What are 8 clinical features of hypercapnia?
-Irritability
-Headache
-Papilloedema
-Warm skin
-Bounding pulse
-Confusion
-Somnolence
-Coma
What are 3 treatments for type II respiratory failure?
-Airway patency
-Oxygen delivery
-Treating primary cause (e.g. antibiotics for pneumonia)
Why might O2 treatment be more difficult for type II respiratory failure?
COPD patients rely on hypoxia to stimulate respiration
What are the 2 types of ventilation used for the treatment of type II respiratory failure?
-Invasive
-Non-invasive
What can show during assisted ventilation treatment on type II respiratory failure?
-Inadequate PaO2 despite increasing FiO2
-Increasing PaCO2
-Patient tiring
For serious illnesses needing high FiO2, what is the oxygen treatment guideline?
-5-10 litres/min face mask
-2-6 litres/min nasal cannulae
-Aim for SpO2 of 94-98%
What is the oxygen treatment guidance if saturation <86% and not at risk of hypercapnic respiratory failure?
10-15 litres/min reservoir mask
What is the oxygen guidance for patients with COPD and other risk factors of hypercapnia?
-Aim for SpO2 of 88-92% pending blood gases
-Adjust to SpO2 of 94-98% if CO2 normal unless previous history of high CO2 or ventilation
Summarise respiratory failure
What is the alveolar surface area the same size as?
A tennis court
Are the airways sterile?
No
What do we regularly inhale?
Particulate matter, e.g. fossil fuel from vehicle exhausts, fossil fuel stoves
Is the lung permanently inflamed?
No
What are the 2 main causes of respiratory admissions to hospital?
Infection and inflammation
What are 5 common signs of inflammation?
-Hot
-Red
-Swollen
-Painful
-Loss of function
What are the 4 basic stages of inflammation?
- Bacteria enter wound
- Vasodilation
- Diapedesis
- Neutrophils clear infection/ capillaries return to normal
What does vasodilation lead to?
Exudation of plasma, including antibodies
What cascades are activated during acute inflammation?
-Biochemical cascades
-e.g. complement cascade & coagulation cascade
What is diapedesis?
-Migration of blood leukocytes into tissues
-Mainly neutrophils but also some monocytes
Why is inflammation considered a double-edged sword?
-Inflammation is our defence against infection
-Produces a hostile environment
How many people does community-acquired pneumonia affect per annum and what are the admittance and mortality rates?
-250,000 adults per annum in UK
-33% admitted to hospital
-Mortality of those admitted is around 10%
What are 2 examples of inflammation-mediated tissue damage in the lung?
-COPD (chronic)
-Acute Respiratory Distress Syndrome (acute)
What is seen in patients with ARDS?
-Respiratory failure
-Water and neutrophils fill the alveoli
-Multi-system failure
What can cause ARDS?
-Any condition causing inadequate tissue oxygenation
-Commonly trauma, lung infections, sepsis, surgery
What are 4 pathophysiological features of ARDS?
-Endothelial leak - leading to extravasation of protein and fluid
-Lungs. - reduced compliance, increased shunting
-Heart - Pulmonary hypertension, reduced cardiac output
-Hypoxia
Name 5 diseases caused by inflammation-mediated tissue damage in the lung:
-COPD
-ARDS
-Bronchiectasis
-Interstitial lung disease
-Asthma
How is acute inflammation initiated?
-It is initiated in the tissues
-Caused by epithelial production of hydrogen peroxide and release of cellular contents
What is acute inflammation amplified by?
-Specialist macrophages such as:
-Kupffer cells (liver)
-Alveolar macrophages (lungs)
-Histiocytes (skin, bone)
Dendritic cells
What do macrophages recognise to respond to tissue injuries?
-PAMPs (hydrogen-associated molecular patterns)
-DAMPs (damage-associated molecular patterns)
How do we recognise pathogens we have never seen before?
Patter recognition receptors (PRRs)
What are 2 examples of signalling receptors?
-Toll-like receptors (TLRs)
-Nod-like receptors (NLRs)
What are 2 examples of endocytic receptors?
-Mannose receptors
-Glucan receptors
-Scavenger receptors
What do toll-like receptors recognise?
-Conserved molecular patterns in pathogens
-Also recognises endogenous mediators of inflammation
Where are toll-like receptors expressed?
Plasma & endosomal membranes of macrophages and dendritic cells
What do TLR4 and TLR2 recognise?
-TLR4 - Lipopolysaccharide (LPS)
-TLR2 - lipotechoic acid (LTA)
What do pulmonary macrophages primarily comprise?
Alveolar macrophages comprise 93% of pulmonary macrophages
Are alveolar macrophages similar or dissimilar to mature tissue macrophages and in what way?
-Similar
-Functionally
-Cytochemically
-Morphologically
Are alveolar macrophages short-lived and what do they arise from?
-No, alveolar macrophages are long-lived
-Alveolar macrophages arise from monocytes
What is macrophage plasticity?
Macrophages can change their phenotypes and behaviours to suit their environment
What percentage of all white blood cells do neutrophils make?
Neutrophils make up 70% of all white blood cells
How many neutrophils are made each minute and when are more made?
-80 million are made each minute
-Sepsis
How many neutrophils are turned over per day?
100 million per day
What type of cell are neutrophils and what are they related to?
-Myeloid cells
-Related to monocytes and macrophages
What do neutrophils contain and what can these be grouped into?
-Neutrophils contain granules
-Primary
-Secondary
Name 4 examples of primary granules:
-Myeloperoxidase (anti-microbial enzyme)
-Elastase (enzyme that breaks down elastin in lungs)
-Cathepsins (anti-bacterial proteins)
-Defensins (anti-bacterial proteins)
Name 3 examples of secondary granules:
-Receptors
-Lysozyme
-Collagenase
Where do neutrophils spend most of their life?
In the circulation
Where in the circulation are neutrophils and in what proportion?
-Half are freely flowing
-Half are marginated - adherent to endothelium
Why is it beneficial for neutrophils to be marginated?
Can provide a large pool of neutrophils to respond to infection
After a period of inflammation, what important process do neutrophils undergo?
Apoptosis
What are the 7 important neutrophil steps?
-Identify threat - receptors
-Activation
-Adhesion
-Migration/chemotaxis
-Phagocytosis
-Bacterial killing
-Apoptosis - programmed cell death
What can neutrophil receptors recognise and what are some examples of them?
-Bacterial structures (cell walls, lipids, peptides)
-Host mediators (cytokines, complement, lipids)
-Host opsonins (FcR immunoglobulin, CR3 complement
-Host adhesion molecules
What occurs during stimulus-response coupling activating of neutrophils?
Signal transduction pathways involving calcium, protein kinases, phospholipases, G proteins
What molecules are released by activated endothelium to cause margination?
Selectins
What molecules allow adhesion of neutrophils to activated endothelium?
Integrins
What does adhesion of neutrophils require?
Changes in endothelium and in neutrophil
What does a CD18 (beta-2-integrin) deficiency cause?
-NO transendothelial migration
-Delayed separation of umbilical cord
-Recurrent severe cutaneous and deep infections
What is neutrophil migration/chemotaxis?
-Ability of a neutrophil to detect a concentration gradient and move along it
-By moving receptors to the leading edge
What is neutrophil phagocytosis?
-Membrane invagination and pinching. to produce a phagosome
-Fusion with granules to form phagolysosome
What is neutrophil bacterial killing?
-Lysosomal enzymes - cathepsins, elastase, ROS destroy bacteria
What are neutrophil ROS generated by?
-A membrane enzyme complex
-NADPH oxidase
What is the difference between necrosis and apoptosis?
-Necrosis - cells swell, then lyse and release ROS and enzymes which damage surrounding tissue
-Apoptosis - More controlled, cell is turned off and packaged to be phagocytosed by neutrophils with no surrounding tissue damage
Why is the lung especially at risk of inflammation?
It is a huge area potentially in contact with the external environment
What are 3 non-respiratory functions of the lung?
-Synthesis, activation and inactivation of vasoactive substances, hormones, neuropeptides
-Lung defence - complement activation, leucocyte recruitment, host defence proteins, cytokines and growth factors
-Speech, vomiting, defecation
What are the lungs exposed to a large amount of?
-Airborne pathogens
-Particulates
What are the 3 types of host defences?
-Intrinsic
-Innate
-Adaptive immunity
What is intrinsic defence?
-Always present
-Physical and chemical
-Apoptosis, autophagy, RNA silencing, antiviral proteins
What is innate defence?
-Induced by infection
-Interferon, cytokines, macrophages,NK cells
What is adaptive immunity?
Tailored to a pathogen (T cell, B cell)
What is epithelium?
-Tissue lining cavities and surfaces of structures in the body
-Forms many glands
-Lies on top of connective tissue
-Basement membrane separates the two layers
What is the function of respiratory epithelium?
-Moisten and protect the airways
-Barrier to potential pathogens and foreign particles
-Prevents infection and tissue injury by action of the mucociliary escalator
Is airway epithelium the sam in all parts of the airway and why?
-No
-it is different in distinct regions to reflect the functions of each region
In distinct regions, what does airway epithelium contain?
Multiple cell types that express multiple cell specific genes
What are chemical epithelial barriers?
Multiple molecules secreted by most epithelial cells that play a role in host defence
What are the 5 chemical epithelial barriers?
-Antiproteinases
-Anti-fungal peptides
-Anti-microbial peptides
-Antiviral proteins
-Opsins
What is an important fact about the dual-function of alveolar epithelium?
It is specialised for gas exchange as well as a host defense function
What 2 factors other than epithelial cell products are important in respiratory tract host defence?
-Physical barriers (mucus)
-Products of submucosal glands
What is airway mucus and what does it contain?
-Airway mucus is a viscoelastic gel
-Contains water, carbohydrates, proteins and lipids
What is airway mucus a secretory product of?
-Mucous cells
-Goblet cells of the airway surface epithelium
-Submucosal glands
What is the function of mucus?
Protects the epithelium from foreign material and from fluid loss
How is mucus transported?
It is transported from the lower respiratory tract into the pharynx by air flow and mucociliary clearance
How does mucus clearance work?
-Via the escalator
-cilia beat in directional waves to move mucus up the airways
What 2 physical actions are significant non-immune defence mechanisms?
Coughing and sneezing
What is a cough?
-An expulsive reflex
-Protects the lungs and respiratory passage from foreign bodies
What are 3 causes of a cough?
-Irritants - smokes, fumes, dusts
-Diseased conditions - COPS, tumours
-Infections - influenza
What are the 2 ways a cough may be initiated?
-Voluntarily
-Reflexively
What pathways does a defensive reflex cough have?
Afferent and efferent pathways
What nerves does the afferent limb of coughing include receptors in?
The sensory distribution of the:
-Trigeminal
-Glossopharyngeal
-Superior laryngeal
-Vagus nerve
What nerves does the efferent limb of coughing include receptors in?
-Recurrent laryngeal nerve
-Spinal nerves
What is a sneeze?
The involuntary expulsion of air containing irritants from nose
What can cause a sneeze?
-Irritation of nasal mucosa
-Excess fluid in airway
What sneezing condition affects 1/3 of the population?
-Photic sneeze reflex
-Sneezing when looking at a bright light
What can airway epithelium do after an insult/injury?
In many cases airway epithelium can effect a complete repair
What does airway epithelium exhibit to effect a complete repair?
-Functional plasticity
-Cells can change their phenotype to carry out. a different function
What happens when functional plasticity of airway epithelium goes wrong?
Pulmonary disease
What underpins many obstructive lung diseases?
Abnormal epithelial responses to injury/insult
What is an example of obstructive lung disease caused by abnormal epithelial responses to injury/insult?
Goblet cell metaplasia in the airway of a heavy smoker
What are associated with severe pulmonary obstructive diseases and are related to genetics?
-Mucus plugs/inflammation
-Mucus and inflammatory cell block the airways
What can completely obstruct the airways?
-Mucus plugs
-Can be fatal
Why don’t we X-Ray everyone?
-X-rays are a form of ionising radiation
-Ionising radiation can damage tissue, cells and DNA
-DNA damage could lead to uncontrolled cell division (cancer)
What considerations are taken to limit ionising radiation to patients?
-Think carefully about whether we really need to perform an x-ray or CT scan
-See if we can use other non-ionising forms of imaging (like ultrasound or MRI)
What do staff working near ionising radiation do to limit their exposure?
-Wear lead aprons if the operate in close proximity to x-rays
-Lead absorbs most x-rays
What regulates safe use of x-rays and other ionising radiation?
Ionising Radiation Medical Exposure Regulations
What do dense body parts (like bone) look like on an x-ray and why?
-White
-They absorb x-rays
What do less dense structures (particularly the lungs) look like on an x-ray and why?
-Much darker, almost black
-They do not absorb many x-rays
What do all other soft tissues look like on an x-ray?
-Shades of grey
Why is the diaphragm higher on the right?
Due to the presence of the liver underneath it
What are used to assess symmetry of an x-ray?
The clavicles
Why are the anterior aspects of the ribs not easily visible on an x-ray?
They are cartilaginous
What are the2 types of x-ray positioning?
-Anterior-posterior
-Posterior-anterior
What are AP x-rays and when are they used?
-Taken from the front to the back
-Detector is behind the patient
-Often performed when the patient is very unwell and not able to get in the ideal position
What is the problem with AP chest x-rays?
-The heart is at the front of the thorax and x-ray beams diverge after hitting the front of the heart, creating a larger shadow on the detector
-Heart may appear large and less crisp
What are PA x-rays and when are they used?
-Taken from the back to the front
-Detector is in front of the patient
-Heart is closer to the detector so less x-ray divergence after hitting it means it produces a more accurate size of image which is less blurry
What does pneumonia look like on a chest x-ray?
-Patchy opacification in the lung field
What is a pneumothorax and what does it look like on a chest x-ray?
-Air in between the parietal and visceral pleura
-May be able to see where the normal lung markings stop, with a rim of very clear black around the lung field - indicating air
-Normally there is fluid in between pleura to provide surface tension, the air in this space compromises breathing as sticky surface tension is lost
What is a pleural effusion and what does it look like on a chest x-ray?
-A collection of fluid in the pleural space
-Caused by infection, cancer or heart failure
-Blood and inflammatory/pleural fluid are the same colour on x-ray
-Difficult to tell if unilateral pleural effusion is pleural fluid or blood (haemothorax)
Are rib fractures easy to see on chest x-rays?
They can. be seen on chest x-rays but are often difficult to see unless displaced
What can rib fractures cause?
They can damage the pleura and cause a pneumothorax
When may a CT scan be a better option for rib fractures?
-If there are multiple rib fractures
-Significant tissue damage is suspected
-Provides a better visualisation of the thorax
What features of heart failure can be seen on a chest x-ray?
-Enlarged heart
-Small bilateral pleural effusion
-Alveolar oedema
-Fluid in the lung fissures
What do CT scans consist of and how is the image produced?
-Consists of many individual x-rays directed through the patient from all sides
-The data from the x-rays detectors is analysed to produce 3D images
Which consists of a high dose of ionising radiation, chest x-rays or CT scans and why?
-CT scans
-They consist of many more individual x-rays to make up the image
What do axial CT images look like?
They are viewed as if you are standing at the patient’s feet as they’re lying down and you’re looking up at the axial image
Where is the heart on this chest x-ray?
Where are the chambers and heart borders on this chest x-ray?
Where is the diaphragm (and abdomen) on this chest x-ray?
Where are the clavicles and scapulae on this chest x-ray?
Where are the ribs on this chest x-ray?
Where is the spine on this chest x-ray?
Where are the trachea and main bronchi on this chest x-ray?
Where are the hilar vessels in this chest x-ray?
Where is the aorta on this chest x-ray?
What is FENO and what is it measured in?
-The fraction of expired Nitrous Oxide
-Parts per billion (ppb)
is FENO generally higher or lower in asthma and what is used to measure it?
-Generally increased in asthma
-Simple machines are used to measure it
-Not diagnostic but useful
What is FENO a reflection of and what are high/normal values?
-It is a reflection of eosinophilic airway inflammation
-High - >50ppb
-Normal - <25ppb
What are the 4 most common workplace causes of asthma that are high molecular weight antigens?
-Grain
-Wood
-Animals (commonly fish)
-Latex
What are the 4 most common workplace causes of asthma that are low molecular weight antigens?
-Glutaraldehyde (used in disinfectant)
-Isocyanates (manufacturing)
-Paints
-metal working fluids
-Metals
What is asthma and what is it characterised by?
-Asthma is a common chronic inflammatory disease of the airways
-It is characterised by:
-Variable and recurring symptoms
-Reversible airway obstruction
-Bronchospasm
What are the 4 most common symptoms of asthma?
-Wheezing
-Coughing
-Chest tightness
-Shortness of breath
What two influences are important on causing/exacerbating asthma?
-Environmental influences
-Occupational influences
What are 6 environmental influences on asthma?
-Pollens
-Infectious agents
-Fungi
-Pets
-Animals
-Air pollution
What are 6 occupational influences on asthma?
-Flour
-Car spray paints
-resins
-Cleaning agents
-Laboratory animal workers
-Wood dusts
Describe asthma epidemiology (6 points):
-5-16% of people worldwide have asthma
-Wide variation between countries
-Prevalence increased in second half of 20th century
-Now plateaued mostly
-US study showed more prevalent in poorer individuals
-Studies identified a wide range of risk factors
What does air pollution do to lung disease?
Aggravates it
Are responses to lung disease similar to viral responses?
-No
-They can be comparable
What do asthma hospitalisations relate to in terms of air pollution?
-PM2.5
-PM10
What did the Swedish birth cohort study evidence in term of air pollution?
No exposure to air pollution in the first year of life related to pollen sensitisation at 4 years old
What is hypersensitivity pneumonitis and what is it significantly influenced by?
-Hypersensitivity pneumonitis is an inflammation of the alveoli within the lung caused by hypersensitivity to inhaled dusts
-Immune complex related disease:
-Antigen reacts with antibody
-Normally IgG response
-Significantly influenced by environmental influences
What are the different form of hypersensitivity pneumonitis?
-Acute
-Sub acute
-Chronic
-Fibrotic
-Non-fibrotic
What are 4 examples of significant environmental influences on hypersensitivity pneumonitis?
-Farmers lung
-Bird fanciers lung
-Metal working fluids
-Hot tub lung
What is hot tub lung?
-Hot tub lung in general identified as a cause of EAA
-Sputum grew mycobacterium fortuitum
-Hot tub drain grew same strain - mystified bacteria into air to be inhaled
What specifically is key in clinical practice to diagnose hypersensitivity pneumonitis?
-Good history taking is key
-Specifically asking about what hobbies/occupation they do
What is COPD and what is it characterised by?
-Chronic Obstructive Pulmonary Disease is a type of obstructive lung disease
-It is characterised by chronically poor airflow
-Typically worsens over time (slowly progressive)
-FEV1/FVC ratio <0.7
What are the 3 main symptoms of COPD?
-Shortness of breath
-Cough
-Sputum production
What is the commonest cause of COPD?
Tobacco smoking (PAR% 80)
What are some other common exposures of COPD?
-Silica
-Coal
-Grain
-Cotton
-Cadmium
Others:
-PAH
-Isocyanates
-iron/steel processing
-Agricultural dust, biomass fuels
-Wood dust
Do we have better information on gene and environmental interactions for asthma or COPD and HP?
Asthma
What are the 2 different circulations present in the lung?
-Pulmonary circulation
-Bronchial circulation
What % outputs of the right and left ventricles do the two types of lung circulations receive?
-Pulmonary circulation - 100% of right ventricle blood flow
-Bronchial circulation (perfuses lung tissues) - 2% of left ventricular output
Describe the pulmonary circulation (4 points):
-Receives 100% of cardiac output 4.5-8L/min)
-Red cell transit time approx 5 sec
-280 billion capillaries & 300 million alveoli
-Gas exchange surface area = 50-100m2
Name the 3 differences between pulmonary and systemic circulations:
What is the main difference between systemic and pulmonary arteries that can be seen histologically?
Pulmonary arteries have much thinner walls than those of systemic arteries
What are the pressures of the main heart chambers and outflow vessels (mmHg)?
Pulmonary:
-RA - 5
-LA - 5
-RV - 25/0
Systemic:
-LV - 120/0
-PA - 25/8
-Aorta - 120/80
Which ventricle sees higher pressure?
Left ventricle
What is Pouiselle’s Law and what does it relate to?
-Relates to Pulmonary Vascular Resistance
-L = Length
-r = radius
What is the effect of transmural pressure on pulmonary vessels during inspiration?
-Alveoli increase in volume
-This causes blood vessels to elongate and narrow
-This increases resistance in the blood vessel according to Pouiselle’s law
Why is radius important in increasing pulmonary vascular resistance?
-As it is to the power of 4 in the equation
-Small changes in radius are magnified in this equation dramatically changing the resistance
What is the equation for pressure across pulmonary circulation?
Pressure across pulmonary circulation = (mPAP - Left Atrial Pressure) x Pulmonary Vascular Resistance
-mPAP = mean pulmonary artery pressure
What equation shows the inverse proportion relationship between Cardiac Output and Pulmonary Vascular Resistance?
CO = (mPAP - PAWP) / PVR
-mPAP = mean pulmonary artery resistance
-PAWP = pulmonary arterial wedge pressure left atrial pressure
Explain recruitment during exercise in terms of mPAP and CO - with reference to equations:
-CO = (mPAP - PAWP) / PVR
-On exercise mPAP remains stable in normal subjects but CO increases significantly
-To balance the equation, PVR must significantly decrease
-Recruitment means an increase in the number of perfused capillaries
-Increased vessel flow means lower PVR
-Perfusion also decreases PVR
What are the pO22 & pCO2 values for type I and type II respiratory failure?
Type I:
-pO2 <8kPa
-pCO2 <6kPA
Type II:
-pO2 <8kPa
-pCO2 >6kPa
What are the 4 causes of hypoxaemia?
-Hypoventilation
-Diffusion impairment
-Shunting
-V/Q mismatch
What is hypoventilation?
What respiratory failure is it seen in?
What can cause it?
-Failure to ventilate the alveoli
-Type II respiratory failure
-Muscular weakness (muscular dystrophy)
-Obesity
-Loss of respiratory drive (drugs, opioids)
What are 3 causes of diffusion impairment?
-Gaseous diffusion
-Pulmonary oedema
-Blood diffusion
-Anaemia
-Membrane diffusion
-Interstitial fibrosis
What is V/Q ratio and what is a V/Q mismatch?What are the general rates in different areas of the lung?
-To be most efficient, the correct proportion of alveolar airflow (ventilation) and capillary blood flow (perfusion) should be available to each alveolus
-Any mismatch between the two is deemed V/Q mismatch
How does perfusion and ventilation change as you go up the lung and why is there a natural V/Q mismatch (Physiological V/Q mismatch)?
Perfusion:
-Increases from 0-7cm up lung
-Decreases as you move further up the lung
Ventilation;
-Decreases as you go down the lung
What does the graph of blood flow, ventilation and V/Q look like?
What are the two extremes that can cause significant V/Q mismatch?
-Shunt
-Dead space
What is a shunt in terms of V/Q mismatch?
-When there is adequate blood flow through areas of the lung but there is no ventilation
-Due to collapsed alveoli
What is dead space in terms of V/Q mismatch?
-There are ventilated alveoli but no blood supply at all
-Could be due to a blood clot
What are the three classes of shunts and examples of each?
Physiological:
-Bronchial arteries
-Thesebian veins
Intracardiac:
-e.g. VSD - R-L Shunt (Eisenmenger’s Syndrome)
Pulmonary:
-ArterioVenous Malformation
-Complete Lobar Collapse
What is Eisenmenger’s Syndrome and what are 3 symptoms?
-R-L ventricle shunt
-Cyanosis
-Clubbing
-Polycythaemia
What are 5 things that can cause V/Q mismatch?
-Physiological
-Pulmonary emboli
-Asthma
-Pneumonia
-Pulmonary Oedema
What is Hypoxic Pulmonary Vasoconstriction?
-Local action of hypoxia on pulmonary artery wall causing change in distribution of blood flow to better ventilated areas
-Weak response as little muscle
-Aims to improve V/Q mismatching
-Local hypoxia
-Generalised hypoxia
What does a graph of blood flow (% control) against alveolar PO2 look like and what phenomenon does it show?
-Hypoxic Pulmonary Vasoconstriction
What are 3 diseases of the pulmonary circulation?
-Pulmonary Embolism
-Pulmonary Hypertension
-Pulmonary AVMs
What is a pulmonary embolism and what does it cause?
-Blocked blood vessel in the lung
-V/Q mismatch
-Central = whole lung = ischaemia = blockage of flow
-Peripheral = part of lung = infarction = cell death
-Often caused by DVT that has travelled in blood to lungs
What are the symptoms of a ‘minor’ PE (peripheral arteries)?
-Pleuritic pain
-Sharp pain
-Worse when breathe in
What are the symptoms of a ‘major’ (central artery) PE?
-Shock
-Central chest pain
-Hypoxia
-Risk of immediate mortality
What is Virchow’s triad?
-The three contributing factors to thrombosis
-Circulatory (venous) stasis
-Endothelial injury
-Hypercoagulable state
Example of physiological problem of Pulmonary Arterial Hypertension:
Increased Pulmonary Vascular Resistance
Enlarged right ventricle
Example of physiological problem of Pulmonary Arteriovenous Malformation:
Shunt
What is the general relationship between allele frequency and effect size for genetically determined lung disease?
-Rare alleles cause monogenetic diseases of higher severity
-Low-frequency variants cause intermediate effects
-Common variants are implicated in common diseases of low effect
What does general lung function trajectory look like for 0-20 years and what are some common causes of catch-up and low lung function growth trajectory?
Catch-up:
-Genetics and host factors
-Exposure avoidance
-Diet
-Physical activity
-Supplementation of beneficial factors
-Prevention and/or treatment of precision medicine
Low lung function:
-Genetics
-Preterm birth
-early life environmental exposures
-LRTI
-Childhood persistent asthma
What do the lung function trajectories look like normally and leading to COPD in 0-70 years?
-Can have normal max FEV1 and rapid decline to COPD
-Can have low maximal FEV1 that doesn’t lead to COPD
What is the genetic relationship for asthma (4)?
-Asthma runs in families
-Children of asthmatic parents at increased risk
-Not follow simple Mendelian inheritance
-Not caused by a single mutation in one gene
What has new genotyping studies made possible for asthma?
-Sequence the whole human genome for asthma-associated variants
-GABRIEL STUDY identified:
-Chromosomes 2,6,9,15,17,22
-ORMDL3 (chromosome 17) particularly associated with childhood onset
-HLA-DQ (chromosome 6) related to later-onset asthma
What is asthma personalised medicine (3)?
-Individualise pharmacotherapy based on genetic polymorphisms
-Certain drugs administered only to patients most likely to respond
-Harmful effects avoided in patients who are most likely to experience toxicity and adverse reactions
What are the candidate genes for asthma personalised medicine?
-Those that encode receptor proteins and enzymes involved in drug:
-Transportation
-Processing
-Degradation
-Excretion
Example:
-Experimental drug blocking IL-4/IL-13 pathway
-Certain amino acid variations in IL4 seemed to predict which patients would have the best therapeutic response
What is cystic fibrosis and its epidemiology (6)?
-Chronic genetic disease
-Multi-organ involvement
-Most common lethal autosomal recessive genetic disorder in Caucasians
-In UK >10,000 people affected
-Static incidence with increasing prevalence
-Median age of death improving
What causes cystic fibrosis?
-Defect in long arm of chromosome 7 coding for cystic fibrosis transmembrane regulator (CFTR) protein (anion channel
Facts about CFTR gene mutations (3):
- > 1600 mutations of CFTR gene identified
-90% within a panel of 70 mutations
-F508del most common mutation causing CF
What is thee proportion of the population that are carriers of a CF mutation and what proportion of births are affected by CF?
-1:25 carriers
-1:2500 births
What is the Cystic Fibrosis Transmembrane Regulator (CTFR) protein and what does an abnormal CTFR cause?
-CFTR is a transport protein on the membrane of epithelial cells
-Abnormal CFTR protein leads to dysregulated epithelial fluid transport
What proportion of CF sufferers only have lung involvement from the abnormal CFTR protein?
-80% lung and gastrointestinal involvement
-15% lung alone
What are the parts of the vicious cycle of Cystic Fibrosis pathophysiology?
- Microbial insult + defect in host defence
- Respiratory tract infection
- Bronchial inflammation
- Respiratory tract damage
- Cycle goes round again
Long term: - Progressive lung disease
What is the pathway of disease in the lungs of a Cystic Fibrosis sufferer?
Bronchitis -> bronchiectasis -> fibrosis
How can Cystic fibrosis be diagnosed?
-Genetic profile and neonatal screening (day 5 IRT)
-Clinical symptoms:
-Frequent infections
-Malabsorption
-Failure to thrive
-Abnormal salt-chloride exchange - raised skin salt
-Late diagnosis via infertility services or gastroenterology team
How are late diagnoses made for cystic fibrosis?
-Infertility service - azoospermia
-Gastroenterology - recurrent pancreatitis/ malabsorption
What are 3 clinical symptoms of cystic fibrosis that can lead to diagnosis?
-Frequent infections
-Malabsorption
-Failure to thrive
What % of cystic fibrosis is diagnosed at what ages?
-505 diagnosed by 6 months
-90% diagnosed by 8 years
What are the 4 groups of symptoms for cystic fibrosis?
-Respiratory
-Digestive
-Reproductive
-Bone
Name 4 respiratory symptoms of cystic fibrosis:
-Persistent cough + thick mucus production
-Wheezing and shortness of breath
-Frequent chest infection
-Sinusitis, nasal polyps
What are the reproductive symptoms of cystic fibrosis?
-90% men are infertile
-20% women are infertile
What are the digestive symptoms of cystic fibrosis?
-Bowel disturbances
-Weight loss
-Obstruction
-Constipation
What are the 2 bone conditions that can be a symptom of cystic fibrosis?
-Osteoporosis
-Arthritis
What is CF pathophysiology in the pancreas?
-blockage of exocrine ducts
-Early activation of pancreatic enzymes
-Eventual auto-destruction of exocrine pancreas
-Most patients require supplemental pancreatic enzymes
What is CF pathophysiology in the intestine?
Bulky stools can lead to intestinal blockage
What is CF pathophysiology in the respiratory system?
-Mucus retention
-Chronic infection + inflammation that eventually destroys lung tissue
What is the most common cause of morbidity and mortality?
Lung disease
What are the 2 most common classes causing CF?
-Class II - CFTR protein is made but is mis-folded (e.g. F508del) (80-90% of patients)
-Class III - CFTR protein is formed into a channel but it does not open properly (e.g. G551D)
What are the 6 classes of CF mutation genotype?
-Class I: no functional CFTR protein is made (e.g. G542X)
-Class II: CFTR protein is made but it is mis-folded (e.g. F508del)
-Class III: CFTR protein is formed into a channel but it does not open properly (e.g. G551D)
-Class IV: CFTR protein is formed into a channel but chloride ions do not cross the channel properly (e.g. R347P)
-Class V: CFTR protein is not made in sufficient quantities (e.g. A455E)
-Class VI: CFTR protein with decreased cell surface stability (e.g. 120del123)
What is important about microorganisms and people with CF?
-Different CF patients of different ages will have different frequencies of certain microorganism strains
-This means 2 CF patients should be kept separate as they may be carrying different strains the other has not previously been exposed to
What are the 3 parts of the CF general treatment strategy?
-Maintenance and prevention management
-Rescue
-Personalised approaches
What are the 5 parts of the CF prevention management?
-Segregation
-Surveillance - minimum 3 months frequent review
-Airway clearance - physio + exercise
-Nutrition
-Psychosocial support
What components make up the nutritional management of a CF sufferer?
-Pancreatic enzymes
-High calorie diet + fat
-Supplements including vitamins
-Percutaneous feeding
What are 5 medical prevention management strategies for CF?
-Suppression of chronic infections - antibiotic nebulisation
-Bronchodilation - salbutamol nebulisation
-Anti-inflammatory - azithromycin, corticosteroids
-Diabetes - insulin treatment
-Vaccination - influenza, pneumococcal, SARS ZoV2
What is a CF rescue course of antibiotics?
-2 week course of IV antibiotics
-At home vs hospital
-Some CF sufferers have rapid venous access
What are 4 issues with frequent antibiotics?
-Allergies
-Renal impairment
-Resistance
-Access problems
What is CF phage therapy?
-The use of lytic bacteriophages to kill infectious bacteria
-Encouraging signs phage therapy may provide clinical benefit
-Needs to be confirmedmed in rigorous trials
Describe the advances of CF treatment in years:
General system of personalised and non-personalised medicine:
What is the CF personalised approach (4)?
-Individual tailored or targeted medicine
-Move away from ‘one size fits all’
-Stratified based on predicted response or risk to disease
-Genetic information a major factor
Name four scenarios that CF personalised approach would be useful for:
-Myogenic disorder (a mutation in a specific gene)
-Well-characterised pathophysiology with clear therapeutic targets
-Genotype-directed therapies
-targeted treatments based on infectious organisms and resistance patterns
What do the first 5 classes of CFTR gene mutation cause?
What are genotype directed therapies?
-Small-molecule agents that facilitate defective CFTR processing or function
-Further research needed as significant problems with delivery
What are 2 examples of genotype directed therapies used for CF?
-Ivacaftor
-G551D (6%)
-Improved FEV1, BMI, QoL
-Orkambi
-F508del
-Mixed outcomes
-Only licensed for compassionate use in UK
What does Ivacaftor (Kalydeco) do and what class of mutations is it used for?
-CFTR potentiator
-Potentiates chloride secretion via increased CFTR channel opening time
-Class III mutations
What does the evidence for Ivacaftor show in CF?
What is Orkambi?
-Ivacaftor & Lumacaftor
-Lumacaftor is a CFTR corrector - corrects cellular misprocessing of CFTR to facilitate transport from ER
-Used for class II mutations
What are 5 challenges of treating CF?
-Adherence to treatment
-High treatment burden
-High cost of certain treatments
-Allergies/intolerances to treatment
-Different infectious organisms and their resistance to drugs
What is Alpha-1 antitrypsin deficiency (AATD)?
-Autosomal recessive genetic disorder
-80 different mutations of SERPINEA1 on chromosome 14
-Lack of a serum antiprotease
Which phenotypes of AATD show major disease associations?
-Z phenotype
-ZS and ZZ
-If M is present, not major
What are the consequences of AATD
-Early onset emphysema
-Bronchiectasis
-Unopposed action of neutrophil elastase in lung
What are the potential gene-editing approaches in the lung?
How was the aqua lung born?
-1942-3
-Jacques-Yves Costeau
-Redesigned car regulator that would automatically provide compressed air to a diver on slightest intake of breath
What values of different pressure units are equal to 1 atmosphere?
-1 bar
-1000 millibars
-760mmHg / torr
-1 atmosphere absolute (ATA)
-10m sea water (msw)
-33.08 feet sea water (fsw)
-101.3 kilopascals (KPa)
-14psi
How does pressure change with increasing average altitude?
Decreases
How does pressure change with increasing depth of water?
-Increases
-Every 10m, increases in. atm
how does gas bubble size change as you decrease depth and what is this called?
-Gas bubble volume increases
-Decompression
What is Boyle’s Law?
-At a constant temperature, the absolute pressure of a fixed mass of gas is inversely proportional to its volume
-P1V1=P2V2
What are Boyle’s Law applications in respiratory medicine?
-Barotrauma
-Arterial gas embolism
-Gas supplies
What 6 features of diving environments?
-Hazardous
-Physically challenging
-Distortion/impairment of special senses
-General and specific sources of emotional stress
-Hyperbaric
-Cold
What are 3 sources of emotional stress in diving environments?
-Claustrophobia
-Agoraphobia
-Marine animals
As water temperature decreases, what happens to expected survival time?
Decreases
What is apnoea diving (6)?
-Diver inhales, pre-hyperventilation
-Diver descends holding breath, gas compresses
-PaO2, PaN2, PaCO2 rise
-Minimal N2 absorption but “taravana syndrome”
-Eventually CO2 builds up enough to induce breathing desire
-Diver returns to surface, PaO2, PaN2, PaCO2 fall
What is taravana syndrome?
-Form of neurological decompression syndrome
-Accumulation of Nitrogen gas in the body
-Rapid accumulation of breath hold dives
What are 3 diving reflexes?
-Apnoea
-Bradycardia
-Peripheral vasocontriction
What is dynamic apnoea?
Breathe holding whilst moving
What is open circuit SCUBA?
-Self-contained underwater breathing apparatus
-Gas on-demand
-Gas delivered on inhalation at ambient pressure
What is SCUBA via octopus?
-Additional single hose second stage regulator connected to first stage regulator
-If primary fails or for buddy breathing
What is Dalton’s law?
Total pressure exerted by a mixture of gases is equal to the sum of the pressures that would be exerted by each of the gases if it alone were present and occupied the same volume
What are the effects of Dalton’s law?
Sea level:
-ppN2 = 0.78 ata
-ppO2 = 0.209 ata
10 msw:
-ppN2 = 1.56 ata
-ppO2 = 0.418 ata
How does partial pressure of oxygen and nitrogen change with increasing depth?
Both increase
What is breathing air at 10msw the same as?
The same PaO2 as breathing 42% O2 at sea level
What is pulmonary oxygen toxicity?
-Lorrain Smith Effect
-PiO2 > 0.5 ata
-Unit of Pulmonary Toxic Dose (UPTD) can. be calculated
-FVC useful to monitor
-Problem with ITU patients
What are the symptoms of pulmonary oxygen toxicity with 100% oxygen?
-Symptoms in 12-24 hours
-Cough
-Chest tightness
-Chest pain
-Shortness of breath
What can cause relief from pulmonary oxygen toxicity?
Relief with PiO2 < 0.5 ata
What is the acronym for CNS Oxygen Toxicity?
conVENTED
V- Vision (tunnel vision)
E- Ears (tinnitus)
N-Nausea
T-Twitching (extremities or facial muscles)
E-Irritability
D-Dizziness
Common final sign will be convulsion
What is inert gas narcosis?
-Commonest is nitrogen narcosis
-Worsens with increasing pressure
-First notice 30-40 msw
-Increased PiN2
-Individual variation
-Narcotic potential related to lipid solubility
What are some influencing factors on inert gas necrosis?
-Cold
-Anxiety
-Fatigue
-Drugs
-Alcohol
-Some medications
What signs/symptoms do you have for inert gas necrosis at what depths?
-10-30m - mild impairment of performance
-30-50m - overconfidence, sense of well-being
-50-70m - sleepiness, confusion, dizziness
-70-90m - loss of memory, stupefaction
-90+ - unconsciousness, death
-death may occur at shallower depths
What is decompression illness (DCI)
-N2 is poorly soluble
-During ascent there is a fall in pressure
-N2 solubility falls
-Gas bubbles form
What are the 2 types of DCI?
-Type I - cutaneous only
-Type II - neurological
What are the treatments for DCI?
-O2 supportive treatments
-Urgent recompression
What is arterial gas embolism?
-Gas enters circulation via torn pulmonary veins
-Small transpulmonary pressure can lead to AGE
-Normally ocurr within 15 minutes of surfacing
What is treatment of AGE?
Urgent recompression
What is pulmonary barotrauma?
Air leaks from burst alveoli
What are 3 things pulmonary barotrauma can cause?
-Pneumothorax
-Pneumomediastinum
-Subcutaneous emphysema
What depth does most animal life live at?
1km above sea level
How do you calculate PiGas?
PiGas = Patm x FiGas
What is the alveolar gas equation?
-PAO2=PiO2-PaCO2/R
-One version
What is the equation for PaCO2?
PaCO2=kV’CO2/V’A
How is the death zone defined?
-8000m
-At this elevation, FiO2 is not high enough to sustain human life without added O2
Where do all peaks above 8000m lie and when was the first Everest summit without supplementary O2?
-Himalayas and Karakoram
-1978
What are considered high, very high and extremely high altitudes?
-High altitude - 1500-3500m
-Very high altitude - 3500-5500m
-Extremely high altitude - 5500m+
In the alveolar gas equation, how can R differ?
-R=0.8 with normal diet
-R approx=1 with primarily carbohydrate diet
-R closer to 0.7 with fat rich diets
What is R and how is it calculated?
-R=Respiratory quotient
-R=CO2 produced / O2 consumed
What is the altitude, pressure and PiO2 at sea level?
-Altitude = 0m
-Atmospheric pressure = 100KPa
-Pi<O2 = 0.20 x 100KPa = 20KPa
State the normal barometric pressures at:
-0m
-4800m
-6300m
-8100m
-8848m
What is the approximate PAO2 at sea level?
-PAO2=PiO2 - PaCO2/R
-20KPa - 6KPa/0.8
=12.5KPa
What is alveolar arterial O2 difference?
-A-aDO2
-A-aDO2 = PAO2 - PaO2 = 1KPa (approx)
How can you calculate PaO2 from PAO2?
PaO2 =PAO2 - A-aDO2
State the normal blood gases for:
-PaO2
-PaCO2
-pH
-PaO2 = 10.5 - 13.5 KPa
-PaCO2 = 4.5 - 6.0 KPa
-pH = 7.36 - 7.44
Name 4 things that can cause the oxygen dissociation curve to right shift:
-Acidity
-2,3 bisphosphoglycerate (DPG)
-Increased temperature
-Increased PCO2
What happens to FiO2 and PiO2 as you increase altitude?
-FiO2 stays constant at about 0.21
-PiO2 falls
What is the body’s normal response to altitude?
-Hypoxia
-Hyperventilation at 10,000ft altitude
-Adaptive changes
What does hyperventilation at increased altitude cause (4)?
-Increase minute ventilation
-Lowers PaCO2
-Alkalosis initially
-Tachycardia
What is an example of adaptive changes to altitude?
Alkalosis is compensated by renal bicarbonate excretion
What are the general trends in alveolar oxygen and carbon dioxide tension with altitude?
Calculate the PiO2 and PAO2 of Mont Du Vallon with an atmospheric pressure of 63KPa:
PiO2 = 0.21 x 62KPa = 13KPa
PAO2 = 13-4/8
Calculate the PiO2 and PAO2 of Mont Du Vallon with an atmospheric pressure of 63KPa:
PiO2 = 0.21 x 62KPa = 13KPa
PAO2 = 13-4/8
What would be approximate PaO2, PaCO2 and pH at an altitude of 3000m?
-PaO2 = 7KPa
-PaCO2 = 3KPA
-pH = 7.44
What are 3 examples of high altitude illness?
-Acute mountain sickness
-High altitude pulmonary Oedema (HAPE)
-High altitude Cerebral Oedema (HACE)
What 3 factors constitute the definition of Acute Mountain Sickness?
-Recent ascent to over 2500m
-Lake Louise score >=3
-Must have a headache and one other symptom
What is the only reliable treatment for Acute Mountain Sickness?
-Descent
-Can. be supplemented by:
-O2
-Recompress
-Acetazolamide
What are the 4 at-risk groups of Acute Mountain Sickness?
-Recent travel over 2500m, after a few hours
-Sea level normal dwelling
-Altitude, rate of acent and history of AMS
-Younger people
What should you never do if you have AMS?
Go higher
What are the symptoms of High Altitude Pulmonary Oedema?
-Cough
-Shortness of breath
When does High Altitude Pulmonary Oedema usually occur?
-Unacclimatised individuals
-Rapid ascent above 8000ft (2438m)
-2-5 days after reaching altitude
What things can affect your risk of High Altitude Pulmonary Oedema?
-Lower if sleeping below 6000ft (1829m)
-Speed of ascent slower (300-350m)
-Individual susceptibility
-Exercise
-Respiratory Tract Infection increases risk
True/False, the rate of HAPO is 5% at 4000m?
-False
-2%
What 6 things can be used to treat HIPO?
-O2
-Urgent descent
-Gamow bag
-Steroids
-Ca2+ blockers
-Sildenafil
What are 2 symptoms of High Altitude Cerebral Oedema?
-Confusion
-Behaviour change
(Serious)
(AMS not. a pre-requisite)
What is the treatment for HACO?
-Immediate descent
-Gamow bag
-Symptoms may resolve quickly
What kind of disease is common in flying populations?
Lung disease
What are the effective cabin atmosphere altitude and pressure in a plane?
-Effective cabin atmosphere - 1890m
-Cabin pressure - 81KPa
What is the relationship between oxygen pressure and oxygen blood saturation?
What is the BTS guidance on SaO2?
- > 95% - No action
-92-95% with no risk factors - No action
-92-95% with risk factors - Hypoxic test - <92% - Needs O2
- <92% on LTOT - Increase flow rate
Under what conditions should you avoid flying (4)?
-Pneumothorax
-Not with closed pneumothorax
-Infectious TB
-Major haemoptysis
-Very high oxygen requirments at sea level
- > 4l/ minute
What are the 4 stages of lung development and time periods?
-Embryonic - 0-5 weeks
-Pseudoglandular - 5-17 weeks
-Cannalicular - 16-25 weeks
-Alveolar - 25 weeks - term
Where do lungs develop from?
-Foregut derivation
-Anterior outpouching
-Oesophageal appendix
-0-5 weeks
Label this diagram:
What does it show?
0-5 weeks respiratory development
What happens in the pseudoglandular respiratory development?
-5-17 weeks
-Exocrine gland only
-Major structural units formed
-Angiogenesis
-Mucous glands
-Cartilage
-Smooth muscle
-Cilia
-Lung fluid
What happens in the cannalicular respiratory development?
-16-25 weeks
-Distal architecture
-Vascularisation i.e. formation of capillary bed
-Respiratory bronchioles
-Alveolar ducts
-Terminal sacs
What happens in alveolar lung development?
-25 weeks - birth
-Alveolar sacs
-Type I and type 2 cells
-Alveoli simple with thick interstitium
-Continue developing from birth to 3-5 years / up to 25?
-Thinning of alveolar interstitium and increase in complexity of alveoli
Summarise the early development of the lung:
What problems can occur during embryonic stage of lung development?
-Laryngeal, tracheal and oesophageal atresia
-Tracheoesophageal fistula
-Tracheal and bronchial stenosis
-Pulmonary agenesis
What problems can occur during pseudoglandular stage of lung development?
-Bronchopulmonary sequestration
-Cystic adenomatoid malformations
-Alveolar-capillary dysplasia
What problems can occur during pseudoglandular stage of lung development?
-Bronchopulmonary sequestration
-Cystic adenomatoid malformations
-Alveolar-capillary dysplasia
What problems can occur during alveolar stage of lung development?
-Acinar dysplasia
-Alveolar capillary dysplasia
-Pulmonary hypoplasia
-Respiratory disease of the newborn
What is the purpose of systemic vessels?
Deliver oxygen to hypoxic tissues
What does oxygen act as in pulmonary circulation and systemic circulation?
-Pulmonary - hypoxic mediated vasoconstrictor
-Systemic - hypoxic mediated vasodilator
What is the function of the lung in the foetus?
-Lung is not a useful organ to the foetus
-PaO2 = 3.2kPa (very low)
-Shunting of blood from right to left
-High pulmonary vascular resistance (hypoxia)
-Fluid filled so high tissue resistance
What is the resistance in the foetal lung and placenta?
-Foetus - tissue resistance (fluid filled)
-Placenta - low systemic resistance
From week 25 onwards what happens inside foetal alveoli?
-Active filling of the alveoli
-Foetal airways are distended with fluid
-Fluid aids in lung development
-Actively secreted by lungs
What diverts oxygenated blood from the mother into the inferior vena cava of the foetus?
-Ductus venosus
-About a 1/3
What connects the pulmonary trunk and aorta in the foetus?
Ductus arteriosus
What shunts blood from the right to left side of the heart in the foetus?
Forman ovale
What are the 3 shunts in the foetus?
-Foramen ovale
-Ductus arteriosus
-Ductus venosus
Describe the ductus arteriosus and how it shuts:
-Pulmonary trunk linked to the distal arch of aorta by the ductus arteriosus
-Permits blood to bypass pulmonary circulation
-Muscular wall contracts to close after birth - mediated by bradykinin
Describe ductus venosus and how it shuts:
-Oxygenated blood entering foetus also needs to bypass primitive liver
-Achieved by passage through ductus venousus
-Shunts 30% of umbilical blood directly to the inferior vena cava
Describe the foramen ovale and how it shuts:
-Passage between the two atria
-Responsible for bypassing the majority of the circulation
What adaptive changes of the lungs happen at birth (pt1)?
-Fluid squeezed out of lungs by birth process
-Adrenaline stress leads to increased surfactant release
-Gas inhaled
What adaptive changes happen at birth (pt2)?
-Oxygen vasodilates pulmonary arteries
-Pulmonary vascular resistance falls
-Right atrial pressure falls, closing foramen ovale
-Umbilical arteries constrict (cutting umbilical cord)
-Ductus arteriosus constricts
How does the pressure system of circulation change at birth?
Swaps from right sided to left sided pressure system
What is Laplace’s Law and how does it relate to alveoli?
-Pressure = 2 x surface tension / resistance
-Smaller alveoli might preferentially shut for a given surface tension
What is surfactant?
-Surface active phospholipis
-Abolishes surface tension in alveoli - laplace’s law - smaller alveoli are patent
-Produced by type 2 pneumocytes from 34 weeks gestation
-Dramatic increase in 2 weeks prior to birth
-No surfactant means alveoli will preferentially collapse
What 5 things can cause surfactant deficiency in newborns?
-Prematurity
-Asphyxia
-Cold
-Stress
-Twins
What does lack of surfactant cause?
-Respiratory distress syndrome
-Loss of lung volume
-Non-compliant lungs
-Uneven aeration
What can improve surfactant?
-Distension of alveoli
-Steroids
-Adrenaline
What can happen when you ventilate premature babies?
-Pulmonary interstitial emphysema
-Lung cysts
-Ruptured alveoli
What is the management of pulmonary interstitial emphysema?
-Warmth
-Surfactant replacement (if intubated)
-Oxygen and fluids
-Continuous positive airway pressure (maintain lung volumes, reduce work of breathing)
-Positive pressure ventilation is needed
What regulates airways tone?
-Autonomic nervous system
-Airway smooth muscle is regulated
-Contract and relax to regulate airway diameter
Label:
What is ACOS?
Asthma and COPD overlap syndrome
What are the 2 things regulating airway tone?
-Autonomic nervous system:
-Contractile signals increase in intracellular calcium in smooth muscle
-Activates actin-myosin contraction
-Regulated by inflammation
Label:
Label:
Label:
Label:
Label:
What do the sympathetic and parasympathetic fibres do in the lungs broadly?
-Parasympathetic - constricts bronchi
-Sympathetic - dilates bronchi
OPPOSITIONAL
What are these types of nerves and their chemical messengers?
Explain parasympathetic bronchoconstriction:
-Vagus nerve neuruons terminate at parasympathetic ganglia in airway wall
-Short post-synaptic nerve fibres reach muscle
-Release ACh which acts on muscarinic receptors of M3 subtype on muscle wall
-Stimulates smooth muscle contraction
What does parasympathetic bronchoconstriction do and how is it inhibited?
-Narrows airway in asthma and COPD
-Inhibition of parasympathetic nervous system beneficial
-Drugs block M3 receptor and called anti-cholinergics or anti-muscarinics
What are SAMAs and LAMAs?
-SAMA = short acting anti-muscarinic drug
-LAMA = long acting anti-muscarinic drug
What is an example of a SAMA?
-Ipratropium bromide
-Inhaled treatment
-Less widely used since development of LAMAs
What are 4 features of LAMAs?
-Long duration of action, often once daily
-Increasebronchodilation and relieve breathlessness in asthma and COPD
-Seem to reduce acute attacks
-Other benefits e.g. on parasympathetic regulation of mucus production
Describe the sympathetic regulation of airway:
Chemicals and receptor + mechanisms!
-Sympathetic NS regulates fight and flight response
-Nerve fibres release noradrenaline which activates adrenergic receptors (alpha/beta)
-Mainly innervate blood vessels in humans, but airway smooth muscle cells have adrenergic receptos (beta)
-Activation of beta2 receptors on airway smooth muscle causes muscle relaxation (activating adenylate cyclase, raising cyclic AMP)
What are SABAs and LABAs?
-SABA = short acting beta2 agonist (salbutamol)
-LABA = long acting beta2 agonist (formoterol, salmeterol)
What are the uses of SABAs and LABAs?
-Given with steroids in asthma, without steriod in COPD
-Given with LAMA in COPD
-Acute rescue of bronchoconstriction
-Prevention of bronchoconstriction
-Reduction in rates of exacerbations
What are 3 adverse effects of beta2 agonists?
-Raising cAMP may activate Na/K exchange pump driving cellular potassium influx
-Tachycardia
-Hyperglycaemia: loss of insulin sensitivity, increased liver glucose release
What are factors in drug deposition with airway diseases?
-Particle size in main factor
-Type of device used
-Flow rate
-Underlying disease
-Regional differences in lung ventilation
What are fundamentals of asthma and COPD treatment?
-Right device selection
-Inhaler education is key
What are the goals of treatment of COPD and asthma?
-Aim to improve control
-Adress important issues for patient
-Maximum relief of symptoms for minimum side effects
What is immediate management of asthma exacerbations?
-Oxygen to maintain sats of 94-98%
-Salbutamol nebuliser 5mg
-Ipratroprium nebuliser 0.5mg
-Prednisolone 30-60mg
-Magnesium or aminophylline
What are 3 basic features of the immune system (hypersensitivty)?
-Kills infection and heals tissue
-Unwanted activation leads to healthy tissue damage
-Understanding mechanism is key to diagnosis and treatment
describe basic immunological environment of lung:
-Immunologically rich environment
-Faces 10,000L/day of unfiltered air full of potential pathogens
-Common site of hyperimmune syndromes (lots. of blood filtration)
Describe:
Describe:
Describe:
What are the cellular components of the immune system?
-Phagocytes e.b. monocytes and neutrophils phagocytose (envelop invader) and some present to other cells
-Lymphocytes - make and release antibodies and kill diseased cells
What does the humoral component of the immune system compose of?
-Immunoglobulins
-Complement (form membrane attack complex)
-Cytokines (allow communication between leukocytes and tissue cells)
What are antibodies?
-Produced by B-lymphocytes (plasma cells)
-Neutralise or eliminate pathogens
-May also cause disease
What are the 5 sub-types of antibodies?
-IgM: Circulating tetramers made at beginning of infection
-IgG: Monomer highly specific antibodies targeting single epitopes
-IgE: Likely to have developed in response to parasitic threats, implicated in allergy particularly alongside eosinophils
-IgA: Expressed in mucosal tissue. Forms dimers, protects neonatal gut (expressed in breast milk)
-IgD: Monomers, induction of antibodies in B cells, activates basophils and mast cells
What is the old classification of hypersensitivity?
-Gell and Coombs classification
-Imperfect classification, still holds as description of pathology
-Does not hold well for complex immune reactions
Describe:
Describe:
Describe:
Describe:
Describe Type 1 hypersensitivity:
-Antigen interacts with IgE bound to mast cells or basophils
-Degranulations of mediators lead to local effects
-Histamine is predominant mediator
-Anaphylaxis
Describe the preformed mediators of type 1 hypersensitivity:
Describe the granule mediators of type 1 hypersensitivity:
Describe the newly synthesised mediators of type 1 hypersensitivity:
Delayed means peak after around 12 hours
Describe type 2 hypersensitivty:
-Antibodies reacting with antigen determinants of host cell membrane
-Usually IgG or IgM
-Outcome depends on whether complement is activated and if metabolism of cell is affected
-Mycoplasma pneumonia
Label (Type II hypersensitivity):
Label (Type II hypersensitivity):
Label (Type II hypersensitivity):
Describe type III hypersensitivity:
-Antigen-immunoglobulin complexes are formed on exposure to allergen
-Deposited in tissues and cause local activation of complement and neutrophil attraction
-Hypersensitivity pneumonitis
Describe type 4 hypersensitivity:
-T-cell mediated, releasing IL2, IFgamma and other cytokines
-Requires primary sensitisation
-Secondary reaction takes 2-3 days to develop
-May result from normal immune reaction - if macrophages cannot destroy pathogen, become giant cells and form granuloma
-Latex (patch testing)
What does this show?
-Lymph node biopsy
-Granuloma
What is sarcoidosis?
-Possible reaction to mycobacteria
-Multisystem disease causing granuloma
-Multi-organ
-80% regress spontaneously
What drugs are often implicated in lung diseases?
-Amiodarone
-ACE-Inhibitors
-Bleomycin
-Methotrexate
-Nitrofurantoin
CHECKPOINT INHIBITORS
Label this diagram:
What does it show?
Cancer cell evading immune system as checkpoint inhibitors not present
What is this?
What does it show?
Checkpoint inhibitor blocking receptor recognising the cell as cancer
What are some consequences of up-regulation of T-cell hyperactivity (drug)?
-Life threatening pneumonitis
-Diabetes
-Thyroid disease
-Hepatitis
-Nephritis
-Myositis
What characterises asthma?
-Characterised by airway hyper-reactivity
-Characterised by disease phenotypes
-Different pathological mechanisms respond to different treatments
Label this diagram of asthma classification:
Label treatments:
