RESPIRATORY PHYSIOLOGY

Anatomy, Structure and Functional interface (1)

Ventilation (1)

Anatomy (1)

2010-2Please draw a diagram showing static lung volumes

Spirometery cannot measure FRC or RV (and therefore TLC)Considerable variation of these values:- TV 500ml - DS 150 ml - TLC 7L - FRC 2L - VC6L

How does physiological dead space differ from anatomical dead space? 2004-2 - Dead space = volume not involved in CO2 elimination- Anatomical dead space: Conducting zones of lung = 150mls (measured by Fowler’s method)- Physiological dead space: Parts of lung with ventilation but no perfusion, or the volume of gas that

does not eliminate CO2 (measured by Bohr’s method)- Volumes nearly same (150 ml or 20-35% of VT) in health, but physiologic DS increased in many

lung diseases- Proportion of DS reduced in force inspiration/expiration- Note: alveolar ventilation = (tidal volume – dead space) x respiratory frequency

How can the physiological dead space be measured? 2004-2 - Bohr’s method calculates fraction of tidal volume by measurement of mixed expired CO2 and

arterial CO2

- Dead space doesn’t contribute to expired CO2- VD = VT x (PaCO2 - PECO2)/ PaCO2

What will lead to increased physiological dead space? 2004-2 - V/Q mismatch = Non-perfused alveoli and alveoli with excessive ventilation

Additional: Alveolar Ventilation Equation- Alveolar ventilation = volume of fresh (non-dead space) gas -> respiratory zone per minute- VA = K.(VCO2/PCO2), i.e. determined from CO2 output/fractional concentration of CO2

- Means that relationship between alveolar ventilation and PCO2 is important- E.g. if alveolar ventilation is halved, PCO2 will double

Regulation & Control (1)2011-2, 2008-2, 2004-2Describe the function of the central chemoreceptors in the regulation of ventilation.- Chemoreceptors: respond to changes in chemical composition in blood or fluid around them

Central chemoreceptors - Most important for minute-by-minute control- Situated in the ventral surface of the medulla near exit of 9th and 10th nerves- Regulates ventilation in response to CSF pH/H+ ion concentration- CO2 in blood changes pH in CSF – increased CO2 -> increased H+ in CSF -> increased

ventilation- Blood brain barrier relatively impermeable to H+ and HCO3- - CSF poor buffering capacity c.f. blood because less protein – thus pH changes more rapid- CSF pH more responsive to renal compensation due to HCO3- transport (takes 2-3 days)- This means chronic CO2 elevation gives normal CSF pH and insensitivity

Describe the function of the peripheral chemoreceptors in the regulation of ventilation.Peripheral chemoreceptors- Located in the carotid & aortic bodies- They contain glomus cells of 2 types: Type I with high concentration of dopamine- Also type II and capillaries w/ high blood flow- Respond to a decrease in PO2 and responsible for all the increased ventilation in hypoxia, begin

to fire at 500mmHg, significant increase in firing <100mmHg and max response occurs <50mmHg- Also to PCO2 (but less important than central, 20% response but more rapid)- Also carotid (but not aortic) respond to pH

2011-1, 2007-1, 2005-1What sensors are involved in the control of ventilation?Central chemoreceptors in medulla-respond to CSF pH (via CO2)Peripheral chemoreceptors in carotid and aortic bodies respond to O2, pH, CO2 (minor)

Lung receptors1. Pulmonary stretch receptors: Minimal adaptation, stimulation (lung distension) -> via vagus ->

slow respiration by prolonging expiration, Hering-Breur reflex largely inactive in adult humans2. Irritant receptors: Noxious stimulation -> myelinated vagus impulse -> bronchoconstriction and

hyperpnea (“rapidly adapting stretch receptors”), ?role in asthma via histamine release.3. J Receptors: Unmyelinated “juxtacapillary” C fibres respond to changes in interstitial fluid (e.g.

CHF, interstitial lung disease) -> rapid shallow breathing4. Bronchial C Fibres: Bronchial (c.f. pulmonary J receptors) -> rapid shallow breathin,

bronchocontriction, mucous secretion

Other Receptors1. Nose and upper airway: Extension of irritant receptors, respond to mechanical and chemical

stimuli -> reflex coughing, sneezing, bronchoconstriction, laryngeal spasm2. Joint and muscle: In exercise3. Gamma system: Via muscle spindles from respiratory muscles -> dyspnea if airway obstruction4. Arterial baroreceptors: BP -> reflex ventilation and visa versa5. Pain and temperature: pain -> apnea then hyperventilation, heat -> hyperventilation

Describe the ventilatory response to metabolic acidosis- Low arterial pH stimulates peripheral chemoreceptors to increase ventilation- Peripheral chemoreceptors dominate the reposnse- Central chemoreceptors or respiratory centre itself may be stimulated in severe cases (BBB

permeability to H+ increases)2005-1What are the basic elements of the respiratory control system?

Central controller- Normal automatic process from brainstem- Voluntary cortical override possible- Medullar respiratory centre in reticular formation of medulla, along with areas in the pons- Receive input from chemoreceptors, lungs and other receptos and the cortex- Major output to phrenic (diaphragm) but also to other respiratory muscles

Additional: Integrated responsesResponse to CO2

- PaCO2 is the important factor in control of ventilation under normal circumstances- Tight control to 3mmHg (when awake/exercising)- Mostly from central chemoreceptors, but also peripheral (response is more rapid)- Reponses is magnified if the PaO2 is lowered- Central sensitivity be decreased by sleep, age, genetic, racial, personality, athleticism (diving),

drugs e.g. opiates and barbituates

Response to O2

- Is only through the peripheral chemoreceptors in aortic and carotid bodies (not central)- If PCO2 is kept low, then appreciable response only noted w/ PO2 <50mmHg- If PCO2 increased then response w/ PO2 <100mmHg- The combined effects exceed the sum of each given separately- Important at high altitude- Important in lung disease where chronically high PCO2 (retainers) means CSF buffered to normal

(abolishing response to further increased CO2), so arterial hypoxic drive is main stimulation and can be adversely affected by O2 therapy

Response to Exercise- Fit healthy people may consume 4Lmin-1 of O2 and have VT 120 Lmin-1

- 15x resting level- Ventilation closely matches O2 uptake and CO2 output- PCO2 constant (or may fall w/ extreme), PO2 increases (may fall w/ extreme) and pH constant

(may fall due to lactic acid w/ extreme) – thus in moderate exercise the chemoreceptors do not account for the increase in ventilation

- Mechanisms involved are unknown: ?muscle movements, ?PCO2 oscillations, ?PCO2 set-point change, ?CO2 load on lungs, ?body temp rise, ?cortical input

Mechanics of breathing (1)

2010-2, 2010-1, 2008-1, 2007-1, 2006-2, 2003-2Please explain the concept of compliance as it relates to the lung- Volume change per unit pressure change (slope of pressure volume curve) = ~200ml/cm H2O- Shows hysteresis between inflation and deflation- Within normal range (-2 to -10 cm H2O) of expanding pressures, lung is very compliant- Non-linear w/ lung becoming stiffer at higher volumes- Depends on structural proteins (collagen and elastin) and surface tension- Specific Compliance = "compliance per unit volume of lung"

What factors affect complianceReduced- Pulmonary venous hypertension (blood engorgement)- Unventilated lung (especially at low lung volumes i.e. atelectasis)- Lung volume - a person with only one lung has halved compliance- Pulmonary fibrosis- Alveolar oedema of any type (prevents inflation of some alveoli)

Increased- Increasing age and emphysema – due to alteration in elastic tissue- Asthma attack (unclear why)- Surfactant (surface tension in alveoli)

2006-2, 2003-2Can you draw the pressure volume curve of a normal lung?

2007-1, 2003-2Describe how regional differences in intrapleural pressure affect the ventilation(How does compliance vary throughout the upright lung?)- The intrapleural pressure is higher (less negative) at the base than at the apex of the lung – due

to the weight of the supported lung in the thoracic cavity- Leads to increased compliance at base, hence better ability to ventilate base compared with apex- Bases therefore have a small resting volume (are compressed by weight), lower expanding

pressure and larger volume change on inspiration -> higher ventilation (opposite for apexes)- At low lung volume (RV from full expiration) the intrapleural pressures at the base > atmospheric

-> compression of bases -> airway closure and no ventilation, whereas the apexes will have favourable ventilation

Note1. Hysteresis: Lung volume at given pressure larger during

deflation than inflation2. Closing volume: Due to small airway closure. Even if

increased pressure about lung, small airways collapse trapping some air in alveoli, this occurs more with larger lungs (age) and in some lung diseases

3. Lung becomes stiffer at higher volumes

2009-1, 2005-2What is surfactant and how does it work?- Surfactant is a phospholipid- Dipalmitoyl phosphatidylcholine (DPPC) is an important constituent- Produced in type 2 alveolar cells- Lamellated bodies within them are extruded into the alveoli and transform into surfactant- Fast synthesis with rapid turnover - Formed relatively late in foetal life- Molecules of DPPC are hydrophobic at one end and hydrophilic at the other- When aligned on the surface, their repulsive forces oppose the normal attractive forces between

the liquid surface molecules reducing the surface tension- With surfactant present, surface tension changes greatly with surface area - it fails to very low

values when area is small (displays hysteresis)

2010-1, 2009-1, 2008-1, 2006-2, 2005-2What are the physiological advantages of surfactant- Reduction in surface tension is greatest when film is compressed and molecules of DPPC are

closest together- Lower surface tension in the alveoli increases lung compliance and decreases work of

breathing- Promotes alveolar stability (reduces tendency for small alveoli to empty into large alveoli) (Law

of Laplace: P = 2 x Tension / Radius (2 c.f. 4 b/c fluid is in a sphere so only one surface involved)- Keep the alveoli dry (surface tension "sucks" fluid into alveolar spaces from capillaries, by

reducing hydrostatic pressure in the tissue)

Note: An additional mechanism that contributes to the stability of the alveoli is interdependence – support offered by lung units by those around them (i.e. the tendency for one group of units to reduce or increase in volume is opposed by the connected units surrounding them)

2005-2Describe the relationship of pressure and wall tension in connected bubbles.- Law of Laplace: P = 4T/r- Two bubbles connected (same surface tension), the smaller with higher pressure will blow up the

larger with lower pressure -> smaller bubble will collapse- Surfactant: reduction in surface tension is greatest when film is compressed and molecules of

DPPC are closest together -> alveolar stability

2008-1What factors impact on resistance in airways?- Size of airway: R highest in medium sized bronchi, low in very small airways- Lung volume: R decreases with expansion as airways pulled open- Bronchial smooth muscle tone: controlled by B sympathetics- Gas density: e.g. heliox -> low R- Forced expiration: intrathoracic pressure compresses airways = ‘dynamic compression’

What factors cause turbulent flow in airways?- Expressed by Reynold’s number Re=DVd/η - d is the fluid density *Reynold hit (viscous) Nick on the head with a DVd- D is the diameter of the tube- V is the velocity of flow- η is the viscosity of the fluid- Flow is likely to be turbulent if Re > 2000- Laminar flow only in small airways (Re ~1 terminal bronchioles), transitional most areas, turbulent

in trachea (rapid breathing)2006-1Discuss the factors that determine airway resistance

- Flow resistance R = 8nl / r4 - Inversely proportional to radius to the power of 4 (half the radius increases resistance 16 fold),

thus Radius is the most important determining factor- Directly proportional to viscosity & length- Is highest in the medium sized-bronchi and low in the very small airways- <20% due to airways <2mm (generation 8), paradox due to large number of small airways

What factors affect the radius of the airway?1. Bronchial smooth muscle tone

- Parasympathetic activity via vagus -> contraction and increased resistance- Adrenergic stimulation of 2 receptors -> bronchodilation (adrenaline, salbutamol)

2. Lung volume- As lung volume increases more radial traction on bronchioles -> decreased resistance- Inversely, at low volumes the small airways may collapse, especially at the bases- Patients w/ increased airway resistance may breath at high lung volumes

Additional: Dynamic compression of airways- Limits air flow in normal subject during a forced expiration- May occur in diseased lungs at low expiratory flow rates (reducing exercise ability)- Determined by alveolar pressure minus pleural pressure (not mouth pressure) – independent of

effortExaggerates in some diseased by reduced lung elastic recoil and loss of radial traction on airways

2003-2What factors determine the work of breathing?1. Elastic forces of the lungs and chest wall2. Viscous resistance of the airways and tissues

What variables affect elastic workload?1. Larger tidal volumes2. Reduced compliance due to

- Lung volume - a person with only one lung has halved compliance- Slightly less during inflation than during deflation- Increased by increased tissue mass - fibrosis or pulmonary congestion or chest wall restriction- Loss of surfactant

What variables affect viscous resistance?1. Higher respiratory rates increasing flow rates2. Decreased airway radius due to: Lower lung volumes, bronchoconstriction3. Increased air density (e.g. SCUBA diving)4. Increased air viscosity

Pulmonary Blood Flow (1)

2011-1, 2008-2, 2007-2, 2005-1Describe the normal distribution of pulmonary blood flow.1. Decreases linearly from base to apex2. Due to hydrostatic pressure,3. Under normal conditions, flow almost ceases at apex4. Distribution more uniform with exercise5. Zones 1 – 3 +/- zone 46. Zone 4 only at very low lung volumes

How is the distribution of pulmonary blood flow actively controlled?Hypoxic pulmonary vasoconstriction (2006-2)- Alveolar hypoxia constricts pulmonary arteries- Direct effect of the low PAO2 on the vascular SMC (via inhibition of v-gated K+ channels -> Ca2+)- Directs blood away from poorly ventilated diseased lung areas reducing effects on gas exchange- Important in foetal life -> birth when the hypoxic lung (high R, only 15% CO) -> oxygen and ROther factors- Vasoactive substances (NO, endothelin-1, TXA2)- Low blood pH leads to pulmonary vasoconstriction- Sympathetic stimulation leads to stiff pulmonary arteries leads to vasoconstriction

Other factors affecting the distribution of pulmonary arterial blood 2007-2 - Vascular resistance pulmonary HT / PE- Pulmonary disease : asthma, CORD, infection, infarction, cancer, fibrosis, pneumothorax, trauma

What EXTRA-PULMONARY factors influence pulmonary blood flow? 2007-2 1. Blood volume2. Cardiac output 3. Atmospheric pressure4. Temperature 5. Pathology eg, anaemia, cancer, infection6. Exercise 7. Posture

Notes- Zone 1 does not occur in normal

conditions b/c Pa just high enough to raise to top of lung

- Aka alveolar dead space- May occur if BP (haemorrhage)

or PA (Positive pressure vent.)

- Zone 2 behaviour often called the Starling resistor, sluice, or waterfall effect

- Zone 4 occurs at low lung volumes (lung poorly inflated) when narrowing of extra-alveolar vessels occurs

Please explain how cardiogenic pulmonary oedema occurs. 2011-1 - Starling’s Law: differences in capillary and interstitial hydrostatic and colloid osmotic pressures- Net fluid out = K[(Pc - Pi) - (c - i)] where K = filtration coefficient, is reflection coefficient

(effectiveness of capillary wall to protein block), P is hydrostatic pressures, is colloid pressures- LVF (CHF) – pulmonary congestion and increase in Pc

- Significant increases in net outward pressure of Starling equation results in interstitial oedema especially at perivascular and peribronchial spaces

- Further increases of outward pressure results in fluid entering alveolar spaces (more severe, interferes with gas exchange, fluid actively pumped out by ATPase pump)

How does the distribution of blood change when the subject becomes supine? 2008-2 - Blood flow from base to apex is almost uniform- Flow in posterior segments exceeds that in anterior segments

2009-2, 2007-2, 2006-2, 2005-1What are the major factors that effect pulmonary vascular resistance in the normal lung?1. Increasing pressure (e.g. exercise) -> reduction in resistance by recruitment and distension - ↑Arterial > Venous Pressure- Recruitment (normally closed capillaries open)- Distension (normally flattened capillaries caliber)2. Lung volume (U/J shaped curve) – i.e. resistance increases at high and low volumes- Large lung volumes pull open extra-alveolar vessels but may narrow pulmonary capillaries so that

resistance rises- Small lung volumes also cause increased resistance of extra-alveolar vessels because smooth

muscle tone closes them if critical opening pressure is not reached3. Hypoxic vasoconstriction (alveolar hypoxia -> increased PVR)4. Vascular Smooth Muscle Tone – response to endogenous/ exogenous factor5. Area of lung (zones) – less flow in apex c.f. bases6. Position change

Why is pulmonary flow so sensitive to pulmonary vascular pressures?- Very low pressure system, 25/8 mmHg, mean 15mmHg (1/6th or systemic)- Few resistance vessels with about 10mmHg drop across the system (100mmHg in systemic)- Vascular resistance = input-output pressure / blood flow- Thus pulmonary vascular resistance is only 1/10th of systemic resistance- Easily distensible vessels- Recruitment- Only just enough pressure for normal gravity/ position to get apical flow- Keeps work of right heart as low as possible for gas exchange to occur

Water and Fluid balance in the lung (1)

2010-1What are the factors that keep fluid out of the alveoli- Starling’s Law: differences in capillary and interstitial hydrostatic and colloid osmotic

pressures (Theoretical Concept, exact values of pressures unknown)- Net fluid out = K[(Pc - Pi) - (c - i)] where K = filtration coefficient, is reflection coefficient

(effectiveness of capillary wall to protein block), P is hydrostatic pressures, is colloid pressure

Net pressure (normally) slightly outward due to:1. Low pressure system and blood proteins, 2. Surfactant – the surface tension of the alveoli ‘sucks’ the fluid from the interstitial space and

surfactant reduces this surface tension greatly3. Lymphatic drainage

- Significant increases in net outward pressure of Starling equation results in interstitial oedema especially at perivascular and peribronchial spaces

- Further increases of outward pressure results in fluid entering alveolar spaces (more severe, interferes with gas exchange

- Alveolar cells via ATPase actively pump fluid out

Pulmonary Metabolic function (1)

2011-2, 2010-2, 2005-2Outline the metabolic functions of the lung.The lung has a substantial fraction of the vascular endothelial cells of the body, and only organ other than the heart to receive the entire circulation.1. Biologic activation- Only known example is ATI -> ATII by ACE2. Biologic inactivation/removal- Serotonin (by uptake), bradykinin (by ACE), PGE1, PGE2 and PGF2a, noradrenaline (30%),

leukotrienes 3. Synthetic function: - Phospholipids such as dipalmitoyl phosphatidylcholine (DCC for surfactant)- Protein synthesis (collagen & elastin)- Carbohydrates: mucopolysaccarides of mucous- AA metabolites:

i. lipoxygenase pathyway -> leukotrienes (esp. SRS-A, slow reacting substance of anaphylaxis)ii. cycloxygenase pathway -> prostaglandins

4. Secrete IgA5. Clotting via heparin production from mast cells

Additional: Substances unaffected by transit through the lung- ATII- ADH- Histamine and dopamine- Prostacyclin (PGI2) and PGA2

Describe the lung defence mechanisms. 2005-2 Cooling or warming air; hairs in nasal passages; NO in paranasal sinuses is bacteriostatic; lymphoid tissue in adenoids, tonsils; secretory IgA in bronchi; ciliary escalator; coughing reflex; release of PGE2 protects epithelial cells; alveolar macrophages are phagocytic.

Ventilation – Perfusion Relationships (1)

2010-1What are the causes of hypoxaemia in a person breathing room air?1. Hypoventilation2. Diffusion limitation3. Shunt4. V/Q (ventilation-perfusion) inequality

Additional: Hypoventilation- Always increases the PACO2 and PaCO2

- Decreases the PO2 unless additional O2 is inspired- Hypoxaemia is easy to reverse by adding O2 to the inspired gas- Causes: drugs (opiates, barbiturates), chest wall damage, resp. muscle paralysis, high resistance

to breathing (e.g. deep dive)- Relationship between the PO2 and PCO2 can be calculated from alveolar gas equation:

PAO2 = PIO2 - PACO2 / R (=0.8 normally) + F (~2mmHg), i.e. PAO2 = PACO2 / 0.8Thus: the fall in alveolar PO2 is slightly higher than the rise in PCO2

- Relationship between ventilation and PCO2 can be calculated from alveolar ventilation equationPCO2 = (VCO2 / VA)K , thus if ventilation (VA) is halved, the PCO2 will double (at steady state)

2007-1Explain the difference between alveolar and arterial oxygen concs in the healthy adult.- The PAO2 is always slightly higher than PaO2

- Caused by:1. Diffusion limitation- Exercise, disease (increase in blood-gas barrier), or low inhaled PO2 will enhance this limitation

2. Shunt- Blood enters arterial system without passing through a ventilated area of lung- Poor response to added inspired O2 (100% O2 -> diagnostic test)- PCO2 may be normal or low (because increased drive)Physiological- Bronchial arterial blood flows to pulmonary veins- Coronary arterial blood flows to coronary veins then thebesian veins in left ventriclePathological- Heart defect (e.g. PDA)- Atelectasis in lung

3. V/Q (ventilation-perfusion) inequality

Explain how V/Q matching varies from apex to base in the normal lung 2008-1, 2005-1

- Linear increase in ventilation and blood flow from top to bottom (hydrostatic pressures)- Although ventilation is less at top, the differences in blood flow are greater, so…- V/Q ratio decreases down the lung (>3 at top, <1 at bottom)- PO2 40mmHg higher at lung apex (difference in PCO2 much less, but lower at apex)- Major share of blood leaves lower zones where PO2 is lowest -> results in PaO2 < PAO2

Explain why ventilation-perfusion inequality causes a reduced arterial PO2 while arterial PCO2 remains relatively normal 2010-1, 2008-1, sample viva, 2006-2 - Basically due to the differences in their dissociation curves- If one could in isolation cause V/Q inequality then gas exchange would deteriorate with hypoxia

and hypercapnia (and all other gasses)- However the chemoreceptors act to increase ventilation- The CO2 dissociation curve is linear at the working range -> increased ventilation is able to

correct the PCO2 by increased CO2 output in units with both high and low V/Q ratios- Units with very high V/Q ratios inefficient at CO2 elim. -> wasted ventilation on this alveolar

deadspace- The O2 dissociation curve is not linear (S-shaped) so only low V/Q areas benefit with increased

ventilation- With hyperventilation PCO2 may normalise but PO2 only has a modest rise, some hypoxia

will remain

2009-1What is the alveoloar gas equationPAO2 = PiO2 – PACO2 / R (~0.8) + F (F~2mmHg)- Defines the relationship between the alveolar PO2 and PCO2 – i.e. if there is a fall in PO2 there will be corresponding rise in PCO2 (and visa versa)

Sample viva, 2006-2, 2009-1

How can we determine the effect of VQ mismatch on oxygenation in clinical practice?- Calculate the A-a gradient = PAO2 - PaO2 - PAO2 can be calculated from the alveolar gas equation giving:- Equation: A-a gradient = (149 - PaCO2 / 0.8) - PaO2

- (On room air (FiO2 = 0.21, or 21%), at sea level ( Patm = 760mmHg ) and assuming 100% humidity in the alveoli (PH2O = 47mmHg) – so PiO2 = (760 – 47) x 0.21 = 149

- A–a gradient increases with age (1mmHg for every 10 years) normal = (age/4) + 4- An abnormally increased A–a gradient suggests a defect in diffusion, V/Q

(ventilation/perfusion ratio) mismatch, or right-to-left shunt- Normals: PiO2 = 149, PAO2 = 100, PACO2 = 40, PaO2 = 40, PaCO2 = 45 (units in mmHg)

Gas Diffusion (1)

2010-2, 2006-1What factors influence the rate of transfer of O2 from the alveolus into a pulmonary capillary?- Process is passive diffusion (Fick’s law of diffusion)

Could you give some clinical examples of when these may be affectedExercise, alveolar hypoxia (altitude), and thickening of blood gas barrier – see below

2003-2Describe the difference between diffusion limited and perfusion limited gas exchange in the lung.- Blood in pulmonary capillary has 0.75 seconds for gas exchange- Ability to reach partial pressure equilibrium depends on reaction with substances in the blood, i.e.

it depends on it’s solubility in the blood-gas barrier compared with blood - No reaction with substances in blood (gas dissolves only in plasma) –> rapid equilibrium reached,

and gas uptake limited by perfusion, e.g. N2O is perfusion limited- High affinity reaction of CO with Hb, so PCO in capillary falls rapidly –> driving force maintained,

slow equilibrium, diffusion limited

Explain how oxygen exchange is limited across the pulmonary capillary?- Perfusion limited under normal circumstances- Large driving pressure gradient (100 – 40mmHg) and thin blood-gas barrier mean the

combination occurs rapidly and PaO2 equalises in about 0.3sec, i.e. about 1/3rd of the time- So in normal conditions there is a large diffusion reserve

What would you expect to be the effect of heavy exercise on oxygen uptake in the pulmonary capillary?- Increased blood flow leads to reduced time for combination with Hb (0.25 seconds)- Normally doesn’t lead to measureable fall, but likely will if other factors contribute to limit diffusion- E.g. thickened blood-gas barrier (A) or hypoxic environment (B) (e.g. altitude)

Notes- Proportional to surface area: 50 – 100m2 in lung- Inversely to thickness: only 0.3m in places- Gradient of O2: Alveolar to O2 bound to Hb- The constant D is proportional to solubility and

inversely to the square root of molecular weight- CO2 diffuses much more rapidly than O2 (20x)

because it is much more soluble

Gas Transport by the Blood and to tissues (1)

How is oxygen transported in the blood? 2006-1 1. Dissolved - Henry’s Law states that amount dissolved is proportional to its partial pressure- For each 1mmHg, 0.003mlO2 per 100ml blood (at 100mmHg only 0.3ml/100ml blood)- Clearly inadequate for required O2 delivery 2. Bound to haem (iron-porphyrin compound), which is joined to globin to form haemaglobin

2011-1, 2009-2, 2006-1Please draw and describe the features of the haemoglobin-oxygen dissociation curve

27mmHg -> SO2 50% (P50), 56mmHg -> SO2 90%; 80mmHg -> SO2 95%, 90mmHg to SO2 97%

What factors cause shift in the curve?

What are the effects of carbon-monoxide on haemoglobin oxygen transport capacity- CO has 240 times the affinity of O2 for Hb (-> carboxyhaemaglobin)- So w/ CO the O2 carrying capacity of Hb and the O2 concentration are greatly reduced - The concentration of Hb, PO2 and SO2 may be normal- CO also shifts O2 dissociation curve to left, interfering with unloading of O2 – also contributing to

its toxicity2009-1, 2008-2, 2006-1, 2003-1How is CO2 transported in the blood

- S-shaped, becomes flatter after PO2 > 50mmHg- Saturation 97.5% at PO2 = 100mmHg (arterial)- Saturation 75% at PO2 = 40mmHg (venous)

Physiologic advantages:- Flat upper part means if PAO2 falls a little, Hb O2

loading will not be affected much- Flat upper part also means there will be a large

partial pressure difference in the pulmonary capillaries hastening diffusion

- Steep lower part means the peripheral tissues can withdraw large amounts of O2 for only small drops in PO2

To right: Temp, PCO2 (Bohr effect), H+, DPG- More O2 unloaded at exercising muscle that

is hot, acidic and has higher PCO2

- DPG produced in chronic hypoxia

To left: The opposite and CO

3 forms:1. Dissolved- Also obeys Henry’s Law, but 20x more soluble- Accounts for 10% CO2 delivery to lung

2. Bicarbonate- CO2 + H2O (CA) H2CO3 H+ + HCO3

-

- Carbonic anhydrase (in RBC) speeds the reaction up- Liberated H+ ions bind to reduced Hb (that is less acidic than HbO2) -> Haldane effect- Unloading of O2 in peripheries facilitates loading of CO2 (the opposite in pulmonary capillaries)- Accounts for 60% CO2 delivery to lung

3. Carbamino compounds- CO2 + HbNH2 Hb.NHCOOH (carbaminohaemoglobin)- Rapid and without an enzyme- Reduced Hb can bind more, so again unloading of O2 in peripheries facilitates loading of CO2

- Accounts for 30% CO2 delivery to lung

How does venous blood carry more CO2 than arterial blood 2009-1 Haldane effect- Deoxygenated (reduced) haemoglobin is less acidic -> binds more H+ - Also forms more carbamino compounds than oxyhemoglobin- Unloading of O2 in peripheries facilitates loading of CO2 (the opposite in pulmonary capillaries)

What is meant by the term ‘chloride shift’? 2008-2 - Carbonic anhydrase is in the RBCs -> leads to increased intracellular H+ + HCO3

-

- The HCO3- can diffuse out (along conc gradient) but the H+ is trapped

- About 70% of the HCO3- formed in the red cells enters the plasma in exchange for Cl- (to

maintain electric neutrality) - the exchange is called the chloride shift- This process is mediated by Band 3, a major membrane protein and is essentially complete in 1

second- Note that for each CO2 molecule added to a red cell, there is an increase of one osmotically active

particle in the RBC (HCO3- or a Cl-) -> consequently, the red cells take up water and increase in

size

Draw and label the CO 2 dissociation curve 2003-1

- The CO2 curve is steeper than the O2 curve- Explains why the PO2 difference between arterial and mixed venous blood is large (100 – 40 =

60mmHg), whereas for PCO2 it is small (45 – 40 = 5mmHg)

Note the CO2 curves at different saturations of O2

- Haldane effectThe insert shows the physiologic curve between arterial and mixed venous blood: Unloading of O2 in peripheries facilitates loading of CO2 (the opposite in pulmonary capillaries)

Respiratory aspects of acid base balance (1)

2007-1, 2005-2What are the buffer systems in blood?1. Bicarbonate H2CO3 H+ + HCO3

-

2. Protein HProt H+ + Prot-

3. Haemaglobin HHb H+ + Hb-

Explain how carbonic acid / bicarbonate system works.- CO2 + H2O (CA) H2CO3 H+ + HCO3

-

- Carbonic anhydrase (in RBC) speeds the reaction up- Increase in H+ (sensed by the peripheral chemoreceptors, or central receptor by transfer to CSF

by CO2) -> hyperventilation -> elimination of CO2 (rapid response, respiratory compensation)- Increase PCO2 at renal tubular cells -> increase acid secretion and HCO3

- reabsorption (base excess, metabolic compensation)

- The lung excretes over 10,000mEq of carbonic acid / day c.f. less than 100mEq of fixed acids by the kidney

2005-2What are the major buffers in cells.Intracellular fluid: HProt H+ + Prot-

H2PO4- H+ + HPO4

2-

Describe the Henderson-Hasselbalch equation- pH = pKA + log [A-] / [HA]- Derived from the acid dissociation constant equation (Ka = [H+] [A-] / [HA])- Describes the derivation of pH as a measure of acidity in biological and chemical systems- Useful for estimating the pH of a buffer solution and finding the equilibrium Ph in acid-base

reactions- Most effective when [A-] / [HA] = 1, so pH = pK

2005-2What clinical conditions might cause metabolic acidosis? / metabolic alkalosis?- Metabolic acidosis: DKA -> ketones, hypoxia -> lactic acid, intoxification, CRF- Metabolic alkalosis: vomiting, diuretics (loop and thiazides), hyperaldosteronism, hypokalaemia

Davenport Diagram:Gives relationships between pH, PCO2 and HCO3

-

A: normal state (pH 7.4, PCO2 40mmHg, HCO3- 24mEq/L)

CAB – buffer line (as carbonic acid added)Kidney can alter the buffer lineUp = base excess (resp acidosis, or metabolic alkalosis)Down = base deficit (resp alkalosis, or metabolic acidosis)

Respiratory System under Stress (2)

2011-2, 2009-2, 2007-2, 2005-1, 2003-1Describe the ventilatory response that occurs as you acclimatise to high altitudes.- Hyperventilation is the most important feature- The barometric pressure (and thus partial pressure of O2) drops exponentially with altitude- As per alveolar gas equation PAO2 = PIO2 - PACO2 / R (= 1.0 with low PACO2, and correction

factor disappears), thus for adequate PAO2 for survival PACO2 must be reduced- Mechanism is hypoxic stimulation of peripheral chemoreceptors -> ventilation- Resulting low CO2 / alkalosis inhibits response, but over ~2-3 days HCO3

- shift from CSF and renal excretion of HCO3

- corrects pH (of CSF and blood respectively) to near normal, allowing further increased ventilation

Outline other compensatory responses to high altitudes.Moderate altitude- Right shift in O2 dissociation curve due to 2,3 DPG- O2 affinity to Hb -> increased unloading of O2 at tissues

Higher altitude- Left shift O2 dissociation curve due to CO2- O2 affinity to Hb -> increased loading of O2 in lungs

- erythropoietin (sensed by renal tubular cells) –> polycythaemia (can be deleterious viscosity)- mitochondria to facilitate O2 transport into tissues- cellular oxidative enzymes (cytochrome oxidase)- capillaries in peripheral tissues- maximum breathing capacity because the air is less dense (assists the very high ventilations of

exercise at altitude)

Pulmonary Hypertension and (R) heart Hypertrophy- Pumonary vasoconstriction due to alveolar hypoxia -> pulmonary arterial pressure and work of

(R) heart- Increased blood viscosity due to Epo -> polycythaemia- Leads to increased work of (R) ventricle and hypertophy- No physiologic advantage (except more uniform blood flow to lungs)- Can result in pulmonary oedema

2003-1Describe the symptoms of acute mountain sickness.- Headache, fatigue, dizzy, palpitations, nausea, loss of appetite & insomnia- Due to hypoxaemia and alkalosis

2004-2In the respiratory system, what changes occur with exercise?- O2 demand (300ml/min -> 3000ml/min or more in athletes)- CO2 production (240ml/min -> 3000ml/min)- Stimulation of receptors -> ventilation rate, tidal volume, minute volume- lactic acid production -> pH and further stimulation of ventilation (ventilation threshold)- Increased diffusing capacity of lung (typically 3 fold) especially upper parts of lung, due to

increased blood flow/volume and increased diffusing capacity of the alveolar membrane- Increased cardiac output -> pulmonary blood flow -> BP -> recruitment and distention of

pulmonary capillaries -> reduced pulmonary vascular resistance- Nb ventilation increase 4x blood flow increase (easier to move air than blood)- More even V/Q ratios due to more even distribution of blood flow- Decreased physiological dead space- O2 curve shifts right (PCO2, H+ and temp) – better offloading of O2 and CO2 loading in muscles

What happens to the pulmonary circulation during exercise?- Increased cardiac output -> pulmonary blood flow -> BP -> recruitment and distention of

pulmonary capillaries -> reduced pulmonary vascular resistance- Nb ventilation increase 4x blood flow increase (easier to move air than blood)- More even V/Q ratios due to more even distribution of blood flow

What changes occur in venous gases during exercise?Total CO2 carried risesDec O2 because increased extractionLactic acidosis

Tests of Pulmonary Function (3)

Forced Expiration (2)

Additional:

FEV1 – forced expiratory volume in 1 secondFVC – total forced vital capacity (often less than relaxed vital capacity)Normally FEV1/FVC = 80%Obstructive lung disease (COPD, bronchial asthma) the FEV1 reduces > FVCRestrictive lung disease the FVC reduces, but the FEV1/FVC is normal/increasedFrequently mixed patterns are seen