CVR🫁💓 Flashcards
What is Gastrulation?
Mass movement and invagination of the blastula to form three layers – ectoderm, mesoderm (middle layer) and endoderm
What forms from the ectoderm?
Skin, nervous system, neural crest (which contributes to cardiac outflow, coronary arteries)
What does the mesoderm form?
All types of muscle, most system, kidneys, blood, bone, cardiovascular system
What does the endoderm form?
Gastrointestinal tract (inc liver, pancreas, but not smooth muscle), endocrine organs
What are the two heart fields and what do they give rise to?
First heart field - gives rise to early structures
Second heart field - gives rise to more advanced things
FHF – future left ventricle
SHF – outflow tract,
future right ventricle,
atria
List some cardiac transcription factors
Nkx2.5, GATA, Hand, Tbx, MEF2, Pitx2, Fog-1
What are the stages of cardiac formation?
1.Formation of the primitive heart tube
2.Cardiac looping
3.Cardiac septation
Describe formation of the primitive heart tube
In week 3, cells form horseshoe shape called the cardiogenic region. Day 19- 2 endocardial tubes form and fuse on day 21 to form a primitive heart tube.
What is the bulbis cordis?
Forms most of the right ventricle and parts of the outflow tracts for the aorta and pulmonary trunk
What does the primitive ventricle become?
Most of the left ventricle
What does the primitive atrium become?
The anterior parts of the right and left atria
What does the sinus venosus in the left and right horns become?
The superior vena cava and part of the right atrium
Describe cardiac looping
-Bulbis cordis moves inferiorly, anteriorly and to the embryo’s right
-The primitive ventricle moves to the embryo’s left side
-The primitive atrium and sinus venosus move superiorly and posteriorly
-The sinus venosus is now posterior to the primitive atrium
Describe cardiac septation
- The one atrium and ventricle are connected by the atrioventricular canal
-Blood exits through the truncus arteriosus
-Endocardial cushions grow from sides of AV canal to partition into 2 separate openings
-At the same time the AV canal is being repositioned to the right side of the heart
-Superior and inferior endocardial cushions fuse to form right and left AV canals - Now blood passes through both of them
How does the heart know to have a left orientated ventricle?
Cilliary motion at the node pushes the protein nodal towards the left. A cascade of transcription factors (e.g. Lefty, Pitx2, Fog-1) transduce looping
Describe arterial system
Conduits of blood; physical properties (elastic arteries) increase efficiency whilst regulatory control (muscular arteries) control distribution
What are Elastic arteries?
Major distribution vessels (aorta, brachiocephalic, carotids, subclavian, pulmonary)
What are muscular arteries?
Main distributing branches
What are arterioles?
Terminal branches (<300mm diameter)
Describe the capillaries
The functional part of the circulation
Blood flow regulated by precapillary sphincters
Between 3-40 microns in diameter
Three types of capillary; continuous (most common), fenestrated (kidney, small intestine, endocrine glands), discontinuous (liver sinusoids)
Describe the venous system
Return blood to the heart
System of valves allows “muscular pumping”
Some peristaltic movement
What is the innermost layer of the artery/veins?
Tunica intima ( endothelium basement membrane)
Second layer of arteries/veins
Tunica media (vascular smooth muscle cells)
Third layer of arteries/veins
Internal elastic lamina
Fourth layer of arteries/veins
Tunica adventitia (fibroblasts)
Outer layer of arteries/veins
External elastic lamina
What do you call capillaries that supply blood vessles?
Vasa vasorum
What are blood islands and when do they form?
Extraembryonic mesoderm
Core of hemoblasts surrounded by
Endothelial cells
Formed on day 17
When does vasculogenesis occur and what is it?
Day 18, formation of a central vessel in the latreral mesoderm
What is angiogenesis?
Driven by angiogenic growth factors and takes place via proliferation and sprouting
from day 18 onwards other mesodermal cells are recruited to form the structure
What drives embryonic vessel development?
Angiogenic growth factors – vascular endothelial growth factor, angiopoietin 1 & 2
Repulsive signals – Plexin / semaphorin signalling, ephrin / Eph interactions
Attractive signals
What do 1st and 2nd aortic arches become?
Become minor head vessels
1st – small part of maxillary
2nd - artery to stapedius
What do the 3rd aortic arches become?
Portion between 3rd and 4th arch disappears
Become common carotid arteries, and proximal internal carotid arteries
Distal internal carotids come from extension of dorsal aortae
What do the right dorsal aorta and right 4th aortic arch become?
R dorsal aorta looses connections with midline aorta and 6th arch, remaining connected to R 4th arch
Acquires branch 7th cervical intersegmental artery, which grows into R upper limb
Right subclavian artery is derived from right 4th arch, right dorsal aorta, and right 7th intersegmental artery
What do the 6th aortic arches become?
Right arch may form part of pulmonary trunk
Left arch forms ductus arteriosus – communication between pulmonary artery and aorta
Describe an erythrocyte
-2-3 million produced and released from marrow/second
-Lifespan 120 days
-Anucleate biconcave discs
-Haemoglobin to carry oxygen
-Millions of antigens on surface (several hundred are blood group antigens)
What is different about the antigens on red blood cells?
They have antigens against the other blood groups even though they have never been in contact with them
What is the antigen that all red blood cells have?
H- antigen, this is the only one on blood group O but A and B have an extra sugar chain on it
Describe ABO antibodies
-Theorised they develop against environmental antigens
-Infants <3 months produce few if any antibodies (maternal prior to this)
-First true ABO antibodies > 3 months
-Maximal title 5-10 years
-Titre decreases with age
-Mix of IgG and IgM
-IgM mainly for group A and B
-Wide thermal range means they are reactive at 37C
What determines your blood group?
The antigens show the blood group that you are. The antibodies are the against the group(s) that you don’t have antigens for. E.g group A has A antigens and B antibodies
What are rhesus antigens
-> 45 different Rh antigens
-2 genes, Chromosome 1
-RHD – codes for Rh D
-RHCE – codes for Rh C and Rh E
-Highly immunogenic
Can cause haemolytic transfusion reactions and haemolytic disease of the fetus and newborn (HDFN)
What is the most important rhesus antigen to look at?
Rhesus D
When do you have rhesus antibodies?
Only when you come into contact with the other rhesus D antigen
What is Haemolytic disease of the fetus/newborn (HDFN)?
-Rh D sensitization most common cause
-Develop anti-Rh antibodies
-Severe fetal anaemia
-Hydrops fetalis
How is HDFN prevented?
-Detect mothers at risk
-Maternal fetal free DNA
-Anti D prophylaxis
How to test for ABO and Rh D grouping?
Forward typing and reverse typing
Describe forward typing
-Mix patient’s red blood cells with a solution of either A of B antibodies
-If the blood cells agglutinate, or clump together, it means the sample has reacted with one of the antibodies and so is the opposite blood group
Describe reverse typing
-Mix plasma from patient with known red cells and see if they clump together
-Positive is a line at the top of the gel
What is cross matching blood?
Units of blood deemed suitable chosen from stocks available:
Either exact match (e.g. A+ for A+) OR
‘Compatible” blood (e.g. O- for A+)
Mix recipient serum with donor RBCS - indirect antiglobulin test
What does the indirect antiglobulin test test for?
Blood grouping for ABO and Rhesus D
Detects antibodies in patient’s serum
Describe direct antiglobulin test
Detects antibodies on patient’s red cells
? Autoimmune haemolysis
? Transfusion reaction
? Haemolysis due to fetal/maternal group incompatibility
Who can donate blood?
-17-65 years old
-Body weight 50-158kg
-Donors screened to highlight those at risk of infectious diseases
-Also screened for health, lifestyle, travel, medical history, medications
Temporary exclusion criteria to donate blood
Travel
Tattoos/Body piercings
Lifestyle
Permanent exclusion criteria for donating blood
-Certain diseases
-Received blood products or organ/tissue transplant since 1980
-Notified at risk of vCJD
What can you donate?
Whole blood
Apheresis
What is Apheresis?
Blood removed and externally separated into Plasma, Platelets
Mandatory tests for blood from blood donors
Hep B Hep C Hep E
HIV Syphilis
HTLV Groups and antibodies
Describe separation and storage of the blood donated
-Whole blood donated into closed system bags
-Blood centrifuged to packed red cells, Buffy coat and plasma
-Plasma only kept from male donors
-Plasma frozen (FFP) or processed to cryoprecipitate
-Red cells passed through leucodepletion filter and suspended in additive
-Buffy coats pooled with matching ABO and D type and then leucodepleted to make platelets
What is a buffy coat and where is it found?
The buffy coat is the fraction of an anticoagulated blood sample that contains most of the white blood cells and platelets following centrifugation
Buffy coat is situated in between the plasma and erythrocytes.
What is done with red cells
Stored at 4degrees celsius, shelf life 35 days
Some units irradiated to eliminate risk of transfusion-associated graft vs host disease
Indications for needing a rbc transfusion
Severe anaemia (not purely iron deficiency)
What is the transfusion threshold?
Haemoglobin <70 g/L or <80 g/L + symptoms
Transfuse 1 unit and recheck FBC (unless massive transfusion needed)
Emergency stocks of O Rh D- available in certain hospital areas
Features of platelet donation
Most units pooled from 4 donations
Some single-donor apheresis units
Stored at 22oC with constant agitation, 7 day shelf life
Indications for giving platelets
Thrombocytopaenia and bleeding
Severe thrombocytopaenia < 10 due to marrow failure (150-450)
Transfusion threshold of platelets (NICE)
(all values x10 to the power 9)
<10 if asymptomatic and not bleeding
<30 if minor bleeding
<50 if significant bleeding
<100 if critical site bleeding (brain, eye)
Part of massive transfusion protocol
ABO type still important (units contain ABO antibodies
Describe fresh frozen plasma donation and transfusion protocal
From whole donations or apheresis
Patients born > 1996 can only receive plasma from low vCJD risk (not UK plasma)
Single donor packs have variable amounts of clotting factors. Pooled donations can be more standardized
Indications for plasma transfusion
Multiple clotting factor deficiencies and bleeding (DIC)
Some single clotting factor deficiencies where no concentrate available
Describe the process of cryoprecipitate transfusion
Made by thawing FFP to 4oC and skimming off fibrinogen rich layer
Used in DIC with bleeding, and in massive transfusion
Therapeutic dose: 2 packs (each pooled from 5 plasma donations)
What is immunoglobulin made from?
Made from large pools of donor plasma
Describe normal IVIg
Contains Ab to viruses common in population
Used to treat immune conditions e.g. ITP
Describe specific IVIg
From selected patients
Known high AB levels to particular infections/conditions
Anti D immunoglobulin used in pregnancy
VZV immunoglobulin in severe infection
When/why do you give granulocytes?
Used very rarely
Effectiveness controversial
Severely neutropaenic patients with life threatening bacterial infections
Must be irradiated (to kill T cells)
Describe single factor concentrates
Factor VIII for severe haemophilia A (recombinant version – no risk of viral or prion transmission)
Fibrinogen concentrate (Factor I)
Describe prothrombin complex concentrate (Beriplex/Octaplex)
Multiple factors
Rapid reversal of warfarin
Important things to remember for the safe delivery of blood
Patient identification
2 sample rule
Hand-written patient details
Blood selected and serologically cross matched
Common mistakes with blood transfusion
Patient identification errors are most common
Wrong blood in wrong tube
Lab errors are much less common
Blood transfusion delayed
Too much blood transfused
How to avoid blood transfusion?
Optimise patients with planned surgical procedures pre-op
Use of EPO-stimulating drugs
In renal failure
In patients with cancers
Intraoperative cell salvage
IV iron for severe iron deficiency
Some patients may tolerate lower haemoglobin concentrations and not require transfusion at all
How safe is blood transfusion?
Blood transfusion now very safe
Heavily regulated and monitored (SHOT, MHRA)
Potential risk of viral transmission now extremely low
Hep B < 1:1,200,000
Hep C < 1:7,000,000
HIV < 1:28,000,000
Transfusion-related GvHD
Risk reduced by leucodepletion and irradiation
Problems more likely after blood leaves the lab
What happens with ABO incompatability?
Rapid intravascular haemolysis
Cytokine release
Acute renal failure and shock
DIC
Can be rapidly fatal
Treatment for haemolytic reactions
STOP transfusion immediately
Fluid resuscitate
Send to the lab
Must be reported to SHOT
Describe bacterial contamination of blood products
Most commonly with platelets (still v. rare)
Symptoms very soon after transfusion starts
Fever and rigors
Hypotension
Shock
Inspection of unit may show abnormal colouration/cloudiness
What is Transfusion related lung injury?
Ab in donor blood reacts with recipient’s pulmonary epithelium/neutrophils
Inflammation causes plasma to leak into alveoli
Symptoms of TRALI
SOB
Cough with frothy sputum
Hypotension
Fevers
What is Transfusion related circulatory overload (TACO)?
-Acute/worsening pulmonary oedema within 6 hours of transfusion
-Older patients more at risk
Symptoms of TACO
Respiratory distress
Evidence of positive fluid balance
Raised blood pressure
How many big squares on an ECG is equal to 1mV?
2 big squares
How do you calculate rate from an ECG?
Rate (bpm) = 300/no. of large squares between cardiac cycles
or
Rate (bpm) = 300/no. of large squares between cardiac cycles
What does positive deflection mean?
Line on ECG goes up
Shows net current flow towards the leas
What is the Baseline (isoelectric point)?
No net current flow in direction towards the lead
What is negative deflection?
Line on ECG goes down
Net current flow away from the lead
What is the P wave?
Depolarisation of the Atria
What is the QRS complex?
Ventricular depolarisation
What is the T wave?
The repolarisation of the ventricles
What is atrial fibrillation?
Random atrial activity
Random ventricular capture
Irregularly irregular rhythm
What is atrial flutter?
Organised atrial activity ~300/min
Ventricular capture at ratio to atrial rate (usually 2:1 so 150 bpm)
Usually regular
Can be irregular if ratio varies
What is the normal PR interval length?
120-200ms ( 3-5 small squares)
What does an elongated PR interval show?
Delayed AV conduction
Heart block
What does a short PR interval show?
Wolff-Parkinson-White-Syndrome
What does a longer QRS complex show?
QRS>120 ms
Bundle branch block most common cause
What is a QT interval?
Measure of time to ventricular repolarization
Time from onset of QRS to end of T
What are the normal values of the QT interval?
Men 350-440 ms
Women 350-460 ms
What is an ECG electrode?
Physical connection to patient in order to measure potential at that point
10 electrodes to record a 12 lead ECG
What is an ECG lead?
Graphical representation of electrical activity in a particular ‘vector’
Calculated by the machine from electrode signals
12 leads for a 12 lead ECG (I-III, aVL, aVF, aVR, V1-6)
What are bipolar leads?
Measures the potential difference (voltage) between two electrodes
One electrode designated positive, the other negative
What are Unipolar leads?
Measures the potential difference (voltage) between two electrodes
One electrode designated positive, the other negative
What does the right leg electrode do?
Neutral electrode
- Reduces artefact – not directly involved in ECG measurement
Describe Lead I
Bipolar lead
Designated so that the positive electrode is the left arm and the negative electrode is the right arm
So if current is flowing from right to left then there will be positive deflection
If the other way around then it will be negative deflection
Tells us what is happening in that direction
Describe lead II
Right arm is negative electrode and left leg is positive electrode
If current flows towards the left leg then there will be positive deflection
If opposite way around then negative deflection
Describe Lead II
Left leg is the positive electrode and the left arm is the negative electrode
If the current flows from the arm to the leg then it is positive deflection, if the other way around then it is negative deflection
What degrees are all of the leads represented as?
Lead I- 0
Lead II- +60
Lead III- +120
What is a normal axis?
Positive towards leads 1 and 2
In the axis range of -30 to +90
What are AVL, AVF and AVR?
Unipolar leads
What axis are the aVL, aVF and aVR leads at?
aVL-> -30
aVF-> +90
aVR-> -150
Is the QRS deflection negative or positive for aVR?
Negative
What does lead I positive and lead II negative mean?
Left axis deviation
What does lead I negative and lead II positive mean?
Right axis deviation
What does the right coronary artery supply?
Inferior LV wall
What does the left circumflex artery supply?
Lateral LV wall
What does the left anterior descending artery supply?
Anterior LV wall
In which leads does a problem with the inferior wall show?
Lead II, lead III and aVF
What leads are used to see electrical activity in the transverse plane?
Chest leads (which are unipolar)
V1-V6
What area of the heart do leads V1 and V2 show electrical activity for?
Septal wall
What area of the heart do leads V3 and V4 show electrical activity for?
Anterior wall
What area of the heart do leads V5 and V6 supply?
Lateral wall
What does ST elevation show?
Blocked major coronary artery
Describe the membrane of the heart muscle
Normally only permeable to K+
Potential determined only by ions that can cross membrane
Describe negative membrane potential
K+ ions diffuse outwards (high to low concentration)
Anions cannot follow
Excess of anions inside the cell
Generates negative potential inside the cell
What are the ion concentrations in the extracellular fluid (mmol/L)?
Na+ -> 145
K+ -> 4
Ca2+ -> 2
Cl- -> 120
What are the ion concentrations in the intracellular fluid?
Na+ -> 14
K+ -> 135
Ca2+ -> 0.0001
Cl- -> 4
Describe Myocyte membrane pumps
K+ pumped IN to cells
Na+ and Ca2+ pumped OUT of cells
Against their electrical and concentration gradients
Therefore requires active transport (Na+-K+ pump)
Requires ATP for energy
Describe phase 4 (resting phase)
Sodium forced out by Na/K ATPases. Generates a concentration gradient and therefore a voltage
The setup is now complete, everything from here on relies on passive movement of ions down their gradients.
Describe phase 0 (depolarisation)
Large number of Na+ ions enter the cell, causing the charge to increase from -90mv to +20mV = (more) DEPOLARISATION
Describe phase 1 (initial repolarisation)
Transient outward current of K+ ions leaving the cell causing a small repolarization
Describe phase 2 (plateau)
Calcium channels open, causing calcium to enter the cell and MAINTAIN depolarized state
Describe phase 3 (repolarisation)
Outward K+ current causes repolarization back to resting potential
Describe action potential propagation
Local depolarization activates nearby Na+ channels
Action potential spreads across membrane
Gap junctions allow cell-to-cell conduction and propagation of action potential through whole myocardium
What does electrical stimulation stimulate the release of to allow for muscle contraction?
CALCIUM
Contraction of the heart muscle requires (appropriately-timed) delivery of Ca2+ ions to the cytoplasm
Also known as “Excitation-contraction coupling”
Describe step 1 of Excitation-Contraction coupling
Step 1: Calcium influx through surface ion channels
Describe step 2 of Excitation-Contraction coupling
Step 2: Amplification of [Ca2+]i with NaCa
Intracellular Calcium concentration
Na Ca = Sodium calcium counter transporter
3 sodium, 1 calcium
Describe step 3 of Excitation-Contraction coupling
Step 3: Calcium-induced Calcium Release
CICR
SR = calcium store
Various pumps on surface of the SR maintain this concentration
RyR on surface of SR.
Activated by calcium, causes sustained calcium release
Describe the Troponin-Tropomyosin-Actin-Complex
Calcium binds to troponin
Conformational change in tropomyosin reveals myosin binding sites
Myosin head cross-links with actin
Myosin head pivots causing muscle contraction
What are the specialist conduction tissues?
SAN
AVN
His / Purkinje system
Describe the ventricle voltage/time graph for the SAN
Upsloping Phase 4
Less rapid phase 0
No discernable phase 1 / 2
Upsloping Phase 4
Less rapid phase 0
No discernable phase 1 / 2
Describe the drift of the ventricle voltage/time graph for the SAN
Sinus node potential drifts towards threshold
The steeper the drift, the faster the pacemaker
What is the phase 4 slope affected by?
Autonomic tone
Drugs
Hypoxia
Electrolytes
Age
What does sympathetic stimulation do?
Increases heart rate (positively chronotropic)
Increases force of contraction (positively inotropic)
Increases cardiac output
What does parasympathetic stimulation do?
Decreases heart rate (negatively chronotropic)
Decreases force of contraction (negatively inotropic)
Decreases cardiac output
Describe sympathetic control of heart rate
Adrenaline and noradrenaline + type 1 beta adrenoreceptors
Increases adenylyl cyclase increases cAMP
What happens to the heart with increased sympathetic stimulation?
Increases heart rate (up to 180-250 bpm)
Increases force of contraction
Large increase in cardiac output (by up to 200%)
What happens to the heart with decreased sympathetic stimulation?
Decreases heart rate and force of contraction
Decreases cardiac output (by up to 30%)
What is parasympathetic stimulation of the heartrate controlled by?
Acetylcholine
M2 receptors – inhibit adenyl cyclase reduced cAMP
What happens to the heart with increased parasympathetic stimulation?
Decreased heart rate (temporary pause or as low as 30-40 bpm)
Decreased force of contraction
Decreased cardiac output (by up to 50%)
What happens to the heart with decreased parasympathetic stimulation?
Increased heart rate
What does the AV node do?
Transmits cardiac impulse between atria and ventricles
Delays impulse
Allows atria to empty blood into ventricles
Fewer gap junctions
AV fibres are smaller than atrial fibres
Limits dangerous tachycardias
Describe the conduction of the heart
Velocity of conduction
Faster in specialised fibres
Atrial and ventricular muscle fibres: 0.3 to 0.5 m/s
Purkinje Fibers: 4m/s
Describe the His-Purkinje system
AV node -> ventricles
Rapid conduction
To allow coordinated ventricular contraction
Very large fibres
High permeability at gap junctions
What is automaticity?
Spontaneous discharge rate of heart muscle cells decreases down the heart
SAN (usually) fastest
Ventricular myocardium slowest
Describe the refractory period
Resting state= closed -> open via depolarisation
Open -> closed and inactivatable via automatic
Closed and inactivatable -> resting state via repolarisation
Describe the normal refractory period
Normal refractory period of ventricle approx 0.25s
Less for atria than for ventricles
Describe the heart muscle during the refractory period
Refractory to further stimulation during the action potential
Fast Na+ +/- slow Ca2+ channels closed (inactivating gates)
What does the refractory period do?
Prevents excessively frequent contraction
Allows adequate time for heart to fill
What happens after an absolute refractory period?
After absolute refractory period
Some Na+ channels still inactivated
K+ channels still open
Only strong stimuli can cause action potentials
Affected by heart rate
What is the importance of platelets in disease?
Thrombosis
- Formation of clot (thrombus) inside blood vessel
- Platelets have a central role in arterial thrombosis
Heart attack (myocardial infarction)
Stroke
Sudden death
Antiplatelet medications can be life-saving
What is atherogenesis and atherothrombosis?
Atherogenesis- Formation of fatty deposits in the arteries
These fatty deposits then form fibrous plaque and atherosclerotic plaque
Atherothrombosis- the rupture of the fatty deposits and plaque causing a blockage of the artery
Why do we need blood flow control?
Maintain blood flow
Maintain arterial pressure
Distribute blood flow
Auto-regulate/homeostasis
Function normally
Prevent catastrophe!
(maladapt in disease)
What are platelets?
Fragments of megakaryocytes in bone marrow
Describe platelet shape change
Activation -> Shape change
Smooth discoid -> spiculated + pseudopodia
Increases surface area
Increases possibility of cell-cell interactions
What is on the surface of the platelets?
Glycoprotein IIb/IIIa (GPIIb/IIIa) receptor (aka integrin aIIbb3)
50,000 to 100,000 copies on resting platelet
Describe platelet activation in terms of the Glycoprotein IIb/IIIa (GPIIb/IIIa) receptor
Increases number of receptors
Increases affinity of receptor for fibrinogen
Fibrinogen links receptors, binding platelets together (platelet aggregation)
What happens after atherosclerotic plaque rupture?
Platelets adhere to damaged vessel wall
Collagen receptors bind to subendothelial collagen which is exposed by endothelial damage
GPIIb/IIIa also binds to von Willebrand factor (VWF) which is attached to collagen
Soluble agonists are also released and activate platelets
What is shear flow?
Blood flow across vessel walls causes shear force
What is Von Willebrand factor?
It is a blood glycoprotein that promotes hemostasis (process to prevent bleeding), specifically, platelet adhesion. Initially adheres to endothelial cell, then is rolled until it forms stable adhesion activation
How do platelets get activated?
Many different agonists can cause platelet activation incl- collagen, thrombin, thromboxane, ADP
This leads to:
Shape change
Cross-linking of GPIIb/IIIa
Platelet aggregation
What does aspirin do?
It inhibits an amplification pathway
Low dose aspirin inhibits COX-1 and high dose aspirin inhibits both COX-1 and COX-2
What does arachidonic acid do?
Converted into prostaglandins by COX
What does Cyclooxygenase 1 (COX-1) do?
Mediates GI mucosal integrity
Thromboxane A2-mediated platelet aggregation
What does Cyclooxygenase 2 (COX-2) do?
Mediates inflammation
Involved in prostacyclin production, which inhibits platelet aggregation and affects renal function
What does ADP do in platelets
Platelet purinergic receptors
Platelet P2Y Receptors- P2Y1 and P2Y12
Different G proteins link to different signalling pathways
What does P2Y1 do?
Activates phospholipase C
which produces protein kinase C and Ca2+
Initiation of aggregation
Shape change
Causes platelet activation
Results in GPIIb/IIIa fibrinogen cross-linking and aggregation
What does P2Y12 do?
Produces P13 kinase and adenylate cyclase
Adenylate cyclase then produces cAMP
Amplification of platelet activation, aggregation and granule release
Sustains platelet activation and aggregation
How is the platelet activation amplified?
ADP causes platelet activation via P2Y receptors
Dense granules release ADP, which causes further activation
Activation of GPIIb/IIIa also amplifies platelet activation
How does thrombin affect platelet activation?
Thrombin activates protease-activated receptors (PAR) on platelets
This leads to platelet activation and release of ADP, which amplifies this activation
Platelet procoagulant activity mediated by changes to membrane lipid bilayer
Platelet activation occurs e.g thrombin activating PAR1
This leads to Ca2+ being released from intracellular stores
This inhibits translocase and activates scramblase which leads to the expression of aminophospholipids on the outer platelet membrane, which allows assembly of prothrombinase complex and generation of thrombin
Describe the mechanisms of platelet activation?
Platelet procoagulant activity: activated platelets catalyse thrombin generation, creating an amplification loop that also links with coagulation (the production of fibrin)
Describe a platelet-fibrin clot
Fibrin strands that surround red blood cells and platelets
What is the Fibrinolytic system?
A dynamic interaction between fibrinolytic and anti-fibrinolytic factors is designed to maintain homeostasis i.e. haemostasis without thrombosis
Mechanism of the fibrinolytic system
Endothelium releases tPA which cleaves plasminogen to plasmin - regulated by PAI-1 to form tPA/PAI
Plasmin cleaves fibrin to fibrin degradation products- regulated by antiplasmin to form plasmin: antiplasmin complex
Platelet alpha granules
Mediate expression of surface P-selectin and release of inflammatory mediators
Platelets and inflammation
Platelets have pro-inflammatory and prothrombotic interactions with leukocytes and release inflammatory mediators from alpha granules
How do monocytes interact with platelets in inflammation?
Cytokines e.g. chemotactic molecules
Proteolytic Enzymes
Pro-thrombotic molecules : Tissue factor
Adhesion Molecules e.g. PSGL-1
How do platelets interact with monocytes in inflammation?
Inflammatory mediators
Adhesion Molecules e.g. P-Selectin
Coagulation Factors
What drugs are anticoagulants?
HEPARINS
FONDAPARINUX
BIVALIRUDIN
RIVAROXABAN
APIXABAN
DABIGATRAN
EDOXABAN
What is aortal-mitro continuity
means that endocarditis can spread
Main components of the myocardium
Contractile tissue, Connective tissue, fibrous frame, specialised conduction system
What does the pumping action of the heart depend on?
The pumping action of the heart depends on interactions between the contractile proteins in its muscular walls.
What does the Cardiac Myocyte do?
-The pumping action of the heart depends on interactions between the contractile proteins in its muscular walls.
-The interactions transform the chemical energy derived from ATP into the mechanical work that moves blood under pressure from the great veins into the pulmonary artery, and from the pulmonary veins into the aorta.
-The contractile proteins are activated by a signalling process called excitation-contraction coupling.
When does the excitation-contraction coupling begin and end?
Excitation-contraction coupling begins when the action potential depolarizes the cell and ends when ionized calcium (Ca2+) that appears within the cytosol binds to the Ca2+ receptor of the contractile apparatus.
Is movement of Ca2+ passive or active?
Movement of Ca2+ into the cytosol is a passive (downhill) process mediated by Ca2+ channels.
When does the heart relax?
The heart relaxes when ion exchangers and pumps transport Ca2+ uphill, out of the cytosol.
All or nothing phenomenon
Either the heart muscle contracts fully or doesn’t contract at all there is no in between
Key features of the myocyte cell
-Filled with cross-striated myofibrils.
-Plasma membrane regulates excitation-contraction coupling and relaxation.
-Plasma membrane separates the cytosol from extra-cellular space and sarcoplasmic reticulum.
-Mitochondria: ATP, aerobic metabolism and oxidative phosphorylation.
Does the relaxation process of the myocardium expend energy?
Relaxation process of the heart expends energy just like contraction
What does the heart rely on during aerobic metabolism?
Free fatty acids
What does the myocardium rely on for energy during hypoxia?
There is no FFA metabolism, thus anaerobic metabolism ensues. This relied on metabolising glucose (anaerobically) producing energy sufficient to maintain the survival of the affected muscle without contraction.
How are contractile proteins arranged?
In a regular array of thick and thin filaments (The so called Myofibrils).
What is the A-band?
The region of the sarcomere occupied by the thick filaments
What is the I-band?
It is occupied only by thin filaments that extend toward the centre of the sarcomere from the Z-lines. It also contains tropomyosin and the troponins.
Where are the Z lines?
Z lines bisect each I-band.
Describe the sarcomere
-The functional unit of the contractile apparatus,
-The sarcomere is defined as the region between a pair of Z-lines,
-The sarcomere contains two half I-bands and one A-band.
Describe the sarcoplasmic reticulum
A membrane network that surrounds the contractile proteins,
The sarcoplasmic reticulum consists of the sarcotubular network at the centre of the sarcomere and the subsarcolemmal cisternae (which abut the T-tubules and the sarcolemma).
What is the transverse tubular system (T-tubule)?
Is lined by a membrane that is continuous with the sarcolemma, so that the lumen of the T-tubules carries the extracellular space toward the centre of the myocardial cell.
Describe contraction of the myocardium
Sliding of actin over myosin by ATP hydrolysis through the action of ATPase in the head of the myosin molecule.
These heads form the crossbridges that interact with actin, after linkage between calcium and TnC, and deactivation of tropomyosin and TnI.
Describe the features of myosin
2 heavy chains, also responsible for the dual heads.
4 light chains.
The heads are perpendicular on the thick filament at rest, and bend towards the centre of the sarcomere during contraction (row.)
alpha myosin and beta myosin.
Describe the features of actin
Globular protein.
Double-stranded macromolecular helix (G).
Both form the F actin.
Describe the features of tropomyosin
Globular protein.
Double-stranded macromolecular helix (G).
Both form the F actin.
What does troponin I do?
With tropomyosin inhibit actin and myosin interaction.
What does Troponin T do?
binds troponin complex to tropomyosin.
What does troponin C do?
High affinity calcium binding sites, signalling contraction.
Drives TnI away from Actin, allowing its interaction with myosin
What is in a contractile unit?
Z, I, A and H zones,
Myosin,
Actin,
Tropomyosin,
Troponins,
Titins,
Calcium,
ATP,
Crossbridges.
How is the contractile cycle controlled
Calcium ions- more means more contraction as more myosin binding sites are exposed
Troponin phosphorylation
Myosin ATPase
What are the three basic events in the cardiac cycle?
- LV contraction,
- LV relaxation,
- LV filling.
What are the steps in LV contraction?
- Isovolumic contraction
- Maximal ejection
What are the steps in LV relaxation?
- Start of relaxation and reduced ejection
- Isovolumic relaxation
- Rapid LV filling and LV suction
- Slow LV filling (diastasis)
- Atrial booster
Describe ventricular contraction (systole)
Wave of depolarisation arrives,
Opens the L-calcium tubule, {ECG: Peak of R},
Ca2+ arrive at the contractile proteins,
LVp rises > LAp:
MV closes: M1 of the 1st HS,
LVp rises (isovolumic contraction) > Aop,
AoV opens and Ejection starts.
Describe ventricular relaxation (diastole)
LVp peaks then decreases.
Influence of phosphorylated phospholambdan, cytosolic calcium is taken up into the SR.
“phase of reduced ejection”.
Ao flow is maintained by aortic distensibility.
LVp < Ao p, Ao. valve closes, A2 of the 2nd HS.
“isovolumic relaxation”, then “MV opens”.
Describe ventricular filling
LVp < LAp, MV opens, Rapid (E) filling starts.
Ventricular suction (active diastolic relaxation), may also contribute to E filling (esp. ex. ?S3).
Diastasis (separation): LVp=LAp, filling temporarily stops.
Filling is renewed when A contraction (booster), raises LAp creating a pressure gradient.(path, S4)
Describe physiologic systole
- Isovolumic contraction,
- Maximal ejection
Describe cardiologic systole
- From M1 to A2,
- Only part of isovolumic contraction (includes maximal and reduced ejection phases)
Physiologic Diastole
- Reduced ejection
- Isovolumic relaxation
- Filling phases
Describe cardiologic Diastole
- A2 to M1 interval (filling phases included)
What is preload?
The load present before the left ventricular contraction has started
What is afterload?
Is the load after the ventricle starts to contract
What is Starling’s law of the heart?
Within physiologic limits, the larger the volume of the heart, the greater the energy of its contraction and the amount of chemical change at each contraction.
What is LV filling pressure?
Is the difference between LAp and LV diastolic pressure
Atrial augmentation
Atrial contraction pushes the remainder of the blood at the end of diastole
What is the Force-length interaction?
The force produced by the skeletal muscle declines when the sarcomere is less than the optimal length (Actin’s projection from Z disc “1m” X 2).
In the cardiac sarcomere, at 80% of the optimal length, only 10% of the maximal force is produced!
What is All or none on a cellular level?
The cardiac sarcomere must function near the upper limit of their maximal length (LMAX) = 2.2 m.
The physiologic LV volume changes are affected when the sarcomere lengthens from 85% of LMAX to LMAX!
Steep relationship: length-dependent activation.
What is the Frank and isovolumic contraction?
The heart can, during the cycle, increase and decrease the pressure even if the volume is fixed.
Increasing diastolic heart volume, leads to increased velocity and force of contraction (Frank 1895).
This is the positive inotropic effect.
Ino: Fibre (Greek); tropus: move (Greek).
What is contractility?
(inotropic state): the state of the heart which enables it to increase its contraction velocity, to achieve higher pressure, when contractility is increased (independent of load)
What is elasticity?
Is the myocardial ability to recover its normal shape after removal of systolic stress.
What is compliance?
Is the relationship between the change in stress and the resultant strain.(dP/dV).
What is Diastolic distensibility?
The pressure required to fill the ventricle to the same diastolic volume.
What does the pressure volume loop reflect?
contractility in the end-systolic pressure volume relationship
When is compliance reflected?
At the end diastolic pressure volume relationship
Describe the blood flow through the organs
Heart 4% Other 3.5%Bronchi 2%Thyroid 1%Adrenal 0.5Heart 4%Other 3.5%Bronchi 2%Thyroid 1%Adrenal 0.5%
Where is most of the blood volume?
Small veins and venules- 43%
Large systemic veins- 20%
Pulmonary circulation- 12%
Heart- 10%
Systemic arteries- 10%
Capillaries- 5%
Important features of the arteries
Low resistance conduits
Elastic
Cushion systole
Maintain blood flow to organs during diastole
Describe features of arterioles and their function
Principal site of resistance to vascular flow
Therefore, TPR = Total Arteriolar Resistance
Determined by local, neural and hormonal factors
Major role in determining arterial pressure
Major role in distributing flow to tissue/organs
Describe TPR
Basically arteriolar resistance
Vascular smooth muscle (VSM) determines radius
VSM Contracts = ↓Radius = ↑Resistance ↓Flow
VSM Relaxes = ↑Radius = ↓Resistance ↑Flow
Or Vasoconstriction and Vasodilatation
VSM never completely relaxed = myogenic tone
Independent of pressure driving it
Describe capillaries
40,000km and large area = slow flow
Allows time for nutrient/waste exchange
Plasma or interstitial fluid flow determines the distribution of ECF between these compartments
Flow also determined by
Arteriolar resistance
No. of open pre-capillary sphincters
Features of veins
Compliant
Low resistance conduits
Capacitance vessels
Up to 70% of blood volume but only 10mmHg
Valves aid venous return (VR) against gravity
Skeletal muscle/Respiratory pump aids return
SNS mediated vasoconstriction maintains VR/VP
Describe the lymphatic system
Fluid/protein excess filtered from capillaries
Return of this interstitial fluid to CV system
Thoracic duct; left subclavian vein
Uni-directional flow aided
What is the lymphatic unidirectional flow aided by?
Smooth muscle in lymphatic vessels
Skeletal muscle pump
Respiratory pump
Equation for cardiac output
Cardiac Output (CO) = Heart Rate (HR) x Stroke Volume (SV)
What is the blood pressure equation?
Blood pressure = CO x Total Peripheral Resistance (TPR)
(like Ohm’s law: V=IR)
What is Ohm’s law?
Flow= pressure gradient/resistance
What is Poiseuille’s equation?
Delta P= 8uLQ/ pi r4
What is the equation for pulse pressure?
Pulse pressure (PP) = Systolic – Diastolic Pressure
What is the equation for mean arterial pressure?
Mean Arterial Pressure (MAP)= Diastolic Pressure + 1/3 PP
What governs flow?
Ohm’s law and Poiseuille’s equation
What is Frank-Starling mechanism?
How the heart responds to volume
SV increases as End-Diastolic Volume increases
Due to Length-Tension (L-T) relationship of muscle
↑EDV = ↑Stretch = ↑Force of contraction
Cardiac muscle at rest is NOT at its optimum length
↑Venous return = ↑EDV = ↑SV = ↑CO
(even if HR constant)
How does stroke volume change in the frank-starling mechanism?
How does blood volume affect circulation?
Venous return important beat to beat (FS mechanism)
Blood volume is an important long term moderator
BV = Na+, H20
Controlling water and sodium conc: Renin-Angiotensin-Aldosterone system; ADH; Adrenals and kidneys
What is the goal of control of circulation?
Maintain blood flow!
CO = SV x HR
This needs pressure to push blood through peripheral resistance
MAP = CO x TPR
What is blood pressure?
Pressure of blood within and against the arteries
What is systolic pressure?
Highest, when ventricles contract (100-150mmHg)
What is diastolic blood pressure?
Lowest, when ventricles relax (not zero, due to aortic valve and aortic elasticity .. 60-90mmHg)
Equation for mean arterial pressure
Mean arterial pressure = D + 1/3(S-D)
How to measure blood pressure?
Measured using a sphygmomanometer
Using brachial artery
Convenient to compress
Level of heart
Sounds at each
0) > Systolic Pressure = no flow, no sounds-
1) Systolic pressure = high velocity = tap
2-4) Between S and D = thud
5) Diastolic pressure = sounds disappear
Components of BP control
Autoregulation
Local mediators
Humoral factors
Baroreceptors
Central (neural) control
What is Myogenic Autoregulation?
Stretch of vascular smooth muscle
Contraction until diameter is normalised or slightly reduced
Describe the variation of autoregulation
Intrinsic ability of an organ
Constant flow despite perfusion pressure changes
Renal/Cerebral/Coronary = Excellent
Skeletal Muscle/Splanchnic = Moderate
Cutaneous = Poor
Brain and heart
intrinsic control dominates to maintain BF to vital organs
Skin
BF is important in general vasoconstrictor response and also in responses to temperature (extrinsic) via hypothalamus
: dual effects:
at rest, vasoconstrictor (extrinsic) tone is dominant;
upon exercise, intrinsic mechanisms predominate
Local humoural factors
Vasoconstrictors and vasodilators
Vasoconstrictors examples
Endothelin-1
Internal Blood Pressure
(myogenic contraction
Vasodilators examples
Hypoxia
Adenosine
Bradykinin
NO
K+, CO2, H+
Tissue breakdown products
How does endothelium control blood pressure
Control functions
Essential for control of the circulation
Nitric Oxide (NO) = potent vasodilator
Prostacyclin = potent vasodilator
Endothelin = potent vasoconstrictor
Nitric oxide and Prostacyclin
The powerful local vasodilators
Produced in endothelium
Endothelin
Powerful vasoconstrictors
Circulating hormonal factors
Vasoconstrictors: Epinephrine (skin), Angiotensin II, Vasopressin
Vasodilators: Epinephrine (muscle),
Atrial Natriuretic Peptide
What are baroreceptors
see slides
Arterial baroreceptors
Key role in short-term regulation of BP; minute to minute control, response to exercise, haemorrhage
If arterial pressure deviates from ‘norm’ for more than a few days they ‘adapt’/’reset’ to new baseline pressure eg. in hypertension
The major factor in long-term BP control is blood volume (Na+, H20)
What are cardiopulmonary barorecteptors
Atria, ventricles, PA stretch:
Secretion of ANP
↓vasoconstrictor centre in medulla, ↓ BP;
and ↓release angiotensin, aldosterone & vasopressin (ADH), fluid loss
Blood volume regulation
Central neural control loop
See slide
Describe the main neural influences on the medulla
Baroreceptors, Chemoreceptors, Hypothalamus, Cerebral cortex, Skin,
Changes in blood [O2] and [CO2]
Other higher centres
CV reflexes also require hypothalamus and pons
Stimulation of anterior hypothalamus ↓ BP and HR;
The reverse with posterolateral hypothalamus
Hypothalamus also important in regulation of skin blood flow in response to temperature
How does the cerebral cortex affect blood flow and pressure?
Stimulation usually ↑ vasoconstriction
Emotion can ↑ vasodilatation and depressor responses eg. blushing, fainting. Effects mediated via medulla but some directly
WHat do central chemoreceptors do
Chemosensitive regions in medulla
↑PaCO2 = vasoconstriction, ↑peripheral resistance, ↑BP
↓PaCO2 = ↓medullary tonic activity, ↓BP
Similar changes with ↑ and ↓ pH
PaO2 less effect on medulla; Moderate ↓ = vasoconstriction; Severe ↓ = general depression
Effects of PaO2 mainly via peripheral chemoreceptors
Short term BP control
Baroreceptors
↑BP ⇒ ↑Firing ⇒ ↑PNS/↓SNS ⇒ ↓CO/TPR = ↓BP
Long term BP control
Volume of blood
Na+, H20, Renin-Angiotensin-Aldosterone and ADH
Key central effectors are peripheral
Blood vessels (vasodilatation and vasoconstriction: affects TPR)
Heart (rate and contractility:
CO = HR x SV)
Kidney (fluid balance:
longer term control)
Homeostasis
See slide
Physiological relevance of blood pressure
Cold
Standing up
Running
Lifting
Injury
Blood loss
Pathological relevance of blood pressure
Fainting
Orthostatic hypotension
POTS
Heart failure
Hypovolaemic shock
Cardiogenic shock
Heart block
Cushing’s syndrome
Respiratory failure
General anaesthetic
Fainting
Aetiology = emotion, heat, standing, dehydration
Symptoms = nausea, air hunger, sweating
Physiology = Fall in HR and Venous Pooling (X nerve)
Signs = Collapse due to ↓ CO
HR falls, CO falls, BP falls, perfusion to brain reduced
‘Neuro-cardiogenic syncope’ = Faint!
Treatment = lay supine and elevate limbs to ↑VR
Frank-Starling leads to improved SV and CO
Long term: fluids, salt .. Midodrine (α agonist)
Lifestyle adaptation
Blood loss
Perfusion to brain must be maintained
Local vasoconstriction
Maintain CO/BP by ↑HR
Sympathetic outflow
Widespread cutaneous vasoconstriction
Eventually .. SHOCK (BP↓, Pulse↑, organ hypoperfusion) and death
Treat: rapid volume replacement EARLY
Orthostatic hypotension
Aetiology = standing quickly, too long, dehydration, hot room
Symptoms = lightheaded, sweating, syncope
Physiology = Fall in BP and Venous Pooling (X nerve)
Failure to reflexly maintain BP and HR
Perfusion to brain reduced
Treatment = lay supine and elevate limbs to ↑VR
Frank-Starling leads to improved SV and CO
Investigate: Lying/ standing BP; tilt test
Common cause: BP drugs, B blockers, vasodilators
Lifestyle adaptation
Postural orthostatic tachycardia syndrome (POTS)
Standing
Palpitation, dizzy, near syncope, sweating, debilitating
Physiology = Excess tachycardia response
Investigate = Tilt test
HR↑ >40bpm; BP usually OK
Not well understood
Describe the nose
Most superior portion of the respiratory tract
Multiple functions
-Temperature of inspired air (0.25 second -contact)
-Humidity (75-80% RH)
-Filter function
-Defence function
Cilia take inhaled particulates backwards to
be swallowed
Splinted open
What does the anterior nares open into?
The enlarged vestibule
- Skin lined
-Stiff hairs
Surface area of the nose
-Doubled by turbinates
Superior meatus- under superior turbinate
-Olfactory epithelium
-Cribriform plate
-Sphenoid sinus
Middle meatus- under middle turbinate
-Sinus openings
Inferior meatus- under inferior turbinate
-Nasolacrimal duct
On the lateral nasal wall
Describe the paranasal sinuses
Pneumatised areas of the;
-Frontal
-Maxillary
-Ethmoid
-Sphenoid bones
Arranged in pairs
Evagination of mucous membrane from the nasal cavity
Extension of the mucosa into the sinus
Describe the frontal sinuses
Within frontal bone
Midline septum
Over orbit and across superciliary arch
Nerve supply – ophthalmic division of V nerve
Describe the maxillary sinuses
Located within the body of the maxilla
Pyramidal shape
Open into the middle meatus
Hiatus semilunaris
Where is each part of the maxillary sinuses?
Base – lateral wall of the nose
Apex – zygomatic process of the maxilla
Roof – floor of the orbit
Floor – alveolar process
Describe the ethmoid sinuses
Between the eyes
Labyrinth of air cells
Semilunar hiatus of the middle meatus
Nerve supply - ophthalmic and maxillary V nerve (trigeminal nerve)
Describe the sphenoid sinuses
Medial to the cavernous sinus
Carotid artery, III,IV, V, VI
Inferior to optic canal, dura and pituitary gland
Empties into sphenoethmoidal recess, lateral to the attachment of the nasal septum
Nerve supply – ophthalmic V
Describe the pharynx
Fibromuscular tube lined with epithelium
Squamous and columnar ciliated, mucous glands
Skull base C6 Oesophagus
Anterior Nasal Cavities, mouth and larynx
Nasopharynx
Oropharynx
Laryngopharynx (hypopharynx)
Describe the nasopharynx
Bounded by
-base of skull
-Sphenoid rostrum
-C Spine
-Posterior nose (choana)
-Inferiorly at soft palate opens to
oropharynx
Eustachian tube orifices (lateral wall)
Supply air to middle ear
Pharyngeal tonsils on posterior wall
Soft palate anteriorly
Palatine tonsils on the lateral walls
Palatoglossal folds
Palatopharyngeal folds
Inferiorly to the hyoid bone
Soft palate anteriorly
Palatine tonsils on the lateral walls
Palatoglossal folds
Palatopharyngeal folds
Inferiorly to the hyoid bone
Describe the larynx
Valvular function
Prevents liquids and food from entering lung
Rigid structure
9 cartilages
Multiple muscles
Arytenoid cartilages rotate on the cricoid cartilage to change vocal cords
Vocal cords approximate anteriorly
What are the laryngeal cartilages?
Single Double
-Epiglottis -Cuneiform
-Thyroid -Corniculate
-Cricoid -Arytenoid
Describe laryngeal innervation
The vagus (X)
-Superior laryngeal nerve
-Recurrent laryngeal nerve
Describe the superior laryngeal nerve
-Inferior ganglion
-Lateral pharyngeal wall
-Divides into
-Internal
-Sensation
-External
-Cricothyroid muscle
Describe the recurrent laryngeal nerve
All muscles except cricothyroid
R and L different
Left
lateral to arch of aorta, loops under aorta, ascends between trachea and oesophagus
Right
R Subclavian artery, plane between trachea and oesophagus
Describe the main features of gas exchange
20m2 gas exchange area per lung
Minute ventilation approx 5 litres
Cardiac output approx 5 litres per minute
Regional differences in ventilation and perfusion (blood supply)
600 million alveoli
lower respiratory structure
-Main airways:
Trachea
Main Bronchi
Lobar Bronchi
Segmental branches
Respiratory Bronchiole
Terminal Bronchiole
Alveolar Ducts and Alveoli
-Pleura
Angle of Louis
Describe the trachea
Larynx to carina (5th thoracic vertebra, T5)
Oval in cross section
Pseudo stratified, ciliated, columnar epithelium
Goblet cells
Semicircular cartilages
Mobile (3 cm and 1cm, superior and inferior)
Sensory innervation- recurrent laryngeal nerve
Describe the bronchi
Left and Right main bronchi
Sharp division between these
The carina
R main bronchus more vertically disposed
1-2.5cm long, related to the R pulmonary artery
L main bronchus
5cm long, related to the aortic arch
Describe the Lobar bronchi
Lobar Bronchi (normal)
-Right
-Upper lobe
-Middle lobe
-Lower lobe
-Left
-Upper lobe and lingular
-Lower lobe
What are the left segmental bronchi?
Upper lobe: Apico-posterior, Anterior
Lingular: Superior and Inferior
Lower lobe: Apical, Ant, Post, Lat
Describe acinus
Distal to the terminal bronchiole
Alveoli more profuse with increasing generation of subdivision
Ducts are short tubes with multiple alveoli
Interconnection between alveoli exist (pores of Kohn)
Describe the alveoli
Type I pneumocytes: Pavement
Type II pneumocytes: Surfactant producers
(keeps alveoli patent)
Alveolar macrophage
Basement membrane
Interstitial tissue
Capillary endothelial cells
Describe the pleura of the lungs
Visceral: Applied to the lung surface
Parietal: Applied to the internal chest wall
Each a single cell layer
Small amount of fluid between
Continuous with each other at lung root
Parietal pleura has pain sensation
Visceral pleura has only autonomic innervation
Describe the blood supply to the lungs
Bronchial and pulmonary circulations
Pulmonary circulation
L and R pulmonary arteries run from R ventricle
17 orders of branching
Elastic (>1mm ) and non elastic
Muscular (<1mm )
Arterioles (<0.1mm )
Capillaries
How much
Requirement to move 5 litres / minute of inspired gas [cardiac output 5 litres / min]
What is the respiratory pump?
Generation of negative intra-alveolar pressure
Inspiration active requirement to generate flow
Bones, muscles, pleura, peripheral nerves, airways all involved
Bony structures support respiratory muscles and protect lungs
Rib movements; pump handle and water handle
What are the muscles of respiration?
Inspiration
Largely quiet and due to diaphragm (C3/4/5) contraction
External intercostals (nerve roots at each level)
Expiration
Passive during quiet breathing
Describe the pleura
2 layers, visceral and parietal
Potential space only between these, few millilitres of fluid
Describe the nerves of the respiratory pump
-Sensory;
-Sensory receptors assessing flow, stretch
etc..
-C fibres
-Afferent via vagus nerve (10th cranial nerve)
-Autonomic sympathetic, parasympathetic balance
What is static lungs
Both chest wall and lungs have elastic properties, and a resting (unstressed) volume
Changing this volume requires force
Release of this force leads to a return to the resting volume
Pleural plays an important role linking chest wall and lungs
what is needed at the alveoli
ventilation and perfusion
Ventilation
Bulk flow in the airways
allows O2 and CO2 movement
Large surface area required, with minimal distance for gases to move across. Total combined surface area for gas exchange 50-100 m2
300,000,000 alveoli per lung
Dead space
Volume of air not contributing to ventilation
Anatomic; Approx 150mls
Alveolar; Approx 25mls
Physiological
(Anatomic+Alveolar) = 175mls
Describe circulation in the bronchi
Blood supply to the lung; branches of the bronchial arteries
Paired branches arising laterally to supply bronchial and peri-bronchial tissue and visceral pleura
Systemic pressures (i.e. LV/aortic pressures)
Venous drainage; bronchial veins draining ultimately into the superior vena cava
Describe pulmonary circulation
Left and right pulmonary arteries run from right ventricle
Low(er) pressure system (i.e. RV / pulmonary artery pressures)
17 orders of branching
Elastic (>1mm ) and non elastic
Muscular (<1mm )
Arterioles (<0.1mm )
Capillaries
Describe alveolar perfusion
1000 capillaries per alveolus
Each erythrocyte may come into contact with multiple alveoli
Erythrocyte thickness an important component of the distance across which gas has to be moved
At rest, 25% the way through capillary, haemoglobin is fully saturated
What does alveolar perfusion depend on?
Pulmonary artery pressure
Pulmonary venous pressure
Alveolar pressure
Capillaries at the most dependent parts of the lung are preferentially perfused with blood at rest
What is hypoxic pulmonary vasoconstriction
Matching ventilation and perfusion important
Pulmonary vessels have high capacity for cardiac output
30% of total capacity at rest
Recruiting of alveoli occurs as a consequence of exercise
Nomenclature of pulmonary physiology
PaCO2- arterial CO2
PACO2- Alveolar CO2
PaO2- arterial O2
PACO2- Alveolar O2
PiO2- Pressure of inspired oxygen
PaCO2=kVco2/VA
Normally PaCO2= 4-6 KPa
Ways that CO2 is carried
Physiological causes of a high CO2
Alveolar gas equation
PAO2= PiO2-PaCO2/R
R=Respiratory Quotient [ratio of Vol CO2 released/Vol O2 absorbed, assume = 0.8]
Causes of low PaO2
Alveolar hypoventilation
Reduced PiO2
Ventilation/perfusion mismatching (V/Q)
Diffusion abnormality
Describe O2/Hb dissociation curve non linear
Sigmoid shape
As each O2 molecule binds, it alters the conformation of haemoglobin, making subsequent binding easier (cooperative binding)
Varying influences
2,3 diphosphoglyceric acid
H+
Temperature
CO2
Describe acid base control in the blood
Body maintains close control of pH to ensure optimal function (e.g. enzymatic cellular reactions)
Dissolved CO2/carbonic acid/respiratory system interface crucial to the maintenance of this control
pH normally 7.40
H+ concentration 40nmol/l [34-44 nmol/l]
Measures you can get from a blood gas
PaCO2- arterial CO2
PaO2- arterial O2
How does the body control acid/base levels?
Blood and tissue buffers important
Carbonic acid / bicarbonate buffer in particular
CO2 under predominant respiratory control (rapid)
HCO3- under predominant renal control (less rapid)
The respiratory system is able to compensate for increased carbonic acid production, but;
Elimination of fixed acids requires a functioning renal system
Carbonic acid equilibrium
CO2 + H2O <-> H2CO3 <-> H+ + HCO3-
Carbonic anhydrase
Henderson-Hasselbalch equation
pH=6.1 + log10[[HCO3-]/[0.03*PCO2]]
when co2 increases
In order to keep pH at 7.4, log of the ratio must equal 1.3
As PaCO2 rises (respiratory failure)
HCO3- must also rise (renal compensatory mechanism) to allow this- as the pH lowers
Four main acid base disorders
Respiratory acidosis, respiratory alkalosis, metabolic acidosis, metabolic alkalosis
Functions of the lung?
Respiration:
Ventilation and gas exchange: O2, CO2, pH, warming and humidifying
Non-respiratory functions:
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.
Intrinsic host defences
Always present: Physical and chemical. Apoptosis, autophagy, RNA silencing, antiviral proteins
Innate defence
induced by infection (Interferon, cytokines, macrophages, NK cells)
Adaptive immunity
Tailored to a pathogen (T cell, B cells)
What is epithelium?
A tissue composed of cells that line the cavities and surfaces of structures throughout the body. Many glands are also formed from epithelial tissue. It lies on top of connective tissue, and the two layers are separated by a basement membrane.
What is respiratory epithelium?
serves to moisten and protect the airways. It also functions as a barrier to potential pathogens and foreign particles, preventing infection and tissue injury by action of the mucociliary escalator.
Chemical epithelial barriers
antiproteinases
anti-fungal peptides
anti-microbial peptides
Antiviral proteins
Opsins
Describe mucous and it’s functions
Airway mucus is a viscoelastic gel containing water, carbohydrates, proteins, and lipids.
It is the secretory product of the mucous cells (the goblet cells of the airway surface epithelium and the submucosal glands).
Mucus protects the epithelium from foreign material and from fluid loss
Mucus is transported from the lower respiratory tract into the pharynx by air flow and mucociliary clearance.
What do cilia do in the lungs?
Beat to move mucus up the airways
What is a cough and what causes it?
A cough is an expulsive reflex that protects the lungs and respiratory passages from foreign bodies
Causes of cough:
1. Irritants- smokes, fumes, dusts ect
2. Diseased conditions like COPD, tumours,ect
3. Infections(influenza)
How does a cough happen
Defence reflex so afferent and efferent pathways
Afferent
What is a sneeze and what causes it?
Sneeze is defined as the involuntary expulsion of air containing irritants from the nose
Causes of sneeze:
1. Irritation of nasal mucosa
2. Excess fluid in airway
Why can injury to airway epithelium repair its self and how?
Injury-> Spreading and dedifferentiation->cell migration->cell proliferation ->redifferentiation -> regeneration
This is because it exhibits a level of functional plasticity
What happens when epithelial changes go wrong?
We get pulmonary diseases
Underpin many obstructive lung diseases
What are mucus plugs/inflammation?
Mucus and inflammatory cells blocking airways
Key facts about the pulmonary and bronchial circulation
Unique dual blood supply of the lungs
Pulmonary Circulation
From Right Ventricle
100% of blood flow
Bronchial Circulation
2% of Left Ventricular Output
Describe the pulmonary circulation system
Receives 100% of cardiac output (4.5-8L/min.)
Red cell transit time ≈5 seconds.
280 billion capillaries & 300 million alveoli.
Surface area for gas exchange 50 – 100 m2
Pulmonary arteries features
Vessel wall-> thin
Muscularization-> minor
Need for redistribution-> not in normal state
Systemic arteries features
Vessel wall-> thick
Muscularization-> significant
Need for redistribution-> yes
Pressures of pulmonary circulation (mmHg)
RA 5
RV 25/0
PA 25/8
Pressures of the systemic circulation
LA 5
LV 120/0
Aorta 120/80
How do you measure wedge pressure
What is Ohm’s law?
Voltage across circuit = Current x Resistance
V = I R
Pressure across circuit = Cardiac Output x Resistance
mPAP – PAWP = CO x PVR
mPAP (mean pulmonary arterial pressure),
PAWP (pulmonary arterial wedge pressure left atrial pressure),
CO (cardiac output)
PVR (pulmonary vascular resistance)
What is pouiseuille’s law?
Resistance = (8 x L x viscosity)/(π r4)
A small change in radius can have a big impact on it
exercise
mPAP – PAWP = CO x PVR
On exercise CO increases significantly but mPAP remains stable/increases slightly
because of recruitment and distention in response to increased pulmonary artery pressure
What are the pO2 and pCO2 values for type I and type II respiratory failure?
Type I Respiratory Failure
pO2 < 8 kPA
pCO2 <6 kPA
Type II Respiratory Failure
pO2 < 8 kPA
pCO2 >6 kPA
Causes of hypoxaemia
Hypoventilation
Diffusion Impairment
Shunting
V/Q mismatch
What is hypoventilation and what are the causes?
Type II Respiratory Failure
pO2 < 8 kPA
pCO2 >6 kPA
Failure to ventilate the alveoli
Causes:
Muscular weakness
Obesity
Loss of respiratory drive
Different causes of diffusion of impairment
Gaseous Diffusion
Pulmonary Oedema
Blood Diffusion
Anaemia
Membrane Diffusion
Interstitial Fibrosis
Abbreviations for lung physiology measures
TLC- total lung capacity
VC- vital capacity
RV- residual volume
TV- tidal volume
FRC- functional residual capacity
Measured values of lung capacity
FEV1- Forced expiratory volume in one second
FVC- Forced vital capacity- All the air to residual volume
Flow volume curve
Peak Expiratory Flow (PEF)
Lung volumes
Transfer factor estimates
[Compliance]
Forced expiration
Most of the air comes out in the first second
Breathe in to total lung capacity (TLC)
Exhale as fast as possible to residual volume (RV)
Volume produced is the vital capacity (FVC)
Volume time graph looks like a sharp increase in the first second then it plateaus
Peak flow
1/10th of a second in
Can see it on a flow volume graph
Single measure of highest flow during expiration
Peak flow meter, spirometer
Gives reading in litres/minute (L/min)
Very effort dependent
May be measured over time, by giving a patient a PEF meter and chart
Flow volume graph for forced expiration
Take the exact same procedure
Re-plot the data showing flow as a function of volume
PEF; peak flow
FEF25; flow at point when 25% of total volume to be exhaled has been exhaled
FVC; forced vital capacity
What are lung volumes?
Expiratory procedures only measure VC, not RV
Various other ways to measure RV and TLC are needed
These include;
Gas dilution
Body box (total body plethysmography; shown in picture)
Describe gas dilution
Measurement of all air in the lungs that communicates with the airways
Does not measure air in non-communicating bullae
Gas dilution techniques use either closed-circuit helium dilution or open-circuit nitrogen washout
Total body/ body box plethysmography
Alterative method of measuring lung volume, (Boyle’s law), including gas trapped in bullae.
From the FRC, patient “pants” with an open glottis against a closed shutter to produce changes in the box pressure proportionate to the volume of air in the chest
The volume measured (TGV) represents the lung volume at which the shutter was closed
FRC, inspiratory capacity, expiratory reserve volume, vital capacity all measured
From these volumes and capacities, the residual volume and total lung capacity can be calculated
TLC = VC+RV
Transfer estimates
Carbon monoxide used to estimate TLCO, as has high affinity for haemoglobin
Single 10 second breath-holding technique
10% helium, 0.3% carbon monoxide, 21% oxygen, remainder nitrogen.
Alveolar sample obtained;
DLCO is calculated from the total volume of the lung, breath-hold time, and the initial and final alveolar concentrations of carbon monoxide.
What is TLco an overall measure of the interaction of?
alveolar surface area
alveolar capillary perfusion
physical properties of the alveolar capillary interface
capillary volume
haemoglobin concentration, and the reaction rate of carbon monoxide and hemoglobin.
Regression equations
Abnormal FEV1 values
Forced expiratory volume in one second in litres
Good overall assessment of lung health
Compare with predicted value
80% or greater “normal”
Above the lower limit of normal for that patient (LLN)
Above mean minus 1.645 SD
Abnormal FVC values
Compare with predicted value
80% or greater “normal”
Above the lower limit of normal for that patient (LLN)
Above mean minus 1.645 SD
Low value indicates likely Airways Restriction
🫁
Abnormal FEV1/ FVC ratio
There is a predicted ratio for each individual, but..
Abnormal ratio < 0.70 = airways obstruction
[Can also use the LLN* for each individual patient]
*Lower limit of normal
Asthma physiology changes
FEV1- Normal or reduced
FVC- Normal
PEF- Typically variable, increased diurnal variation of 20%
MEF- Low, typically ‘scalloped’ shape to the flow volume curve
TLC- High or normal
TLco and Kco- Normal or elevated
eNO- High
RAW- High when airway narrowing present
Asthma typical blood gases
PaO2 Normal
PaCO2 Low
pH Normal or elevated
HCO3- Normal
COPD characteristics
COPD is a progressive condition
Typified by wheeze and shortness of breath on exercise, progressively worse with time
Intermittent exacerbations
Typified by airways obstruction and lack of significant PEF variation
Typified by reduced mid expiratory flows
Typified by partial or poor response to treatments
FEV1- Reduced significantly
FVC- May be normal or reduced
PEF- Typically not variable
MEF- low typical scalloped shaped to the flow volume curve
DLco and Kco- low
eNO- normal
RAW- high
COPD typical blood gases
PaO2 Low
PaCO2 High in type 2 respiratory failure
Low in type 1 respiratory failure
pH Normal
HCO3- May be elevated if chronic acidosis
Asbestosis (pulmonary fibrosis due to asbestos) changes to values
FEV1- Reduced significantly
FVC- Reduced significantly
PEF- Typically not variable
MEF- Low or normal
TLC- Reduced
Dlco and Kco- Low
eNO- Normal
RAW- no typical change
Asbestosis typical blood gases
PaO2 Low
PaCO2 Low
pH Normal
HCO3- Low
What is the requirement for respiration?
Ensure haemoglobin is as close to full saturation with oxygen as possible
Efficient use of energy resource
Regulate PaCO2 carefully
variations in CO2 and small variations in pH can alter physiological function quite widely
Breathing is automatic so…
No conscious effort for the basic rhythm
Rate and depth under additional influences
Depends on cyclical excitation and control of many muscles
Upper airway, lower airway, diaphragm, chest wall
Near linear activity
Increase thoracic volume
What is taking a breath dependent on?
CO2 levels
Basic breathing rhythm -Pons
Pneumotaxic and Apneustic Centres
Basic breathing rhythm in medulla oblongata
Phasic discharge of action potentials
Two main groups
Dorsal respiratory group (DRG)
Ventral respiratory group (VRG)
When are the DRG and VRG active?
DRG; predominantly active during inspiration
VRG; active in both inspiration and expiration
Each are bilateral, and project into the bulbo-spinal motor neuron pools and interconnect
Describe the central pattern generator
Neural network (interneurons)
Located within DRG/VRG
Precise functional locations not known
Start, stop and resetting of an integrator of background ventilatory drive
Describe Inspiration
Progressive increase in inspiratory muscle activation
Lungs fill at a constant rate until tidal volume achieved
End of inspiration, rapid decrease in excitation of the respiratory muscles
Describe expiration
Largely passive due to elastic recoil of thoracic wall
First part of expiration; active slowing with some inspiratory muscle activity
With increased demands, further muscle activity recruited
Expiration can be become active also; with additional abdominal wall muscle activity
What is the impact of chemoreceptors in the respiratory system?
Central (60% influence from PaCO2) and peripheral (40% influence from PaCO2)
Stimulated by [H+] concentration and gas partial pressures in arterial blood
Brainstem [primary influence is PaCO2]
Carotids and aorta [PaCO2, PaO2 and pH]
Significant interaction
What are the central chemoreceptors
Located in brainstem
Pontomedullary junction
Not within the DRG/VRG complex
Sensitive to PaCO2 of blood perfusing brain
Blood brain barrier relatively impermeable to H+ and HCO3-
PaCO2 preferentially diffuses into CSF
Where are the peripheral chemoreceptors?
Carotid bodies
Bifurcation of the common carotid
(IX) cranial nerve afferents
Aortic bodies
Ascending aorta
Vagal (X) nerve afferents
What are the peripheral chemoreceptors?
Responsible for [all] ventilatory response to hypoxia (reduced PaO2)
Generally not sensitive across normal PaO2 ranges
When exposed to hypoxia, type I cells release stored neurotransmitters that stimulate the cuplike endings of the carotid sinus nerve
Linear response to PaCO2
Interactions between responses
[Poison (e.g. cyanide) and blood pressure responsive]
What are the lung receptors and what do they do?
Stretch, J and irritant
Afferents; vagus (X)
Combination of slow and fast adapting receptors
Assist with lung volumes and responses to noxious inhaled agents
What are stretch lung receptors?
Smooth muscle of conducting airways
Sense lung volume, slowly adapting
What are irritant lung receptors?
Larger conducting airways
Rapidly adapting [cough, gasp]
J; juxtapulmonary capillary lung receptors
Pulmonary and bronchial C fibres
Airway receptors in the nose, nasopharynx and larynx
Chemo and mechano receptors
Some appear to sense and monitor flow
Stimulation of these receptors appears to inhibit the central controller
Airway receptors in the pharynx
Receptors that appear to be activated by swallowing
respiratory activity stops during swallowing protecting against the risk of aspiration of food or liquid
Describe muscle proprioceptors
Joint, tendon and muscle spindle receptors
Intercostal muscles > > diaphragm
Important roles in perception of breathing effort
What happens in ascent
Ascending; PiO2 falls (FiO2 remains constant)
Decreased PAO2
Decreased PaO2
Peripheral chemoreceptors fire (e.g carotid)
Activates increased ventilation (VA)
Increased PAO2
Increased PaO2
CO2 elimination equation
PaCO2=kVco2/ VA
How is CO2 carried
Physiological causes of high CO2
Causes of low PaO2
Alveolar hyperventilation
Reduced PiO2
PAO2 normal value
20KPa-6KPa/0.8=
20
Resp failure blood gases
PaO2 <8KPa <60mmHg [10.5 - 13.5]
PaCO2 >6.5KPa >49mmHg
[4.7 – 6.5]
Hypoxaemia
decrease in pp of oxygen in the blood
What is Hypoxia
Reduced level of tissue oxygenation
Respiratory failure type I
PaO2- Low (hypoxaemia)
PaCO2- Low/Normal (hypocapnia/normal)
PaCO2- low (
types of time course for resp failure
Acute, rapidly
For example; opiate overdose, trauma, pulmonary embolism
Chronic, over a period of time
For example; COPD, fibrosing lung disease
Resp failure type 1 mechanisms
Most pulmonary and cardiac causes produce type I failure
Hypoxia
Mismatching of ventilation and perfusion
Shunting
Diffusion impairment
Alveolar hypoventilation
Similar effects on tissues seen with;
Anaemia, carbon monoxide poisoning, methaemoglobinaemia
Treatments for resp failure type I
Airway patency
Oxygen delivery
Many differing systems
Increasing FiO2
Primary cause (e.g. antibiotics for pneumonia
common cause of both type 1 and type 2
COPD
Respiratory failure; type II mechanisms
Lack of respiratory drive
Excess workload
Bellows failure
clinical features of hypoxia
Central Cyanosis
Oral cavity
May not be obvious in anaemic patients
Irritability
Reduced intellectual function
Reduced consciousness
Clinical features of hypercapnia
Irritability
Headache
Papilloedema
Warm skin
Bounding pulse
Confusion
Somnolence
Coma
Respiratory failure type II treatments
Airway patency
Oxygen delivery
Primary cause (e.g. antibiotics for pneumonia)
Treatment with O2 may be more difficult
For example; COPD patients rely on hypoxia to
stimulate respiration
How to measure exhaled nitric oxide and what does it show?
Simple measure of nitric oxide in exhaled breath
Simple machines able to do this
Measured in ppb
Generally increased in asthma
Not “diagnostic”
A reflection of eosinophilic airway inflammation
High >50ppb, normal <25ppb
Asthma and occupation
15% of asthma is due to occupation
common causes
High molecular allergens: latex, wood, animals and fish
Low molecular allergens:Glutaraldehyde
Isocyanates
Paints
Metal working fluids
Metals
What is the prevalence of asthma?
5-16% of people worldwide have asthma
Wide variation between countries
Increase in prevalence second half of the 20th century
Now plateaued mostly
US study; Poorer individuals, African-Americans
Many studies identify a wide range of risk factors
How is asthma affected by the environment?
Pollens, Infectious agents and microorganisms, Fungi, pets, air pollution
All aggrivate/ cause asthma
silica, coal grain cotton cadmium
What is hypersensitivity pneumonitis?
is an inflammation of the alveoli within the lung caused by hypersensitivity to inhaled agents
Acute, sub acute and chronic forms (fibrotic, non fibrotic)
Immune complex related disease
Antigen reacts with antibody
Normally IgG response
Very significant environmental influences; farmers lung, bird fanciers lung, metal working fluids
CF genotype classification
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)
More than 2000 CF - causing CFTR mutations have been found
Most common of which is F508del [a class II mutation found in up to 80% to 90% of patients]
CF prevention management
Segregation
Surveillance – frequent review minimum every 3 months
Airway clearance – physio & exercise
Nutrition – pancreatic enzymes, diet high calorie & fat, supplements including vitamins, percutaneous feeding
Psychosocial support
CF prevention drugs
Suppression of chronic infections – antibiotic nebulisation
Bronchodilation – salbutamol nebulisation
Anti inflammatory – azithromycin, corticosteroids
Diabetes – insulin treatment
Vaccinations – influenza, pneumococcal, SARS CoV 2
Describe CF rescue antibiotics
2 week course IV antibiotics
Home vs hospital
Issues with frequent antibiotics
Allergies
Renal impairment
Resistance
Access problems
If antibiotics are needed frequently then a port can be put in
Genotype directed therapies for cystic fibrosis
Small-molecule agents facilitate defective CFTR processing or function
Ivacaftor in G551D (6%) and other specific mutations
Improved lung function (FEV1), BMI, QoL
Orkambi in F508del – only licensed for compassionate use in UK
Mixed outcomes
Gene therapy – further research needed as significant problems with delivery
How does Ivacaftor (Kalydeco) work?
CFTR potentiator - potentiates chloride secretion via increased CFTR channel opening time
Class III mutations
How does lumacaftor (Orkambi) work?
Lumacaftor is a CFTR corrector - corrects cellular misprocessing of CFTR (e.g. folding) to facilitate transport from the endoplasmic reticulum
Class II mutation - F508del/F508del
Describe some challenges with 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
Describe Alpha-1 antitrypsin deficiency (AATD)
Autosomal recessive genetic disorder
80 different mutations of SERPINEA1 gene on chromosome 14
Serum antiprotease
M phenotype normal and healthy
S and Z phenotypes major disease associations
Leads to:
Early onset emphysema and bronchiectasis
Unopposed action of neutrophil elastase in the lung
Autonomic nervous system
The peripheral autonomic nervous system divides into sympathetic and parasympathetic branches, which typically have opposing effects
The autonomic nervous system conveys all outputs from the CNS to the body, except for skeletal muscular control
Two nerves in series, the pre- and post-ganglionic fibres
The parasympathetic ganglia are near their targets with short post-ganglionic nerves, whereas the sympathetic ganglia are near the spinal cord with longer post-ganglionic fibres
Parasympathetic bronchoconstriction
Vagus nerve neurons terminate in the parasympathetic ganglia in the airway wall
Short post-synaptic nerve fibres reach the muscle and release acetylcholine (ACh), which acts on muscarinic receptors of the M3 subtype on the muscle cells
This stimulates airway smooth muscle constriction
Anti muscularinics
Ipratropium bromide (Atrovent) can be used as inhaled treatment to relax airways in asthma and COPD, but is a short acting antimuscarinic (SAMA)
SAMA less widely used since long acting muscarinic antagonists (LAMAs) were developed
Ipratropium is still used in high dose in nebulisers as part of acute management of severe asthma and COPD
LAMAs
Have long duration of action (many hours), often given once daily (tiotropium)
Increase bronchodilatation and relieve breathlessness in asthma and COPD
Seem to reduce acute attacks (exacerbations) as well
Have other benefits, e.g. on parasympathetic regulation of mucus production
Sympathetic regulation of the bronchi
Sympathetic NS Regulates the fight-and-flight response
Nerve fibres release noradrenaline which activates adrenergic receptors, of which there are two main types (alpha/beta)
Nerve fibres in humans mainly innervate the blood vessels, but airway smooth muscle cells have adrenergic receptors (beta)
Activation of beta2 receptors on the airway smooth muscle causes muscle relaxation (by activating adenylate cyclase, raising cyclic AMP)
What are SABAs and LABAs?
Short-acting (salbutamol) and long-acting (formoterol, salmeterol) beta2 agonists are valuable drugs
Given with steroids in asthma, often without steroids in COPD
Often given with LAMA in COPD
Acute rescue of bronchoconstriction
Prevention of bronchoconstriction
Reduction in rates of exacerbations
Mechanism of action of Beta 2-agonists
Stimulation of β2 adenoreceptors results in activation of adenylate cyclase, increased intracellular cAMP and subsequent airway smooth muscle relaxation
Adverse effects of beta2 agonists
Describe type I hypersensitivity
Mediators-> IgE antibodies
Timing-> immediate (within 1 hour)
Examples-> anaphylaxis and hayfever
Antigen interacts with IgE bound to mast cells or basophils
Degranulation of mediators lead to local effects
Histamine the predominant mediator
Describe type II hypersensitivity
Mediators-> Cytotoxic antibodies bound to cell antigen
Timing-> Hours to days
Examples-> Transfusion reactions Goodpastures (Anti GBM disease)
Antibodies reacting with antigenic determinants on the host cell membrane
Usually IgG or IgM
Outcome depends on whether complement is activated and if metabolism of cell is affected
Describe type III hypersensitivity
Mediators-> Deposition of immune complexes
Timing-> Typically 7-21 days
Examples-> Hypersensitivity pneumonitis; lupus; post streptococcal Glomerulonephritis
Antigen-immunoglobulin complexes are formed on exposure to the allergen
These are deposited in tissues and cause local activation of complement and neutrophil attraction
Describe type IV hypersensitivity
Mediators-> T-cells (lymphocytes)
Timing-> Days to weeks or months
Examples-> Tuberculosis; Stevens-Johnson syndrome
T-cell mediated, releasing IL2, IFᵧ 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, they become giant cells and form granuloma
Medical history
Age, Gender, Occupation
Presenting complaint
History of presenting complaint
Previous medical condition
Drug history and allergies
Social history- hobbies
Family history+ extended family history
Review of systems
Respiratory rate
Ususally 10-12 per minute
Units of pressure
1 bar -1000 millibars
760 mmHg / torr
1 atmosphere absolute (ATA)
10 metres of sea water (msw)
33.08 feet of sea water (fsw)
101.3 kilopascals (kPa)
14psi
What is Boyle’s law and what are its applications?
At a constant temperature the absolute pressure of a fixed mass of gas is inversely proportional to its volume
P1V1=P2V2
Applications
barotrauma
arterial gas embolism
gas supplies
What is the diving reflex?
When cold water is splashed on someone’s face then they might have
apnoea
bradycardia
peripheral vasoconstriction
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 total volume
What are the effects of Dalton’s law at sea level and at 10 msw?
At sea level;
partial pressure N2 = 0.78 ata, O2 = 0.209 ata
At 10 msw;
partial pressure N2 = 1.56 ata, O2 = 0.418 ata
[Breathing air at 10 msw same PaO2 as breathing 42% O2 at sea level]
What is the Lorrain Smith Effect (pulmonary oxygen toxicity)?
PiO2 > 0.5 ATA
100% oxygen -> symptoms in 12 - 24 hours
Cough, chest tightness, chest pain, shortness
of breath
Also a problem with ITU patients
Relief with PiO2 < 0.5 ATA
Unit of Pulmonary Toxic Dose (UPTD) can be calculated
Forced Vital Capacity (FVC) can be useful to monitor
Describe CNS Oxygen toxicity
V - Vision (tunnel vision etc)
E - Ears (tinnitus)
N - Nausea
T - Twitching (extremities or facial muscles)
I - Irritability
D - Dizziness
common final (and often the first) sign will be a convulsion
ConVENTID
What is inert gas narcosis?
Commonest is nitrogen narcosis
worsens with increasing pressure
first noticed between 30-40 msw
Increased PiN2
individual variation
influencing factors- cold, anxiety, fatigue, drugs, alcohol and some medications
Narcotic potential related to lipid solubility
What are the signs and symptoms of inert gas narcosis?
10-30m. - Mild impairment of performance
30-50m. - Over confidence, sense of well being
50-70m - Sleepiness, confusion, dizziness
70-90m. - Loss of memory, stupefaction
90+ - Unconsciousness, death
Note: death may occur at much shallower depths
What is decompression illness?
N2 poorly soluble
Ascent fall in pressure
fall in solubilty
gas bubbles
Type I Cutaneous only
Type II Neurologic
O2, supportive treatments and urgent recompression
Describe arterial gas air embolism
Gas enters circulation via torn pulmonary veins
Small transpulmonary pressures can lead to AGE
Normally occur within 15 minutes of surfacing
Urgent recompression
What is pulmonary barotrauma?
Air leaks from burst alveoli:
Pneumothorax
Pneumomediastinum
Subcutaneous emphysema
Alveolar gas equation
PAO2 = PiO2 – PaCO2/R**
- One version, not taking into account pH2O
**R=respiratory quotient, = CO2 produced / O2 consumed
A=Alveolar, a=arterial
R = 0.8 with a normal diet
R approx = 1 with primarily carbohydrate diet
R closer to 0.7 with fat rich diets
Normal barometric pressure at different altitudes
Barometric pressure Altitude (m)
101 (760) 0
57 (429) 4800
46 (347) see slide 12
What is the equation for alveolar arterial O2 difference?
Alveolar Arterial O2 difference
Whilst normal pretty complete equilibration of O2, there normally is a small difference between Alveolar and arterial oxygen partial pressure
= PAO2 – PaO2 = (approx) 1KPa
Normal blood gases
PaO2 10.5 - 13.5 KPa
PaCO2 4.5 - 6.0 KPa
pH 7.36 - 7.44
Describe right shift of the oxygen dissociation curve
Shifts to the right bc you want to deliver the oxygen to the tissues that are metabolically
active
causes
Acidity
2,3 DPG*
Increased temperature
Increased PCO2
[*2,3 biphosphoglycerate]
WHat happens to FiO2 and PiO2 as you ascend?
FiO2 remains constant at approx 0.21
PiO2 falls with altitude
Describe the response of the lungs at altitude
Hypoxia leads to..
Hyperventilation at 10000ft altitude
Increases minute ventilation
Lowers PaCO2
Alkalosis initially
Tachycardia
Adaptive changes
Multiple
Alkalosis compensated by renal bicarbonate excretion
What is acute mountain sickness?
Recent ascent to over 2500m
Lake Louise score 3
Must have a headache and one other symptom
What are the risk factors for acute mountain sickness?
Recent travel to over 2500m, after a few hours
Sea level normal dwelling
Altitude, rate of ascent and previous history of AMS
Younger people
Descend; the only reliable treatment [o2, recompress, acetazolamide]
You should never go up higher if you have AMS
What increases risk of high altitude pulmonary oedema?
Unacclimatised individuals
Cough, shortness of breath
Rapid ascent above 8000ft (2438m)
2-5 days
What decre
Risk less if sleeping below 6000ft (1829m)
Speed of ascent slower (300-350m/day)
Individual susceptibility
Exercise
Respiratory Tract Infection
Incidence 2% at 4000m
What are the treatments of pulmonary oedema
O2
Decent urgent
Gamow bag
Steroids
Ca2+ blockers?
Sildenafil
What are the main features of High Altitude Cerebral Oedema?
Serious
AMS not a pre requisite
Confusion
Behaviour change
Treatment for high altitude cerebral oedema?
Immediate descent
Symptoms may resolve relatively quickly
Gamow bag
What to do at different sea level SaO2s
Patients need physiological assessment if they have low O2 levels at sea level
Stages of lung development
Embryonic 0-5 weeks
Pseudoglandular 5-17 weeks
Cannalicular 16-25 weeks
Alveolar 25 weeks- term
Embryonic
Describe the pseudoglandular phase of lung development
5-17 weeks
Exocrine gland only
Major structural units formed.
Angiogenesis
Mucous Glands
Cartilage
Smooth Muscle
Cilia
Lung fluid
Describe canalicular phase
16-25 weeks.
Distal Architecture
Vascularisation i.e formation of capillary bed
Respiratory bronchioles.
Alveolar ducts.
Terminal sacs
Describe alveolarisation from 25 weeks to birth
Alveolar sacs
Type 1 and Type 2 cells
Alveoli simple with thick interstitium
Describe alveolarisation from birth to 3-5 years
Thinning of alveolar membrane and interstitium
↑ complexity of alveoli
5-17
Major airways defined
Nests of angiogenesis
Smaller airways down to respiratory bronchioles
16-25
Terminal bronchioles
Capillary Beds
Alveolar ducts
25-40 weeks
Alveolar budding, thinning and complexification
What goes wrong in the embryonic phase
Laryngeal,
Tracheal and oesophageal atresia,tracheal and bronchial stenosis,pulmonary agenesis
What goes wrong in the pseudoglandular phase
Bronchopulmonary sequestration,cystic adenomatoid malformations, alveolar-capillary dysplasia,
Things that go wrong in the alveolar phase
Acinar Dysplasia,
alveolar capillary dysplasia,
Pulmonary hyoplasia
What are the types of cystic adenomatoid malformations?
Type 0- Trachebronchial
Type 1- Bronchial
Type 2- Bronchiolar
Type 3- Alveolar duct
Type 4- Distal acinar
Systemic blood vessles
Purpose: deliver oxygen to hypoxic tissues
Hypoxia/acidosis/CO2
is vasodilator
Oxygen is vasoconstrictor
Pulmonary blood vessles
Purpose: pick up oxygen from oxygenated lung
Oxygen is vasodilator
Hypoxia/acidosis is vasoconstrictor
Describe the important parts of fetal circulation
Lung is not useful organ to fetus
PaO2 = 3.2 kPa (31,000 feet)
Shunting of blood Right Left via ductus arteriosus
High Pulm Vasc Resistance (hypoxia)
Tissue resistance (fluid filled)
Low systemic resistance (placenta)
What is in fetal lungs and why?
Fetal airways are distended with fluid
Fluid aids in lung development
Actively secreted by lungs
Describe the ductus arteriosus
Pulmonary trunk linked to the distal arch of aorta by the ductus arteriosus, permitting blood to bypass pulmonary circulation
muscular wall contracts to close after birth (a process mediated by bradykinin)
What is the ductus venosus?
Oxygenated blood entering the foetus also needs to bypass the primitive liver. This is achieved by passage through the ductus venosus, which is estimated to shunt around 30% of umbilical blood directly to the inferior vena cava
Describe the foramen ovale
The foramen ovale is a passage between the two atria, which is responsible for bypassing the majority of the circulation
What happens to the ductus arteriosus immediately after birth
Describe the ductus venosus after birth
WHat happens in the lungs at birth
Fluid squeezed out of lungs by birth process
Adrenaline stress leads to increased surfactant release.
Gas inhaled
What happens in the blood vessels at birth
Oxygen vasodilates pulmonary arteries
Pulmonary vascular resistance falls
Right atrial pressure falls, closing foramen ovale
Umbilical arteries constrict
Ductus arteriosus constricts
Switch as left side becomes higher pressure than
Different types of surfactant
Surface active phospholipid
Phosphatidyl choline
Phosphatidyl glycerol
Phosphatidyl inositol
Surfactant proteins A, B, C, D
When is surfactant produced and what does it do?
Virtual abolition of surface tension
Allows homogeneous aeration
Allows maintenance of functional residual capacity
Produced by Type 2 Pneumocytes from 34 weeks gestation
Dramatic increase in 2 weeks prior to birth
What causes a surfactant deficiency?
Prematurity
+ Asphyxia
+ Cold
+ Stress
+ Twins
Respiratory Distress Syndrome
Loss of lung volume
Non-compliant lungs
Uneven aeration
How to treat surfactant deficiency?
Distension of alveoli
Steroids
Adrenaline
What is Pulmonary Interstitial Emphysema?
Lung cysts rupture and let air out of the ruptured alveoli into the interstitium between the alveoli and capillary
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 if needed
