CVR Flashcards
What is the lifespan of an RBC?
100 -> 120 days.
How big is an RBC?
~ 7 x 2.2 um
What is the function of an RBC?
O2/CO2 carrier.
Describe some problems with RBCs.
- Anaemia-hypoxia.
- Polycythaemia (PRV)-
thrombosis. - Sickle cell disease.
Give corpuscular examples of anaemia.
Membrane, haemoglobin, and enzymes.
Give extra-corpuscular examples of anaemia.
Reduced production, increased destruction/loss, and redistribution.
What is the lifespan of a WBC?
Normally hours or days, some for years.
How big is a WBC?
7 -> 30 um (bigger than RBCs).
What is the function of a WBC?
Non-specific and specific immunity.
List some WBC abnormalities.
- Neutrophil leukocytosis/
neutropenia. - Eosinophilia/ eosinopenia.
- Basophilia.
- Monocytosis/
monocytopenia. - Lymphocytosis/
lymphopenia. - Myeloid malignancies.
- Lymphoid/ plasma cell
malignancies.
What is GVHD?
Graft-versus-host-disease.
WBCs in donated stem cells/bone marrow attack your own body cells, as it sees them as foreign.
What are BiTE molecules?
Molecules designed to form a bridge between cancer cells and cytotoxic T cells. Cytotoxic T cells are WBCs that can destroy other cells that pose a threat.
What is CAR-T therapy?
Chimeric antigen receptor T-cell therapy. Reprogramming patients T-cells to enable them to locate and destroy cancer cells more effectively.
What is the difference between humoral and cellular immunity?
B cells activate humoral, T cells activate cellular.
Humoral produces antigen specific antibodies, cellular does not depend on antibodies.
Describe lymphocyte maturation.
B cells mature in bone marrow.
T cells mature in thymus.
Mature cells enter the circulation and peripheral lymphoid organs surveying for pathogens or tumours.
What is haematopoiesis?
The formation of a wide variety of blood cellular components.
What is the lifespan of a platelet?
7 -> 10 days.
How big is a platelet?
2 -> 5 um.
Where are platelets found?
In bone-marrow blood.
What is the function of platelets?
Essential for blood clotting.
What makes up the structure of platelets?
Plasma membrane, cytoskeleton, dense tubular system, secretory granules (alpha, dense, lysosome, peroxisome).
What are the platelet activation stages?
Initiation, propagation, and stabilisation.
What are the two different types of bleeding?
- Platelet type: thrombocytopenia /thrombocy topathy.
- Haemophilia type : factor deficiency.
Describe the presentation/history of platelet type bleeding.
- History of skin and mucosal bleeding (gastrointestinal and genitourinary).
- Early post procedural bleeding (minutes).
- Petechial rash.
What can cause platelet-type bleeding?
- Medication reactions.
- Liver disease.
- Renal disease.
Describe the presentation/history of haemophilia-type bleeding.
- History of muscle/joint bleeding.
- Late post procedural bleeding (hours/days).
- Large suffusions, haematomas.
What can cause haemophilia type bleeding?
- Haemophilia A, B, C.
What is plasma? What % of blood volume can be attributed to it?
- Liquid component of blood, holding cellular elements in suspension.
- 55% of total blood volume.
What is plasma made up of?
- Water (up to 95%).
- Electrolytes.
- O2, CO2.
- Proteins: albumin, globulins, coagulation factors, transport proteins.
What is blood serum?
Blood plasma without clotting factors.
How is cryoprecipitate prepared?
FFP is thawed to 4 degrees celsius, the fibrinogen rich layer is skimmed off, and the precipitate is collected.
What does every cell in our body need?
- To be bathed in fluid.
- To be within 2mm of a source of oxygenation.
What are the four major types of blood group? What is the name of a rare variant?
- A, B, AB, O.
- Bombay subtype.
How many antigens are on the surface of an erythrocyte? How many of these are blood group antigens?
- Millions of antigens.
- Several hundred are blood group antigens.
Which blood group is the universal recipient?
AB.
Which blood group is the universal donor?
O.
What ages and what weights can donate blood?
17 -> 65 year olds.
Body weight: 50->158kg.
What are temporary blood transfusion exclusion criteria?
- Travel.
- Tattoos/body piercings.
- Lifestyle.
What are permanent blood transfusion exclusion criteria?
- Certain diseases.
- Received blood products or organ/tissue transplant since 1980.
- Notified at risk of vCJD.
Which tests are mandatory in blood donation?
- Hep B.
- Hep C.
- Hep E.
- HIV.
- Syphilis.
- HTLV.
- Groups and antibodies.
Which tests are sometimes done before blood donation?
- CMV.
- West Nile Virus.
- Malaria.
- Typanosoma.
How do antibodies against other ABO antigens occur?
Naturally, without ever being exposed to the other blood types - potently antigenic system.
Where does coding for ABO antigens occur? How?
- By genes on chromosome 9, one gene has 2 alleles: A and B (co-dominant), a different gene has just O alleles (recessive).
- The genes code for enzymes that produce the sugars that differentiate the blood groups.
What determines an individuals blood group?
Antigens on RBCs.
What is the similarity and difference between the ABO antigens?
- All have common H antigen.
- Different groups have different sugars added to the H antigen.
When do we develop ABO antibodies?
- First true ABO antibodies start developing at ~ 3 months old.
- Infants less than 3 months old have only maternal antibodies.
- Maximum concentration of ABO antibodies occurs between 5 -> 10 years old.
- Decreases with age.
- Mix of IgG and IgM types.
How many different Rh antigens are there?
More than 45.
Where does coding for Rh antigens occur? How?
- Genes on chromosome 1.
- RHD gene codes for Rh D
- RHCE gene codes for Rh C and Rh E.
How do antibodies against other Rh antigens occur?
Only have antibodies if exposed to the opposite type.
How does haemolytic diseases of the fetus and newborn (HDFN) occur?
- Rh+ father and Rh- mother.
- Develop anti-Rh antibodies in mothers bloodstream.
- Attacks second child if they are Rh+.
- Severe fetal anaemia and hydrops fetalis.
How is blood cross-matched?
Mix recipient serum with donor RBCs to check for either an exact match (A+ for A+) or compatible blood (O+/- for A+)
What is the difference between direct and indirect antiglobulin tests?
- Indirect = detects antibodies in patients serum.
- Direct = detects antibodies on patients RBCs.
When giving blood, what can you donate?
- Whole blood.
- Apheresis removes and externally separates blood - plasma, platelets.
Describe the storage of RBCs.
- Stored at 4 degrees celsius.
- Shelf life = 35 days.
- Some units irradiated to eliminate risk of GVHD.
Describe the storage of platelets.
- Stored at 22 degrees celsius.
- Shelf life = 7 days
- ## Most units pooled from 4 donations, some single-donor units.
Describe FFP.
- From whole donations of apheresis.
- Patients born > 1996 can only receive FFP from low vCJD risk (not UK).
- Single donor packs have variable amounts of clotting factors, pooled donations can be more standardised.
Describe immunoglobulin.
- Made from large pools of donor plasma.
- Normal and specific IVIg.
Describe granulocytes.
- Used very rarely.
- Effectiveness = controversial.
- Must be irradiated to kill T cells.
Describe factor concentrates.
- Single factor concentrates.
- Prothrombin complex concentrates.
What is an indication for RBCs?
Severe anaemia.
What is an indication for platelets?
Thrombocytopaenia.
What are 2 indications for FFP?
- Multiple clotting factor deficiencies and bleeding. (DIC)
- Some single clotting factor deficiencies where no concentrate available.
When is it appropriate to use cryoprecipitate?
- DIC with bleeding.
- Massive transfusion.
When is normal IVIg used?
To treat immune conditions e.g. ITP.
Give an example of use of a specific IVIg.
Anti D immunoglobulin used in pregnancy to neutralise any RhD positive antigens.
When is it appropriate to use granulocytes?
With severely neutropaenic patients with life threatening bacterial infections.
Give an example of the use of a single factor concentrate?
Factor VIII for severe haemophilia A.
Give an example of the use of prothrombin complex concentrates.
The rapid reversal of warfarin.
How can you provide the safe delivery of blood?
- Patient identification.
- 2 sample rule.
- Hand-written patient details.
- Blood selected and serologically matched.
- Mistakes can happen.
Give 3 examples of ways to avoid blood transfusion.
- Cell salvage.
- IV iron if severely iron deficient.
- Some people can tolerate lower haemoglobin concentrations.
Describe an ABO incompatability reaction.
Rapid intravascular haemolysis -> cytokine release -> acute kidney failure and shock -> DIC -> rapidly fatal.
Can be acute or delayed.
How can you treat/manage an ABO incompatibility reaction?
Stop transfusion immediately.
Send bloods to the lab for further typing.
Report to SHOT.
Describe a bacterial contamination reaction.
Most common with platelets.
Symptoms start soon after transfusion begins, and include fevers, hypotension, shock, and rigors.
Abnormal colouration may be seen in the unit.
How can you treat/manage a bacterial contamination reaction?
Stop transfusion immediately.
Send bloods to the lab for further typing.
Treat the infection.
Describe a transfusion-related lung injury (TRALI).
Inflammation causes plasma to leak into alveoli.
Symptoms include SOB, cough with frothy sputum, hypotension and fever.
Describe a transfusion-associated circulatory overload (TACO) reaction.
Acute/worsening pulmonary oedema within 6hrs of transfusion.
Older patients = higher risk.
Symptoms include respiratory distress, evidence of positive fluid balance, and raised blood pressure.
What is the importance of platelets in disease?
Platelets contribute to thrombosis, having a central role in arterial thrombosis which can lead to heart attack, stroke, or sudden death.
What is thrombosis?
The formation of a clot (thrombus) inside a blood vessel.
What happens to platelets when they are activated? What does this do and allow?
- They change shape, from smooth discoid -> spiculated with pseudopodia.
- Increases surface area, therefore increasing possibility of cell-cell interactions.
- They activate GP IIb/IIIa receptors to allow platelet aggregation via fibrinogen cross-linking.
Where are glycoprotein IIb/IIIa receptors found?
On the surface of platelets. 50,000 -> 100,000 copies on resting platelet.
How does platelet activation affect GPIIb/IIIa receptors?
- Increases number of receptors.
- Increases receptors’ affinity for fibrinogen.
- Fibrinogen links receptors, binding platelets together (platelet aggregation).
How do platelets/ platelet receptors respond to atherosclerotic plaque rupture of a vessel?
- Collagen receptors on the platelet bind to exposed subendothelial collagen.
- GP IIb/IIIa also binds to von Willebrand factor which is attached to collagen.
- Soluble agonists are also released and activate platelets.
What role does aspirin play involving platelets? How does this work?
Inhibits the thromboxane A2 amplification pathway.
Low-dose aspirin inhibits COX-1 -> inhibition platelet activation.
High-dose aspirin inhibits COX-1 and 2 -> inhibition of inflammatory pathways.
Which G proteins are linked to platelet P2Y receptors?
P2Y1 linked to Gq protein.
P2Y12 linked to Gi protein.
What binds to and activates platelet P2Y receptors?
Adenosine diphosphate (ADP).
What does the activation of P2Y1 do?
Causes platelet activation and therefore platelet aggregation.
What does the activation of P2Y12 do?
Amplifies platelet activation and aggregation, and the release of granules.
Describe the platelet activation and amplification loop.
ADP -> activates P2Y receptors -> platelet activation.
Dense granules from the platelet -> ADP -> activates P2Y receptors -> further platelet activation.
Activation of GPIIb/IIIa also amplifies platelet activation.
How is thrombin involved in platelet activation?
Thrombin activates protease-activated receptors (PARs) on platelets -> platelet activation and release of ADP -> amplifies activation through P2Y receptors.
What does platelet procoagulant activity produce and cause?
Drives thrombin generation, creating a thrombin-mediated amplification loop increased platelet activation, whilst also linking with coagulation.
How are platelet-fibrin clots formed?
Platelets aggregate, thrombin cleaves fibrinogen to form fibrin strands, that form a mesh with the aggregated platelets creating a clot, and trapping RBCs.
Describe the role of the fibrinolytic system.
To maintain homeostasis and avoid thrombosis.
What is the function of platelet alpha granules?
Released during platelet activation, have coagulation factors, but also inflammatory mediators. Also mediate the expression of surface P-selectin.
How can platelets interact with leukocytes, and what does this interaction lead to?
Leukocytes have a PSGL-1 counter receptor, allowing a platelet to bind and link to a leukocyte using P-selectin. This connection contributes to both the thrombotic response and the inflammatory response.
What are the typical setting on an ECG?
Speed = 25mm/sec
Voltage = 10mm/mV
How do you calculate rate (bpm) from an ECG?
Either:
300/(no. of large squares between cardiac cycles)
OR
(Cycles in 10 secs) x 6
What does an ECG measure/show?
The net change in voltage in the whole heart.
What does the P wave on an ECG represent?
Atrial depolarisation.
What does the QRS complex on an ECG represent?
Ventricular depolarisation.
What does the T wave on an ECG represent?
Ventricular repolarisation.
Describe atrial fibrillation.
- Random atrial activity.
- Random ventricular capture.
- Irregularly irregular rhythm.
Describe atrial flutter.
- Organised atrial activity ~300/min.
- Ventricular capture at ratio to atrial rate (usually 2:1, so 150bpm).
- Usually regular.
- Can be irregular if ratio varies.
What are the normal values for the PR interval?
120 -> 200ms (3 -> 5 small squares).
What does a prolonged PR interval suggest?
Conduction disease (heart block).
What are the normal values of the QRS complex width?
Less than 120ms (less than 3 small squares).
What does a prolonged QRS interval width suggest?
Issue in conduction system -> bundle branch block, when one ventricle is depolarising faster than the other.
What are the normal values for the QT interval?
Men: 350 -> 440 ms.
Women: 350 -> 460ms.
What does a prolonged QT interval suggest? What can cause a prolonged QT interval?
Serious arrhythmia.
Drugs (most common) and genetic predisposition.
How can you identify left axis deviation on an ECG?
Lead I = positive.
Lead II = negative.
(L)eaving each other = (L)eft axis deviation.
How can you identify right axis deviation on an ECG?
Lead I = negative.
Lead II = positive.
(R)eaching for each other = (R)ight axis deviation.
Describe leads I and II on a normal axis.
Both positive.
What does ST elevation suggest?
Blocked coronary artery, can tell which by which leads are affected on the ECG.
Which limb leads are involved with the lateral wall of the LV, which artery are they therefore involved with?
aVl and lead I.
Circumflex artery.
Which limb leads are involved with the inferior wall of the LV, which artery are they therefore involved with?
Leads II, aVF, and III.
Right coronary artery.
Which chest leads are involved with the septal wall of the LV?
V1 and V2.
Which chest leads are involved with the anterior wall of the LV?
V3 and V4.
Which chest leads are involved with the lateral wall of the LV?
V5 and V6.
Which are the bipolar limb leads? How do they work?
- Leads I, II, and III.
- Measure potential difference between two electrodes (one designated +ve and the other -ve).
Which are the unipolar limb leads? How do they work?
- aVL, aVF, aVR.
- Measures the potential difference between a +ve electrode, and a -ve combined reference electrode.
- AKA augmented leads.
What are the names of the chest leads? Are these unipolar or bipolar?
- V1, 2, 3, 4, 5 and 6.
- Unipolar.
How are cardiac muscle cells connected?
Intercalated discs that contain gap junctions, adhering junctions, and desmosomes.
What is the role of gap junctions in cardiac muscle?
Allow direct communication between cells, for example if iron changes in one cell, iron will change in the next.
What is the role of desmosomes in cardiac muscle?
Physical link between cardiac muscle cells, ensure that they work together and contract as a unit.
What is the resting membrane potential of the heart?
Around -90mV.
Explain negative membrane potential.
- High K+ conc inside.
- Low Na+ and Ca2+ conc inside.
- K+ diffuse out (high -> low).
- Anions cannot follow.
- Excess of anions inside = -ve membrane potential.
What is phase 0 of cardiac action potential?
Depolarisation, Na+ in.
What is phase 1 of cardiac action potential?
Initial repolarisation, K+ out.
What is phase 2 of cardiac action potential?
Plateau, Ca2+ in, K+ out.
What is phase 3 of cardiac action potential?
Repolarisation, K+ out.
What is phase 4 of cardiac action potential?
Resting potential, 2K+ in for every 3Na+ out. Against their gradients, therefore requires active transport and ATPase for energy,
What is the Nernst Equation used for?
To work out membrane potential under non-standard conditions.
What is action potential propagation?
Wave of depolarisation in which action potential spreads across membrane via gap junctions, kicking off sodium channels through the whole myocardium.
What is the point of cardiac action potential?
- Calcium!!!
- Contraction of heart muscle requires appropriately-timed delivery of Ca2+ ions to the cytoplasm.
Describe calcium in cardiac muscle cells.
- Excitation-contraction coupling.
- Calcium enters, triggers release of more from the sarcoplasmic reticulum.
- Calcium tightly regulated, kept in SR.
- Conc in cytoplasm usually low, high in SR.
- Ryanodine receptors activated by calcium influx of cytoplasm, allow calcium to leak out of SR.
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 cardiac muscle contraction.
Describe the sino-atrial node’s cardiac action potential phases.
- Upsloping phase 4.
- Less rapid phase 0.
- No discernable phase 1 or 2.
What is the velocity of conduction in the specialised fibres of the hearts conduction system?
Atrial and ventricular muscle fibres = 0.3 -> 0.5m/s.
Purkinje fibres = 4m/s.
What is the pacemaker of the heart? Why? What would happen is this was lost?
- Sinoatrial node as it has the fastest leak of current between impulses to trigger depolarisation.
- Heart beat would still occur if lost as all cardiac tissue leaks some charge that eventually triggers depolarisation, but it would be unreliable and slow.
- Next fastest will take over e.g. atrioventricular node.
What is sympathetic stimulation of the heart controlled by?
- Adrenaline and noradrenaline, and Type 1 beta adrenoreceptors.
- Increases adenylyl cylcase -> increases cAMP.
What does increased sympathetic stimulation of the heart cause?
- Increased heart rate (up to 180->250bpm).
- Increased force of contraction.
- Increase in cardiac output (by up to 200%).
What does decreased sympathetic stimulation of the heart cause?
- Decreased heart rate.
- Decreased force of contraction.
- Decreased cardiac output (by up to 30%).
What is parasympathetic stimulation of the heart controlled by?
- Acetylcholine
- M2 receptors inhibit release of acetylcholine.
What does increased parasympathetic stimulation of the heart cause?
- Decreased heart rate (temporarily pause or as low as 30->40 bpm).
- Decreased force of contraction.
- Decreased cardiac output (by up to 50%).
What does decreased parasympathetic stimulation of the heart cause?
- Increased heart rate.
What is the refractory period of myocardial contraction?
A period of time during which a cell is incapable of repeating an action potential.
What are the 3 states of sodium channels involved in the refractory period and myocardial contraction?
- Open and activatable.
- Closed and inactivatable.
- Closed but activatable (resting).
What is the normal refractory period of ventricles and atria?
Approx 0.25s for ventricles, less for atria.
What is the purpose of the refractory period of myocardial contraction?
Prevents excessively frequent contraction, and allows time for the heart to fill.
What is the absolute refractory period?
Period in which another impulse cannot be stimulated, so another depolarisation cannot occur.
What is the relative refractory period?
Period in which a high stimulus is needed to trigger another impulse, so it is difficult to get another depolarisation to occur.
What are the main components of the myocardium?
- Contractile tissue.
- Connective tissue.
- Fibrous frame.
- Specialised conduction system.
What does the cardiac myocyte do?
Pumping action of the heart is dependent on interactions between contractile proteins in muscular walls. These proteins are activated by excitation-contraction coupling.
Describe the working myocardial cell.
- Filled with cross-striated myofibrils.
- Plasma membrane regulated E-C coupling and relaxation.
- Plasma membrane produced part of T-tubule.
- Plasma membrane separates cytosol from extra-cellular space and sarcoplasmic reticulum.
- Mitochondria: ATP, aerobic metabolism, oxidative phosphorylation.
Describe myocardial metabolism.
Aerobic: relies on free fatty acids (efficient energy production).
Anaerobic: during hypoxia, no free fatty acids, relies on glucose metabolism.
What is the A-band of a myocardial working cell?
Region of the sarcomere occupied by thick filaments.
What is the I-band of a myocardial working cell?
Region occupied only by thin filaments that extend towards the centre of the sarcomere from the Z-lines. Also contain tropomyosin and troponins.
What are the Z-lines of a myocardial working cell?
Bisect each I-band.
What is a sarcomere?
- The functional basic unit of contractile apparatus.
- Defined as the region between a pair of Z-lines.
- Contains two half I-bands, and one A-band.
What is the sarcoplasmic reticulum?
Membrane network surrounding contractile proteins, consists of the sarcotubular network and the subsarcolemmal cisternae.
What is the sarcolemma?
The plasma membrane of muscle.
What is the transverse tubular system (T-tubule)?
Lined by a membrane continuous with the sarcolemma, so the lumen carries extracellular space towards the centre of the myocardial cell.
What are the important contractile proteins of the heart?
- Myosin.
- Actin.
- Tropomyosin.
- Troponin (I, T, and C).
Describe myosin.
- Thick filament.
- 2 heavy chains (responsible for dual heads).
- 4 light chains.
- Heads are perpendicular at rest, join with actin, bend towards centre of sarcomere during contraction.
- ATPase in head.
- Alpha and beta myosin.
Describe actin.
- Thin filament.
- Globular protein (G-actin).
- Linear polymers of globular proteins (F-actin).
- Double-stranded macromolecular helical structure.
- Has a myosin binding site, partially covered by tropomyosin and held in place by troponin
Describe tropomyosin.
- Thin filament.
- Elongated molecule, made of two helical peptide chains.
- Wire like structure occupying each of the longitudinal grooves between two actin strands.
- Regulates interactions between the other three contractile proteins.
Describe troponin.
- Thin filament.
- 3 types: I,T, and C.
- I: inhibits actin and myosin interaction.
- T: binds troponin complex to tropomyosin.
- C: high affinity calcium binding sites, signalling contraction, also drives troponin I away from actin, allowing its interaction with myosin.
When is the myocardium normally perfused?
During diastole, via the coronary arteries.
Describe physiologic systole.
Isovolumetric contraction and ejection.
Describe cardiologic systole.
From M1 -> A2, between 1st and 2nd heart sounds.
Describe physiologic diastole.
Reduced ejection, isovolumetric relaxation, and filling phases.
Describe cardiologic diastole.
A2 -> M1 interval.
Describe preload.
Amount of blood present in ventricles just before ventricular contraction has started.
Describe afterload.
The pressure against which you heart has to contract to eject the blood.
What is Starling’s Law (1918)?
The greater the stretch on the myocardium before systole, the stronger the ventricular contraction.
Define force-length interaction.
Force produced by skeletal muscle declines when the sarcomere is less than optimal length.
Define contractility.
The state of the heart which enables it to increase its contraction velocity, to achieve higher pressure, when contractility is increased (independent of load).
Define elasticity.
The myocardial ability to recover its normal shape after removal of systolic stress.
Define compliance.
The relationship between the change in stress and the resultant strain. (dP/dV).
Define diastolic distensibility.
Pressure required to fill the ventricle to the same diastolic volume.
What are the components of the circulation?
- Anatomy.
- Blood.
- Pressure (CO).
- Volume.
- Flow.
Which structures hold the greatest proportion of blood volume in the circulation?
Small veins and venules (43%).
Describe arteries.
- Low resistance conduits.
- Elastic.
- Cushion systole.
- Maintain blood flow -> organs during diastole.
Describe arterioles.
- Principle site of vascular flow resistance.
- TPR (total peripheral resistance), basically 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.
- Total peripheral resistance, basically arteriolar resistance.
- Vascular smooth muscle (VSM) determines radius.
- VSM contracts: radius decreases, resistance increases, flow decreases.
- VSM relaxes: radius increases, resistance decreases, flow increases.
- Vasoconstriction and vasodilation.
- VSM never completely relaxed = myogenic tone.
Describe capillaries.
- 40,000km and large area = slow flow.
- Allows time for nutrient/waste exchange.
- Plasma or interstitial fluid flow determines distribution of ECF between compartments.
- Flow determined by arteriolar resistance and the number of open pre-capillary sphincters.
Describe veins.
- Low resistance conduits.
- Compliant.
- Capacitance vessels.
- Valves aid venous return against gravity.
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Describe lymphatics.
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Equation for blood pressure:
Blood pressure = CO x TPR
(cardiac output x total peripheral resistance).
Equation for cardiac output:
CO = HR x SV
(heart rate x stroke volume).
Equation for pulse pressure:
PP = systolic - diastolic pressure
Equation for mean arterial pressure:
MAP = diastolic pressure = 1/3 pulse pressure
Describe systolic BP.
Ventricles contract, highest BP (100 -> 150 mmHg).
Describe diastolic BP.
Ventricles relax, lowest BP (not 0, 60 -> 90 mmHg).
How is BP measured?
Using a sphygmomanometer on the brachial artery as it is convenient to compress, and level to the heart.
Describe the basics of Korotkoff sounds.
0) BP greater than systolic, no flow = no sounds.
1) Systolic, high velocity = sounds.
2) Between S and D = thud.
3) Diastolic = sounds disappear.
What is autoregulation?
The intrinsic ability of a structure to maintain constant blood flow despite perfusion pressure changes.
Which organs/systems have excellent autoregulation?
- Renal.
- Cerebral.
- Coronary.
Which organs/systems have moderate autoregulation?
- Skeletal muscle.
- Splanchnic.
Which organs/systems have poor autoregulation?
- Cutaneous.
In which scenarios are extrinsic and intrinsic control of blood flow dominant?
- Brain and heart: intrinsic.
- Skin: extrinsic.
Skeletal: rest = extrinsic, exercise = intrinsic.
In local control of blood flow, name 2 vasoconstrictors:
- Endothelin-1.
- Internal blood pressure.
In local control of blood flow, name 8 vasodilators:
- Hypoxia.
- Adenosine.
- Bradykinin.
- NO.
- K+.
- CO2.
- H+.
- Tissue breakdown products.
Describe the blood flow control functions of endothelium.
- Essential for circulation control.
- Rubbing off endothelium -> constriction.
- Nitric oxide released = vasodilator.
- Prostacyclin released = vasodilator.
- Endothelin released = potent vasoconstrictor.
Name 3 circulating (hormonal) vasoconstrictors:
- Epinephrine (skin).
- Angiotensin II.
- Vasopressin.
Name 2 circulating (hormonal) vasodilators:
- Epinephrine (muscle).
- Atrial natriuretic peptide (ANP).
Where are primary/arterial baroreceptors found?
- Carotid sinus.
- Aortic arch.
Where are secondary/cardiopulmonar baroreceptors found?
- Vein.
- Myocardium.
- Pulmonary vessels.
Describe the baroreceptor reflex in regulating blood pressure.
Increased BP -> increased baroreceptor activity -> increased impulse firing -> increased PSNS and decreased SNS -> decrease in CO, and vasodilation to reduce BP.
Vice versa for BP decrease.
What are the main neural influences on the medulla?
- Baroreceptors.
- Chemoreceptors.
- Hypothalamus.
- Cerebral cortex.
- Skin.
- Changes in blood [O2] and [CO2].
What effects on BP and HR occur when different parts of the hypothalamus are stimulated?
- Anterior stimulated -> decreased BP and HR.
- Posterolateral stimulated -> increased BP and HR.
What important role does the hypothalamus have regarding skin blood flow?
Regulates skin blood flow in response to temperature.
What effect does stimulation of the cerebral cortex have on blood pressure?
Stimulation -> vasoconstriction -> increased BP.
What effect can emotion have on blood pressure (via the cerebral cortex)?
Emotion -> vasodilation and depressor responses e.g. blushing and fainting.
Can be direct or mediated via medulla.
How do chemoreceptors affect blood pressure?
- Chemosensitive regions in medulla.
- Increased PaCO2 -> vasconstriction -> increased BP.
- Opposite for decreased PaCO2.
- Similar changes occur with pH level changes.
What is responsible for short term BP regulation?
Baroreceptors.
What are the physiological relevancies of control of the circulation?
- Cold.
- Standing up.
- Running.
- Lifting.
- Injury.
- Blood loss.
Describe the intrinsic pathway of the coagulation cascade.
- Mainly within blood vessel by breakdown of wall and release of collagen.
- Collagen = primary activator of factor XII -> activates factor XI -> factor IX -> VIII -> X.
- Positive feedback loops within.
Describe the extrinsic pathway of the coagulation cascade.
- Tissue factor released at site of injury, combines with inactivated factor VII, activating it.
- Activated factor VII -> activates factor X.
What is the purpose of the plasminogen pathway n the coagulation cascade?
To maintain balance.
Name 4 functions of the nose:
- Temperature of inspired air.
- Humidity.
- Filtration.
- Defence.
Describe the area from the anterior nares to the vestibule.
- Skin lined.
- Stiff hairs.
Where are turbinates of the nasal cavity found? How many are there? What do they do?
- On the lateral nasal wall.
- 3 large shelves effectively.
- Increase SA.
What are the three turbinates called? What lies beneath each of these?
- Superior, middle, and inferior turbinates.
- Superior, middle, and inferior meatuses lie beneath respectively.
What are the paranasal sinuses? How many are there? What are they called?
- Pneumatised areas of the frontal, maxillary, ethmoid and sphenoid bones.
- 4: named after their bones.
How are the paranasal sinuses arranged?
- In pairs.
- Not necessarily symmetrical.
Describe how the paranasal sinuses are related to the nasal cavity.
- Evagination of mucous membrane from nasal cavity.
- Extension of mucosa, like a ‘room’ of nasal cavity with the same lining.
Describe the nerve supply of the frontal sinuses.
Ophthalmic division of the trigeminal nerve (CN V).
Describe the nerve supply of the ethmoid sinuses.
Ophthalmic and maxillary divisions of trigeminal nerve (CN V).
Describe the nerve supply of the sphenoid sinuses.
Ophthalmic division of trigeminal nerve (CN V).
Describe the location of the frontal sinuses.
- Within frontal bone.
- Midline septum.
- Over orbit and superciliary arch.
Describe the location of the maxillary sinuses.
- Within body of the maxilla.
- Pyramidal shape:
- Base = lateral wall of nose.
- Apex = zygomatic process of the maxilla.
- Roof = floor of orbit.
- Floor = alveolar process.
Describe the location of the ethmoid sinuses.
- Between the eyes.
- Labyrinth of air cells/pockets, not a single space.
Describe the location of the sphenoid sinuses.
- Medial to the cavernous sinus.
- Very close to carotid artery, CN III, IV, V, and VI.
- Inferior to optic canal, dura, and pituitary gland.
What is the function of the larynx?
- Valvular function.
- Prevents liquids and food from entering the lungs.
How many cartilages make up the larynx? How many are single, how many are paired?
- 9 cartilages.
- 3 single.
- 3 pairs.
What are the 3 single cartilages of the larynx called?
- Epiglottis.
- Thyroid.
- Cricoid.
What are the 3 pairs of cartilages of the larynx called?
- Cuneiform.
- Corniculate.
- Arytenoid.
Which cranial nerve is responsible for innervation of the larynx? What are the names of its branches responsible?
- The vagus nerve (CN X).
- Superior laryngeal nerve.
- Recurrent laryngeal nerve.
Describe how the superior laryngeal nerve innervates the larynx.
- Divides into internal and external.
- Internal brings sensory innervation to the larynx.
- External innervates only the cricothyroid muscle.
Describe how the recurrent laryngeal nerve innervates the larynx.
- Innervates all muscles except cricothyroid.
- Divides into left and right branches.
How much gas exchange area is there per lung?
20 metres squared.
Where is the trachea found?
- Commences at cricoid cartilage.
- From larynx -> carina.
- Down the midline, slightly to the left.
Describe the structure of the trachea.
- C-shaped cartilages,
- Trachealis muscle joins incomplete circuit.
- Pseudostratified ciliated columnar epithelium.
- Goblet cells.
What provides sensory innervation to the trachea?
Recurrent laryngeal nerve.
What provides the arterial supply of the trachea?
Inferior thyroid artery.
How many main bronchi are there? Where do they occur?
- 2: right and left.
- Sharp division at the carina.
Describe the right main bronchus.
- More vertically disposed than L main.
- 1-> 2.5cm long.
- More likely to aspirate into.
- Related to R pulmonary artery.
Describe the left main bronchus.
- Less vertically disposed than R main.
- 5cm long.
- Less likely to aspirate into.
- Related to aortic arch.
What do the lobar bronchi supply?
Right: upper, middle, and lower lobes.
Left: upper and lower lobes, and lingular.
What are the names of the right segmental bronchi?
- Upper lobe: apical, anterior, posterior.
- Middle lobe: medial and lateral.
- Lower lobe: apical, anterior, posterior, medial and lateral.
What are the names of the left segmental bronchi?
- Upper lobe: apico-posterior and inferior anterior.
- Lingular: superior and inferior.
- Lower lobe: apical, anterior, posterior, and lateral.
If you are listening to the back of the chest, which lobe/s of the lungs are you predominantly listening to?
The lower lobes.
If you are listening to the front of the chest, which lobe/s of the lungs are you predominantly listening to?
Upper and middle lobes.
As the bronchi continue to divide, what happens to the walls?
They become thinner.
What are the names of the 2 types of pleura?
Visceral and parietal.
Where can the visceral and parietal pleuras be found?
- Visceral: lung surface.
- Parietal: internal wall of chest.
Describe the pleura.
- Each a single cell layer.
- Pleural cavity with pleural fluid between them to maintain surface tension.
- Continuous with each other at the lung root.
What are the three type of host defence?
- Intrinsic.
- Innate.
- Acquired/adaptive.
Describe intrinsic host defences. Give an example.
- Always present.
- Physical and chemical.
- E.g. apoptosis.
Describe innate host defences. Give an example.
- Induced by infection.
- E.g. macrophages.
Describe acquired/adaptive host defences. Give an example.
- Tailored to a pathogen.
- T cells.
What do host defences in the respiratory tract rely on?
- Epithelium.
- Physical barriers (mucus).
- Products of the submucosal glands.
How does epithelium play a role in host defence?
- Epithelium = intrinsic physical barrier.
- Secreted molecules from epithelium = intrinsic chemical barrier.
- Secreted molecules from most/all epithelial cells include:
- Antiproteinases.
- Anti-fungal peptides.
- Anti-microbial peptides.
- Antiviral proteins.
- Opsins.
Describe airway mucus.
Viscoelastic gel containing:
- Water.
- Carbohydrates.
- Proteins.
- Lipids.
Describe the production of airway mucus.
Secretory product of mucous cells, both goblet cells of the epithelium, and submucosal glands.
How does airway mucus play a part in host defence?
Protects epithelium from foreign material and fluid loss.
How is mucus moved in the airways?
- By air flow and mucociliary clearance (via the mucociliary escalator).
- Cilia beat in directional waves to move mucus.
Describe coughing as a defence mechanism.
An expulsive reflex that protects the lungs and respiratory passages from foreign bodies.
What causes coughing?
- Irritants.
- Diseases/conditions.
- Infections.
- Can be voluntary of reflexive.
What are the 2 pathways of coughing as a defence reflex?
- Afferent limb: receptors within the sensory distribution of the trigeminal, glossopharyngeal, superior laryngeal, and vagus nerves.
- Efferent limb: recurrent laryngeal nerve, and the spinal nerves.
Describe sneezing as a defence mechanism.
The involuntary expulsion of air containing irritants from the nose.
What causes sneezing?
- Irritation of nasal mucosa.
- Excess fluid in the airway.
Describe epithelial repair.
Following an injury, airway epithelium can often effect a complete repair as it exhibits a level of functional plasticity in multiple cells.
What happens if there is an abnormal epithelial response to injury? Give examples.
- Epithelium repair does not happen as it should.
- This can cause lung diseases.
- Goblet cell metaplasia: airway epithelial cells differentiate -> mucin producing goblet cells.
- Obstructive lung disease: mucus plugs/inflammation blocking the airway, which can be fatal
Is all airway epithelium the same?
No, it is different in distinct regions to reflect the different functions needed.
Describe the pulmonary circulation.
- From right ventricle.
- Supplies the lungs with oxygenated blood.
- 100% of blood flow (4.5 -> 8L/min).
- Red cell transit time = 5 secs
- 280 million capillaries.
- 300 million alveoli.
- SA for gas exchange = 50 -> 100m squared.
Describes the bronchial circulation.
- Supplies the architecture of the lungs.
- 2% of left ventricular output.
Describe pulmonary arteries.
- Thin vessel walls.
- Minor muscularisation.
- No need for redistribution in their normal state.
Describe systemic arteries.
- Thick vessel walls.
- Significant muscularisation.
- Need for redistribution.
What causes the differences in pulmonary and systemic arteries?
- Pulmonary circulation has much lower pressure than systemic.
- LV sees higher pressure than RV.
Which area of the heart is being measured in pulmonary arterial wedge pressure?
The left atrium.
Give the equation for pressure based on Ohm’s Law:
Pressure = cardiac output x resistance.
Define Pouiseuille’s Law:
Resistance =
(8 x length x viscosity)/
(pi x r^4)
Which measurement of a vessel is important to resistance?
The radius.
What are the two ways to reduce pulmonary vascular resistance?
- Recruitment of closed vessels of the capillary bed.
- Distention of vessels.
What are 4 causes of hypoxaemia?
- Hypoventilation.
- Diffusion impairment.
- V/Q mismatch.
- Shunt.
Describe the 3 types of diffusion impairment and the effects of these.
- Gaseous diffusion impairment = pulmonary oedema.
- Membrane diffusion impairment = interstitial fibrosis.
- Blood diffusion impairment = anaemia.
- All of which can cause hypoxaemia.
Describe the pressures and perfusion of zone 1 of the lung.
PA > Pa > PV.
(Alveolar > arterial > venous).
No perfusion.
Describe the pressures and perfusion of zone 2 of the lung.
Pa > PA > PV.
(Arterial > alveolar > venous).
Some perfusion, increasing as you go down the zone.
Describe the pressures and perfusion of zone 3 of the lung.
Pa > PV > PA.
(Arterial > venous > alveolar).
Constant perfusion.
What is the trend of perfusion across the lung?
Increases down the lung with gravity.
What is the trend of ventilation across the lung?
Increased down the lung, less steep change than perfusion.
What is the ideal V/Q across the lung?
1.
Describe V/Q at the top of the lung.
- High V/Q.
- Wasted ventilation.
Describe V/Q at the bottom of the lung.
- Low V/Q.
- Wasted perfusion.
What is the average V/Q across the lung?
0.8.
Describe how V/Q mismatch can cause hypoxaemia.
Reduced ventilation caused by pneumonia or COPD -> low V/Q, as perfusion remains steady. This means some blood isn’t undergoing gas exchange -> hypoxaemia.
Describe how a shunt can cause hypoxaemia.
Complete blockage causing no ventilation such as a lobar collapse -> V/Q = 0. Blood isn’t undergoing gas exchange -> hypoxaemia.
What is shunting?
Large amount of blood bypassing the alveolar bed.
What are three types of shunting? Give examples.
Pulmonary:
- Complete lobar collapse.
- Arteriovenous malformation.
Intracardiac:
- Ventricular septal defect, Right -> left shunt. (Eisenmenger’s Syndrome).
Physiological:
- Bronchial arteries.
Describe the symptoms of Eisenmenger’s syndrome.
- Cyanosis.
- Clubbing.
- Erythrocytosis.
Describe hypoxic pulmonary vasoconstriction.
- Low alveolar oxygen -> pulmonary vasoconstriction.
- Redistributes blood away from poorly ventilated areas.
- Trying to maintain V/Q matching.
When is hypoxic pulmonary vasoconstriction a good/bad thing?
Good: in one area of the lung, maintains V/Q.
Bad = throughout the lung, increases resistance, meaning heart may not be able to handle pressure increase.
Describe partial reduced perfusion and it’s effect on V/Q.
Reduced perfusion due to peripheral pulmonary embolism -> high V/Q, as ventilation remains steady.
Describe dead space ventilation.
Complete blockage of pulmonary arterial perfusion due to central pulmonary embolism -> alveolar dead space -> V/Q = infinity, as ventilation remains steady.
How do pulmonary embolisms generally start?
As a clot in a vein in the leg.
What are two differential diagnoses for pulmonary embolism?
- Deep-vein thrombosis.
- Skin infection.
What are the 2 types of pulmonary embolism?
- Minor PE.
- Major PE.
What can we use to determine how prone an individual is to clots?
-Virchow’s Triad:
- Circulatory stasis.
- Endothelial injury.
- Hypercoagulable state.
Describe pulmonary hypertension.
- Increased pulmonary vascular resistance.
- Lumen becomes increasingly smaller.
- Afterload will increase significantly.
- Right ventricle becomes larger, left becomes much smaller.
Describe what a pulmonary arteriovenous malformation is.
- Direct connection between an artery and vein.
- Large amount of blood shunts through the lungs, without going near capillaries or alveoli, for example.
What are the 2 main dangers of pulmonary arteriovenous malformations?
- Low oxygen (hypoxaemia).
- Capillaries normally filter the blood for things such as small clots, as these are being shunted, clots could remain and cause issues elsewhere in the body.
What is FeNO/eNO? Explain it’s clinical significance.
- Simple measure of nitric oxide in exhaled breath.
- Measured in ppb.
- Not diagnostic, but generally increased in asthma.
- Reflects eosinophilic airway inflammation: high >50ppb, normal <25ppb.
What percentage of asthma is related to occupation?
15%.
Give 6 examples of high molecular allergens involved in asthma.
- Latex.
- Grain.
- Flour.
- Laboratory animals.
- Enzymes.
- Sea food.
Give 5 examples of low molecular allergens involved in asthma.
- Sterilising agents.
- Isocyanate paints.
- Metal working fluids.
- Chemicals.
- Metals.
What percentage of people have asthma worldwide?
5 -> 16%.
Wide variation between countries.
When was there an increased prevalence of asthma?
Second half of 20th century, now plateaued mostly.
Give 4 other influences on asthma than occupation.
- Infectious agents.
- Fungi.
- Pets.
- Air pollution.
What percentage of COPD is related to occupation?
Around 15%.
What is the main cause of COPD?
Tobacco smoking.
Give 5 occupational exposures that can cause COPD.
- Silica.
- Coal.
- Grain.
- Cotton.
- Cadmium.
Give 5 asbestos associated conditions.
- Pleural plaques.
- Pleural thickening.
- Benign pleural effusions.
- Asbestosis.
- Lung cancer.
What is hypersensitivity pneumonitis?
Inflammation of the alveoli within the lung, caused by hypersensitivity to inhaled agents.
Give 6 environmental influences for hypersensitivity pneumonitis.
- Farmers lung.
- Bird fanciers lung.
- Metal working fluids.
- Mouldy straw.
- Mould in saxophone.
- Hot tub lung.
Describe asthma in relation to genes.
- Runs in families.
- Children of asthmatic parents at greater risk.
- Not caused by a single mutation in one gene.
- Does not follow simple Mendelian inheritance.
Describe the possible future treatment of asthma.
- Personalised medicine.
- Individualise pharmacotherapy based on genetic polymorphisms.
- Certain drugs only administered to those likely to respond.
What is the most common lethal autosomal recessive genetic disorder in Caucasians?
Cystic fibrosis.
Describe the prevalence of cystic fibrosis in the UK.
More than 10,000 affected.
1/25 are carriers.
1/2500 births have CF.
Describe cystic fibrosis.
- Chronic genetic disease.
- Multi-organ involvement.
- Defect in long arm of chromosome 7, which codes for CFTR protein.
How many mutations of the CFTR gene have been identified? Which is the most common cause of CF?
- More than 1600 mutations identified.
- 90% within a panel of 70.
- F508del is most common mutation causing CF.
Describe how cystic fibrosis can be diagnosed.
- Genetic profile and neonatal screening (day 5 IRT).
- Clinical symptoms: frequent infections, malabsorption, and failure to thrive.
- Raised skin salt due to abnormal salt/chloride exchange.
At what age do most diagnoses of cystic fibrosis occur?
50% diagnosed by 6 months.
90% diagnosed by 8 years old.
Describe the pancreatic pathophysiology of cystic fibrosis.
- Blockage of exocrine ducts.
- Early activation of pancreatic enzymes.
- Eventual auto-destruction of exocrine pancreas.
Describe the intestinal pathophysiology of cystic fibrosis.
Bulky stools, causing intestinal blockage.
Describe the respiratory pathophysiology of cystic fibrosis.
- Mucus retention.
- Chronic infection.
- Inflammation, which destroys lung tissue.
How many different genotypic classifications are there of cystic fibrosis?
6, called class I -> class VI.
Different properties of CFTR mutation.
How can cystic fibrosis symptoms be prevented?
- Segregation.
- Surveillance (review every 3 months min.).
- Airway clearance - physio and exercise.
- Suppressing chronic infections.
- Bronchodilation.
- Anti-inflammatories.
- Vaccinations.
What are cystic fibrosis rescue antibiotics?
2 week course of IV antibiotics, at home or hospital.
What are some issues with frequent antibiotic use?
- Allergies.
- Renal impairment.
- Resistance.
- Access problems.
What is cystic fibrosis bacteriophage therapy?
Use of lytic phages (bacteria specific viruses) to kill infectious bacteria.
Give 2 examples of genotype directed therapies, and which class of mutation they target?
Ivacaftor in G551D = class III mutations.
Lumacaftor/Orkambi in F508del = class II mutation.
What are some challenges in treating cystic fibrosis?
- Adherence to treatment.
- High treatment burden.
- High cost.
- Allergies/intolerances.
- Different infectious organisms and their resistance to drugs.
What type of condition is alpha-1 antitrypsin deficiency?
Autosomal recessive disorder
What is the normal SERPINA1 gene phenotype in a healthy individual?
PiMM.
How many different mutations have been found of SERPINA1 gene?
80.
Which chromosome is the SERPINA1 gene forund on?
Chromosome 14.
What is the most harmful phenotype of SERPINA1? Which other phenotype has major disease associations?
PiZZ.
Both S and Z phenotypes have major disease associations
What is a possible consequence of alpha-1 antitrypsin deficiency?
PiZZ -> early onset emphysema and bronchiectasis.
What is the usual age of onset of asthma vs COPD?
Asthma = <50.
COPD = >35.
What is the usual smoking history of patients with asthma vs COPD?
Asthma = no clear aetiology.
COPD = >10 pack-years.
What is the usual disease course of asthma vs COPD?
Asthma = stable, with exacerbations.
COPD = progressive, with exacerbations.
What is the usual sputum production in asthma vs COPD?
Asthma = infrequent.
COPD = common in chronic bronchitis.
What is the usual spirometry with asthma vs COPD?
Asthma = likely to normalise with treatment.
COPD = may improve, but never normal.
What is the usual treatment response with asthma vs COPD?
Asthma = responds well.
COPD = less responsive.
What is ACOS?
Asthma and COPD Overlap Syndroe.
What are the two systems within the autonomic nervous system?
Parasympathetic system, and sympathetic system.
Describe the autonomic nervous systems general structure.
2 neurons, separated by the autonomic ganglion; pre- and post-ganglionic fibres.
Describe the parasympathetic nervous systems structure.
- Ganglion within/very close to effector organ/their target.
- Short post-ganglionic fibres.
Describe the sympathetic nervous systems structure.
- Ganglion is within a chain adjacent to the spinal cord.
- Long post-ganglionic fibres.
Describe parasympathetic bronchoconstriction.
- Vagus nerve neurons terminate in ganglia near airway wall.
- Short post-ganglionic fibres reach muscle and release acetylcholine.
- ACh acts on muscarinic receptors of M3 subtye on the muscle cells.
- Stimulates airway smooth muscle contraction.
Would stimulation or inhibition of the parasympathetic nervous system be beneficial in asthma and COPD?
Inhibition, as stimulation narrows the airway.
Which drugs can inhibit the parasympathetic systems effects on the airway? How?
Anti-muscarinics, which block the M3 receptors that ACh acts on to constrict the airway.
What are SAMAs? Give an example.
Short-acting muscarinic antagonists.
E.g. ipratropium bromide.
What are LAMAs? Give an example.
Long-acting muscarinic antagonists.
E.g. tiotropium.
Are SAMAs or LAMAs more widely used?
LAMAs, but SAMAs still used in high doses in nebulisers for severe asthma and COPD.
What do SAMAs do?
Inhaled treatment to relax airways in asthma and COPD.
What do LAMAs do?
Increased bronchodilation and relieve breathlessness in asthma and COPD. Seem to also reduce exacerbations and have other benefits,
Which nervous system is ‘fight or flight’?
Sympathetic.
Which nervous system is ‘rest and digest’?
Parasympathetic.
How does the sympathetic nervous system have an effect on the airways?
- Nerve fibres release noradrenaline, which activates adrenergic receptors.
- Two types of these receptors: alpha or beta.
- Mainly innervate blood vessels, but airway smooth muscle cells have beta adrenergic receptors.
- Activating beta2 receptors in airway smooth muscle cells causing muscle relaxation by activating adenylate cyclase, raising cyclic AMP.
What are SABAs? Give an example.
Short-acting beta2-agonists.
E.g. salbutamol.
What are LABAs? Give an example.
Long-acting beta2-agonists.
E.g. formoterol, salmeterol.
How are SABAs and/or LABAs usually given in asthma?
- Both given.
- With steroids.
How are SABAs and/or LABAs usually given in COPD?
- Often without steroids,
- Often with a LAMA.
What are the 3 main effects of beta2-agonists?
- Prevent bronchoconstriction.
- Acute rescue of bronchoconstriction.
- Reduce rates of exacerbations.
What are the 3 fundamentals of treatment of asthma or COPD?
Concordance with therapy = poor.
Inhaler education = key.
Device selection = vital.
What are the 3 main goals of treatment of asthma or COPD?
- Aim to improve patients control.
- Address important issues for patient.
- Maximum relief of symptoms for minimum side effects.
Describe the immediate management of an asthma attack.
- Oxygen is needed to maintain O2 sats 94 -> 98%.
- Salbutamol nebuliser 5mg.
- Ipratropium nebuliser 0.5mg.
- Prednisolone 30 -> 60mg (+/- hydrocortisone 200mg iv).
- Magnesium of aminophylline iv.
What are 6 adverse effects of beta-2 agonists?
- Raising cAMP may activate NA/K pump -> cellular influx of potassium.
- Tachycardia.
- Tremors.
- Cramps.
- Headache.
- Hyperglycaemia.
What is the role of the immune system?
To kill infection and heal tissues.
What can happen if there is unwanted or excessive activation of the immune system?
Healthy tissue can be damaged.
Describe the innate immune system.
- First line of defence.
- Immediate response.
- Phagocytes, NK cells, mast cells, basophils, eosinophils.
- E.g. sputum and cilia.
Describe the adaptive immune system.
- Often second line.
- Delayed response, often >4 days.
- B and T-lymphocytes.
- E.g. pus, swelling, and granuloma.
What are antibodies/ immunoglobulins produced by, and what do they do?
- Produced by B-lymphocytes.
- Neutralise or eliminate pathogens.
- May also cause disease.
What are the 5 types of antibody/immunoglobulin?
- IgM.
- IgG.
- IgE.
- IgA.
- IgD.
How many types of hypersensitivity are there?
4 (named type I, II, III, IV).
Describe type I HP. (Give mediators, timing, and examples).
Mediators: IgE antibodies.
Timing: immediate (within 1hr).
Examples: anaphylaxis and hayfever.
Describe type II HP. (Give mediators, timing, and examples).
Mediators: cytotoxic, antibodies bound to cell antigen.
Timing: hours to days.
Examples: transfusion reactions and Goodpastures (Anti GBM disease).
Describe type III HP. (Give mediators, timing, and examples).
Mediators: Deposition of immune complexes.
Timing: typically 7 -> 21 days.
Examples: hypersensitivity pneumonitis and lupus.
Describe type IV HP. (Give mediators, timing, and examples).
Mediators: T-cells (lymphocytes).
Timing: days to weeks/months.
Examples: tuberculosis, sarcoidosis, and Stevens-Johnson syndrome.
What is the predominant mediator in type I HP?
Histamine.
Which 2 antibodies are usually involved in type II HP?
IgG and IgM.
When are antigen-immunoglobulin complexes formed in type III HP?
On exposure to the allergen.
How long can a secondary reaction in type IV HP take?
2 -> 3 days.
Which type of HP requires primary sensitisation?
Type IV.
What are 5 consequences of T-cell hyperactivity?
- Diabetes.
- Thyroid disease.
- Hepatitis.
- Nephritis
- Life threatening pneumonitis.
(Any -itis really!).
What is dead space in ventilation?
Volume of air inspired not contributing to ventilation/gas exchange.
How much air do we inspire in a breath?
Around 500ml.
How much total dead space is there, how is this calculated?
Anatomic = approx. 150mls.
Alveolar = approx. 25 mls.
Physiological = anatomic + alveolar.
Therefore = approx. 175mls.
What can cause dead space?
- Air not reaching alveoli (anatomic).
- Air reaching alveoli, but alveoli is damaged or not perfusing properly (alveolar).
How much gas does the respiratory pump need to move per minute?
5 litres/minute.
How many capillaries are there per alveolus?
1000 capillaries per alveolus.
Does each erythrocyte only come into contact with one alveolus, or multiple alveoli?
Each may come into contact with multiple alveoli.
At rest, how far through the capillary is haemoglobin fully saturated?
25% through.
What 3 things can perfusion of capillaries depend on?
- Pulmonary artery pressure.
- Pulmonary venous pressure.
- Alveolar pressure.
Describe hypoxic pulmonary vasoconstriction.
- Blood seeks areas of oxygen.
- Therefore, would not perfuse alveoli without oxygen.
- Vasconstriction.
- Opposite of normal hypoxia, in which the systemic system causes vasodilation to increase oxygen to hypoxic area.
What are the four main acid-base disorders?
- Respiratory acidosis.
- Respiratory alkalosis.
- Metabolic acidosis.
- Metabolic alkalosis.
What is normal pH and why is this maintained? What system is crucial to this maintenance?
- Normal = 7.40 (7.36 -> 7.44).
- Maintained to ensure optimal function.
- Respiratory system crucial to maintenance.
What do these stand for:
TLC,
VC,
RV,
FRC?
TLC = total lung capacity.
VC = vital capacity.
RV = residual volume.
FRC = functional residual capacity.
What do these stand for:
FEV1,
FVC?
FEV1 = forced expiration volume in one second.
FVC = forced vital capacity.
What do these stand for:
PEF,
FEF25?
PEF = peak expiratory flow (single measure of highest flow during expiration).
FEF25 = flow at point when 25% of total volume to be exhaled has been exhaled.
What is the equation for TLC?
TLC = VC + RV.
How do you determine if an FEV1 is normal?
Compare to a predicted value; if 80% +, result is normal.
How do you determine is an FVC is normal?
Compare to a predicted value; if 80% +, result is normal.
At what point is the FEV1/FVC ratio considered abnormal? What does this suggest?
< 0.70.
Suggests airway obstruction.
What apparatus is used to measure FEV1 and FVC?
A spirometer.
Give one problem with spirometry,
It is effort dependent.
What is a problem with expiratory procedures measuring?
Doesn’t measure residual volume (RV).
Give 2 methods for measuring RV.
- Gas dilution.
- Body box (total body plethysmography).
Describe the gas dilution technique of measuring RV.
Measures all of the air in the lungs that communicates with the airways.
Won’t measure areas of non-communication.
Describe the total body plethysmography technique of measuring RV.
Measures all air, including air trapped in non-communicative areas.
Ask patients to pant against a closed shutter to produce change in box pressure proportionate to volume of air in the chest.
What is a TL CO test?
A gas transfer test, using carbon monoxide due to its high affinity for haemoglobin.
What does a TL CO test measure (6)?
The interaction of:
- Alveolar surface area.
- Alveolar capillary perfusion.
- Physical properties of the alveolar capillary interface.
- Capillary volume.
- Haemoglobin concentration.
- Reaction rate of carbon monoxide and haemoglobin.
Describe the TL CO tests administration and make-up.
Single 10 second breath-holding technique.
Breathed in substance is:
10% helium,
0.3% carbon monoxide,
21% oxygen,
68.7% nitrogen.
In asthma, what changes would we expect in:
FEV1,
FVC,
PEF,
TLC,
TL CO,
eNO?
FEV1 = normal or reduced.
FVC = normal.
PEF = typically variable.
TLC = normal or high.
TL CO = normal or elevated.
eNO = high.
In COPD, what changes would we expect in:
FEV1,
FVC,
PEF,
TLC,
TL CO,
eNO?
FEV1 = reduced significantly.
FVC = normal or reduced.
PEF = typically not variable.
TLC = normal or high.
TL CO = low.
eNO = normal.
In asbestosis, what changes would we expect in:
FEV1,
FVC,
PEF,
TLC,
TL CO,
eNO?
FEV1 = reduced significantly.
FVC = reduced significantly.
PEF = typically not variable.
TLC = reduced.
TLCO = low.
eNO = normal.
What would be the typical blood gases in asthma?
(PaO2, PaCO2, pH, and HCO3-).
PaO2 = normal.
PaCO2 = low.
pH = normal or elevated.
HCO3- = normal.
What would be the typical blood gases in COPD?
(PaO2, PaCO2, pH, and HCO3-).
PaO2 = low.
PaCO2 = low in type I, high in type II.
pH = normal.
HCO3- = may be elevated (if chronic acidosis).
What would be the typical blood gases in asbestosis?
(PaO2, PaCO2, pH, and HCO3-).
PaO2 = low.
PaCO2 = low.
pH = normal.
HCO3- = low.
What is asbestosis?
Pulmonary fibrosis due to asbestos.
What are the 3 requirements of respiration?
- Ensure haemoglobin is as close to full saturation with oxygen as possible.
- Efficient use of energy source.
- Regulate PACO2 carefully.
What are the two types of chemoreceptor?
Central chemoreceptors, and peripheral chemoreceptors.
Where can central chemoreceptors be found?
In the brainstem. at the pontomedullary junction.
Not within DRG/VRG complex.
Where can peripheral chemoreceptors be found?
In carotid bodies (bifurcation of common carotid, and CN IX afferents) and in aortic bodies (ascending aorta and CN X afferents).
Describe how central chemoreceptors are stimulated/triggered.
Sensitive to PaCO2.
- Blood-brain barrier = relatively impermeable to H+ and HCO3-.
- PaCO2 preferentially diffuses into CSF.
- Change in pH of CSF is detected (H+ is detected).
- This triggers chemoreceptors to cause ventilation.
Describe how peripheral chemoreceptors are stimulated/triggered.
Respond to reduced PaO2, also respond to PaCo2.
Carotid bodies also detect pH. Aortic bodies do not.
Which type of chemoreceptor can be desensitised over time by hypoxaemia?
Central chemoreceptors.
Which type of chemoreceptor has a greater impact on ventilation control?
Central chemoreceptors.
What are the 3 types of lung receptor?
- Pulmonary stretch receptors.
- ‘J’ (juxtacapillary) receptors.
- Irritant receptors.
Are lung receptors slow or fast-adapting?
A combination.
What do lung receptors do in relation to respiration?
Assist with lung volumes and responses to noxious inhaled agents.
Which two types of airway receptors can be found in the nose, nasopharynx and larynx?
Chemoreceptors and mechanoreceptors.
What do airway receptors in the nose, nasopharynx and larynx appear to sense and monitor?
Flow.
What do airway receptors in the pharynx appear to be activated by?
Swallowing.
Where is basic breathing rhythm generated?
Pons:
- Pnuemotaxis centre.
- Apneustic centre.
Medulla oblongata:
- Dorsal respiratory group (DRG).
- Ventral respiratory group (VRG).
When is the DRG predominantly active?
During inspiration.
When is the VRG predominantly active?
During both inspiration and expiration.
Are the DRG and VRG unilateral or bilateral? Are they connected to one another?
Both are bilateral. Interconnected by a complex system of neurons.
Describe the central pattern generator.
- Neural network.
- Located within DRG/VRG.
- Precise functional location = unknown.
Where can muscle proprioreceptors be found?
In all parts of the moving thorax there are joint, tendon and muscle spindle receptors.
Define respiratory failure.
Failure of gas exchange, causing an inability to maintain normal blood gases.
Low PaO2 (<8kPa), +/- an elevated PaCo2 (>6.5kPa).
Give the blood gases of type I respiratory failure.
Low PaO2 (hypoxaemia -> hypoxia).
Low/normal PaCO2 (hypocapnia/normal).
Give 4 mechanisms of type I respiratory failure.
- Ventilation/perfusion mismatch.
- Shunting.
- Diffusion impairment.
- Alveolar hypoventilation.
Give 5 specific causes of type I respiratory failure with examples.
Infection -> pneumonia.
Congenital -> cyanotic congenital heart disease.
Airway -> COPD/asthma.
Vasculature -> pulmonary embolism.
Parenchyma -> pulmonary fibrosis.
What are 4 treatments for type I respiratory failure.
- Airway patency.
- Oxygen delivery.
- Increasing FiO2.
- Treat the primary cause (e.g. antibiotics for pneumonia).
Is type I or type II respiratory failure more common?
Type I - most pulmonary and cardiac causes produce type I respiratory failure.
Give the blood gases of type II respiratory failure.
Low PaO2 (hypoxaemia -> hypoxia).
High PaCO2 (hypercapnia).
Give 3 mechanisms of type II respiratory failure.
- Lack of respiratory drive.
- Excess workload.
- Bellows failure.
Give 3 specific causes of type II respiratory failure with examples.
Airway -> COPD/asthma.
Drugs/metabolic -> opiates, poison.
Neurological -> head and cervical spine injury.
Give 3 treatments for type II respiratory failure.
- Airway patency.
- Oxygen delivery.
- Treat the primary cause (e.g. antibiotics for pneumonia).
Which treatment can be more difficult with type II respiratory failure than type I? Why is this?
Oxygen delivery.
As central chemoreceptors have habituated to high levels of CO2, their drive to breath comes from low O2 instead.
If O2 is given, drive to breath could stop = stop breathing.
Define hypoxia.
Reduced level of tissue oxygenation.
Define hypoxaemia.
Decrease in level of oxygen in the blood.
Give 7 symptoms of hypoxia.
- Central cyanosis (oral cavity).
- Irritability.
- Reduced intellectual function.
- Reduced consciousness.
- Convulsion.
- Coma.
- Death.
In what type of patient may hypoxia not be obvious?
Anaemic patients.
Give 9 symptoms of hypercapnia.
- Irritability.
- Headache.
- Papilloedema.
- Warm skin.
- Bounding pulse.
- Confusion.
- Somnolence (abnormal drowsiness).
- Coma.
- Death.
Does hypercapnia present the same in all patients?
No, it is variable patient-to-patient.
What is the purpose of systemic vessels?
To deliver oxygen to hypoxic tissues.
What is the purpose of pulmonary vessels?
To pick up oxygen from oxygenated lung.
Name the vasodilator/s of systemic vessels.
Hypoxia, acidosis, CO2.
Name the vasoconstrictor/s of systemic vessels.
Oxygen.
Name the vasodilator/s of pulmonary vessels.
Oxygen.
Name the vasoconstrictor/s of pulmonary vessels.
Hypoxia, acidosis, CO2.
What is Boyle’s Law?
P1V1 = P2V2
As a constant temperature, the absolute pressure of a fixed mass of gas is inversely proportional to its volume.
At 150m depth, how many atmospheres would this be?
16 (multiple of 10 it is = 15, +1 = 16).
What is Dalton’s law?
The total pressure exerted by a mixture of gases is equal to the sum of the partial pressures of the individual gases.
Describe apnoea diving.
- Diver inhales (pre-hyperventilation).
- Diver descends whilst holding breath, gas compresses.
- PaO2, PaN2, PaCO2 rise.
- Eventually CO2 builds up to induce desire to breathe.
- Diver returns to surface, PaO2, PaN2, and PaCO2 fall.
Describe the diving reflex.
Occurs when cold water is splashed on the face.
Causes apnoea, bradycardia, and peripheral vasoconstriction to optimise respiration by preferentially distributing oxygen stores to the heart and brain.
When may apnoea diving be commonly used? Why?
Military operations to remain covert.
Describe SCUBA diving.
- SCUBA = self contained underwater breathing apparatus.
- Gas on demand.
- Gas delivered on inhalation at ambient pressure.
Describe pulmonary oxygen toxicty.
- PiO2 > 0.5 ATA.
- Cough, chest tightness and pain, SOB.
- Also a problem with ITU patients.
- Relief with PiO2 < 0.5 ATA.
Describe CNS toxicity’s symptoms and how to remember these.
Use ‘ConVENTID’.
Con = convulsion (common final, and often first, sign).
V = vision (tunnel vision etc).
E = ears (tinnitus).
N = nausea.
T = twitching.
I = irritability.
D = dizziness.
Describe inert gas narcosis.
Commonest in nitrogen narcosis.
Worsens with increasing pressure.
First noticed between 30 -> 40 msw. Increased PiN2.
Individual variation.
Influencing factors; cold, anxiety, fatigue, drugs, alcohol.
Describe the symptoms of inert gas narcosis.
10 -> 30m: mild impairment of performance.
30 -> 50m: over confidence, sense of well being.
50 -> 70m: loss of memory, stupefaction.
90+m: unconsciousness, death.
Death may occur at much shallower depths.
Describe decompression illness.
N2 = poorly soluble.
Ascent -> fall in pressure, fall in solubility, gas bubbles of nitrogen formed in tissues and blood.
O2 supportive treatments and urgent recompression.
Describe arterial gas embolism.
Scuba dives 3m deep on air, panicked and returned quickly, shortly after - week R arm, generalised seizure.
Gas gets into the circulation via torn pulmonary arteries.
Small transpulmonary pressures can lead to AGE.
Normally occurs within 15 minutes of surfacing.
Urgent recompression necessary.
Describe pulmonary barotrauma.
Air leaks from burst alveoli -> pneumothorax, pneumomediastinum, subcutaneous emphysema.
What is the death zone? At what height does this occur?
Death zone = altitude above which it is difficult to sustain life without added O2.
Over 8000m.
What heights are described as high altitude, very high altitude, and extremely high altitude?
High = 1500 -> 3500m.
Very high = 3500 -> 5500,.
Extremely high = 5500+m.
What is the altitude and atmospheric pressure at sea level?
Altitude = 0m.
Atmospheric pressure = 100kPa.
What is the equation for pressure of inspired gas (PiGas)?
PiGas = FiGas x Patm.
What is the equation for alveolar oxygen pressure (PAO2)?
PAO2 = PiO2 - PaCO2/R.
(R = 0.8).
What os the equation for arterial oxygen pressure (PaO2)?
PaO2 = PAO2 - (A-aDO2).
A-aDO2 = alveolar arterial O2 difference (approx 1kPa).
Give the normal blood gas range of PaO2.
10.5 -> 13.5 kPa.
Give the normal blood gas range of PaCO2.
4.5 -> 6.0 kPa.
Give the normal blood gas range of pH.
7.36 -> 7.44.
What shape is the oxygen dissociation curve?
Sigmoidal.
Give 4 factors that mediate a shift in the oxygen dissociation curve.
- Acidity.
- 2,3 DPG.
- Increased temp.
- Increased PCO2.
What happens to FiO2 and PiO2 as altitude increases?
FiO2 remains constant at 0.21.
PiO2 falls.
Describe the normal response to elevation.
Hyperventilation:
- Increases minute ventilation.
- Lowers PaCO2.
- Initially become alkalotic.
- Become tachycardic.
Which system compensates for alkalosis? How?
The renal system. by excreting bicarbonate to restore acid-base balance.
Describe elevation in terms of blood gases.
Ascend = PiO2 falls.
- Decreased PAO2.
- Decreased PaO2.
Peripheral chemoreceptors fire, activates increased ventilation, reducing PaCo2.
- Increased PAO2.
- Increased PaO2.
Give the altitude, atmospheric pressure, PiO2 and PaO2 of Mont Du Vallon.
Altitude = 3000m.
Atmospheric pressure = 62kPa.
PiO2 = 13kPa.
PaO2 = 8kPa approx.
Give the normal blood gases for Mont Du Vallon.
PaO2 = 7.0kPa.
PaCO2 = 3.0kPa.
pH = 7.44.
Give the altitude, atmospheric pressure, PiO2 and PaO2 of Everest.
Altitude = 8848m.
Atmospheric pressure = 33.5kPa.
PiO2 = 7kPa.
PaO2 = 5kPa approx.
Give the normal blood gases for Everest.
PaO2 = 4.0kPa.
PaCO2 = 1.5kPa.
pH = 7.56.
What is AMS?
Acute mountain sickness.
What factors put a person at risk of acute mountain sickness (AMS)?
- Recent travel to over 2500m (a few hours).
- Normal dwelling at sea level.
- Altitude, rate of ascent, and history of AMS.
- Being a younger person.
How is AMS diagnosed?
Lake Louise score of 3+.
Must have a headache and at least one other symptom.
How is AMS treated?
Only reliable treatment is descent, NEVER go up higher with AMS.
What is HAPE?
High altitude pulmonary oedema.
What are the symptoms of HAPE?
Cough and SOB.
Which factors increase the risk of HAPE?
- Rapid ascent above 8000ft.
- Sleeping above 6000ft.
- Speed of ascent (rapid = higher risk).
- Individual susceptibility.
- Exercise.
- Respiratory tract infection.
How is HAPE treated?
- Descend urgently.
- O2.
- Gamow bag.
- Steroids?
- Ca2+ blockers?
What is HACE?
High altitude cerebral oedema.
What are the symptoms of HACE?
- Confusion.
- Behaviour change e.g. agitation, lethargy.
- AMS is not necessarily a pre-requisite.
How is HACE treated?
- Immediate descent needed.
- Symptoms may resolve relatively quickly.
- May need gamow bag recompression.
Give the altitude, atmospheric pressure, effective cabin atmosphere, and cabin pressure of a Dreamliner.
Altitude = 10,000m.
Atmospheric pressure = 21kPa.
Effective cabin atmosphere = 1890m.
Cabin pressure =81kPa.
In what cases may individuals need assessment before going on an aircraft? Why?
If they have lung disease, or low sea level O2.
To ensure they do not desaturate.
When should individuals avoid flying?
- Pneumothorax.
- Infectious TB.
- Major haemoptysis.
- Very high O2 requirements at sea level (> 4 litres/minute).
