Midterm 3/Final Flashcards
what is the etiology of reperfusion injury?
- osmotic overload
- pH paradox
how does osmotic overload cause reperfusion injury?
- large increase in number of small molecules in the cytoplasm increases osmolarity from 300 mOsm/l to 400 mOsm/l
- causes water to enter the cell making them swell and rupture
- intracellular organelles also swell and rupture
how do the number of small molecules in the cytoplasm increase with reperfusion?
- breakdown to ATP -> ADP + Pi
- breakdown of phosphocreatine -> creatine + Pi
- breakdown of glycogen to lots of lactate molecules
what is the pH paradox?
rapid reperfusion causes further harm
- reperfusion washes away extracellular H+, creating a gradient for H+ to leave the cell (NHE1 - Na+/H+ exchanger)
- H+ in the cell inhibits Na/K-ATPase
- [Na+] in cell goes up, driving NCX to bring in Ca2+
- increased Ca2+ causes Ca2+ overload causing 1) activated proteases and 2) mitochondrial Ca2+ overload
- ultimately causes cell death
how does subendocardial ischemia present as a diastolic injury current?
- causes elevated (depolarized) RMP in injured subendocardium
- causes diastole to be more depolarized than systole (elevated T-Q segment)
- atrial depol. and ventricular repol. elevated (less potential difference between endo and epi)
how does subendocardial ischemia present as a systolic injury current?
occurs when ischemic injury prevents normal depolarization (Vepi > Vendo)
- net flow of positive charges is away from electrode during systole, displaying S-T depression
what is a transmural infarct? how does it show on ECG?
dead tissue from subendo to subepi
- some endocardial depol persists due to increased preconditioning in endocardium
- shows as S-T elevation (gradient towards electrode during systole)
what ECG changes are present with myocardial infarction?
- heightened T waves
- followed by T wave inversion (altered directionality of repolarization)
- ST segment elevation due to injury current
- deep Q waves
what serum changes occur during myocardial infarction?
- lactate dehydrogenase (LDH)
- creatine kinase (CK)
- Troponin I (TnI)
- cardiac myosin-binding protein C (CmyC)
how does TnI detect MI?
TnI:
- calpain degrades TnI
- blood TnI levels raise during infarct
what is preconditioning?
- repeated brief, mild ischemia
- multiple angina episodes may offer protection
- almost every insult (reduction in blood flow) in life offers protection
how does repeated brief, mild ischemia offer protection?
- increased Katp activity
- increased vasodilator metabolites (adenosine, CO2, hypoxia)
- release of NA, bradykin, opioids (activate G proteins, protein kinases (PKC, PI3-K))
what is postconditioning?
- restarting the flow in brief bursts rather than all at once
- short bursts of reperfusion produce the least damage
what consists of the upper and lower respiratory tracts?
upper:
- nasal cavity
- pharynx
- larynx
lower:
- trachea
- bronchi
what are the functions of the respiratory system?
1) gas exchange
2) conditioning inspired air
- warming and moisturizing
- filtering particles >10 um
3) secretion of mucus
- clear debris from airways
- host defense (immunoglobins, inflammatory mediators
4) filter small emboli from the blood (reduce blood clots)
5) secrete surfactant and ACE
6) acid-base balance of blood (CO2-HCO3- buffering)
7) vocalization at the larynx
8) olfaction (nerve endings in the roof of nose extend from olfactory epithelium to bulb)
9) heat loss
what makes up the physiological dead space?
- anatomical dead space: conducting airways
- alveolar dead space: alveoli that are ventilated but not perfused
what generations make up the conducting airways? have cartilage? have alveoli?
- conducting = 1-16
- cartilage = 1-10
- alveoli = 17-23
what makes up the respiratory epithelium in the conducting airways?
- goblet cells (make mucus, secrete mucin - lubrication, chemical barrier, virus protection) - present as
~ every 5th cell in epithelial layer - submucosal glands (secrete water, ions, mucus, bactericidal compounds)
- sol layer (allows free movement of cilia)
- mucus layer (traps airborne particles)
how do goblets change in smokers?
increases with smoking (why you have more mucus)
when does respiratory epithelium lose submucosal glands and goblet cells? how does airway epithelium change with size of conducting airway?
- submucosal glands and goblet cells absent after gen 11-12 (at bronchioles)
- airway epithelium thins in small conducting airways
what is the function of cilia? of microvilli?
cilia:
- trap particles
- contain ATPase thought to mediate beating motion (active movement of wafting particles up mucus elevator)
- sweep mucus out of airways
microvilli:
- brush cells
- increase surface area for secretion
how does air move within airways?
- by convection (air moves from high to low pressure areas) in conducting airways
- by diffusion in alveolar airways
what are type I alveolar pneumocytes?
- flat, elongated, 95% of alveolus surface
- primary site for gas exchange
- fused to endothelium (to vasculature)
what are type II alveolar pneumocytes?
- small, cuboidal, 2% of alveolus
- synthesize surfactant
- can replicate if alveoli are damaged
what are type III alveolar pneumocytes?
- brush cells found throughout lung
- closely associated with nerves
what are Pores of Kohn?
inter-alveolar pores and canals (connect alveoli together)
- allow gas diffusion between alveoli and bronchioles (especially if an alveoli is congested)
- prevent alveolar collapse due to surface tension
where do the lungs receive their entire CO from? what are the 2 pulmonary blood supplies?
RV
1) pulmonary artery carrying deoxygenated blood supply
2) large airways receive dedicated bronchial artery supply (to keep tissues alive)
what are properties of the pulmonary artery blood supply?
- provide blood to pulmonary capillaries - enhanced gas exchange, single file RBC passage
- 750 ms transit time for each RBC
- very close to alveolus (short diffusion distance)
- like a sheet of blood surrounding alveoli
what are properties of the bronchial artery blood supply?
- oxygenated blood supply to bronchioles
- 1/3 drains to bronchial veins (RA)
- 2/3 drains to pulmonary veins (LA)
how is pulmonary vasculature different than systemic?
- pulmonary arteries and arterioles are thinner and larger in diameter than in the systemic circulation -> increases compliance of pulmonary circulation
1) can contain large volume of blood
2) reduces pulse pressure
3) distensibility protects against edema
how do pulmonary pressures differ from systemic pressures (mm Hg)?
- pulmonary a. vs aorta: 15 vs 95
- start of capillary: 12 vs 35
- end of capillary: 9 vs 15
- LA: 8 vs 2
- net driving P: 7 vs 93
pulmonary vasculature = low pressure system (highly compliant b/c receive blood from whole body at a lower P)
what is the pulmonary blood volume? how can it change?
~10% (500mL) of total blood volume
- can decrease by 50% or increase by 200% -> due to capillary recruitment
what is the driving force for convection?
difference between atmospheric (Pb) and alveoli pressure (PA)
what is Boyle’s Law? how is it relevant in breathing?
when temperature and mass are constant, P is inversely proportional to V
- changes in the volume of the lungs during inspiration and expiration generate the pressure changes required for ventilation
what muscles are recruited during quiet inspiration?
- diaphragm (increases thoracic volume)
- external intercostals (lift rib cage/lifts ribs up)
what muscles are recruited during forced inspiration?
- diaphragm
- external intercostals
- scalenes (lift first 2 ribs)
- sternocleidomastoids (lift sternum)
- neck and back muscles (trapezius)
- upper respiratory tract muscles (reduce airway resistance)
what muscles are recruited during quiet expiration?
none - passive process
what muscles are recruited during forced expiration?
- abdominal muscles (rectus abdominus, external obliques)
- internal intercostals (pulls ribs down)
- neck and back muscles
what nerves innervate the inspiratory muscles?
- traps and SCM: C1-C2
- diaphragm: C3-C5
- scalenes: C4-C7
- external intercostals: T1-T12
what nerves innervate the expiratory muscles?
- internal intercostals: T1-T12
- abdominal muscles: T6-T12
how would different spinal cord injuries affect breathing (above T12, above C5, above C3)?
- above T12: will influence respiratory function (ex. during exercise - difficulty recruiting muscles)
- above C5: inspiration dependent on accessory muscles
- above C3: requires artificial ventilation
what makes up the intrapleural space? what is inside it?
space between parietal pleura (stuck to chest wall) and visceral pleura (stuck to lungs)
- filled with pleura fluid (allows lungs to slide over chest wall, sticks lungs to chest wall)
what kind of pressure is in the intrapleural space? why?
negative pressure
- counters elastic recoil of the alveoli + keeps the alveoli open
- becomes more negative towards end of inspiration, where recoil reaches maximum
- elastic recoil of lungs pulls visceral pleura inwards, chest wall expanding moves parietal pleura outwards -> countering forces make Pip negative
how does alveolar pressure change during the respiratory cycle?
when air is not moving, Palv=Pb (atmospheric)
- at the beginning/end of inspiration/expiration, Palv=0=Pb
- negative during inspiration
- positive during expiration
what is a pneumothorax?
puncture of pleural space; air enters the intrapleural space, making it no longer negative
- lung collapse, alveoli collapse = atelectasis
what is lung compliance (distensibility)? what is it determined by? what happens when compliance is decreased?
ease with which the lungs can expand under pressure
- compliance = change in V/change in P
- determined by elastin and collagen fibres in lung parenchyma -> lung inflation elongates these fibres, exerting more elastic force/recoil so lungs revert to initial size following distension
- decreased compliance = increased resistance to distension (inflation)
what is hysteresis?
more pressure is needed to open an airway than for it to collapse; lung inflation has to overcome:
- elastic recoil
- surface tension
- collapsed alveoli have high surface tension and less surfactant
inspiration is active, expiration is passive
what is emphysema? how does it affect compliance?
increased compliance (expiration difficult)
- easier to inspire but reduced stored elastic energy -> creates active expiration
- smoking: causes immune system to release elastase, breaking down elastin
what is fibrosis? how does it affect compliance?
decreased compliance (inspiration difficult)
- particulate matter (ex. from bad air quality) triggers immune response -> macrophages
- macrophages secrete growth factors causing proliferation of fibroblasts, which increase collagen deposition
what is LaPlace’s Law?
P=2T/r
- inward pressure trying to collapse a bubble
- it will take twice the inspiratory pressure to keep a small alveolus open compared to one twice as large
why don’t alveoli collapse?
- mechanical tethering: alveoli tend to open their neighbours during lung expansion
- alveoli contain surfactant: reduces surface tension
what is surface tension?
occurs at an air-fluid interface, fluid molecules create an inward directed pressure
what is the composition of surfactant? how does it work?
surface active agent
- 90% lipid (hydrophobic)
- 10% protein (hydrophilic)
- hydrophilic heads pull strongly upwards on h2o molecules, reducing the net force on h2o molecules to move into bulk water
- hydrophobic tails prevent surfactant from going deeper into water; exert counter-force that pull surfactant upward towards the air
why is it important that surfactant reduces surface tension?
- minimizes the tendency for small alveoli to collapse -> maximizes surface area for gas exchange
- increases compliance and decreases elastic recoil so the lungs are easier to inflate
- keeps the alveoli moist
- minimizes fluid accumulation in alveoli (prevents pulmonary edema)
- maintains alveolar size
how does alveolar surface tension affect compliance?
reduces compliance
- surface tension is responsible for most of the lung’s elastic recoil
how does surfactant equalize alveolar expansion?
prevents different alveoli from expanding at different rates
- in rapidly expanding alveoli, surfactant becomes more dispersed -> increases surface tension and slows down expansion
what is infant respiratory distress syndrome? what is its etiology? what are its symptoms? what are its treatments?
- most common for births <28 weeks; reduced/absent surfactant (high surface tension)
- shortness of breath (high breathing rate), lungs are stiff and hard to inflate (alveoli collapse in exhalation)
- treated with high O2 + humidity, artificial ventilation, artificial surfactant
what are the pressures of the respiratory cycle?
- Pip (intrapleural pressure): always negative, driven by thoracic volume (how much the chest wall moves)
- Ptp (transpulmonary pressure): reflects elastic recoil of the lungs, determined by VL (more VL = more recoil)
- PA (alveolar pressure): equal to atmospheric pressure (Pb) when flow stops
what equation connects all the relevant pressures?
what is the flow of air equal to?
PA = PIP + PTP
- PTP = PA - PIP = 0 - (-4) = 4 mmHg
V (flow) = change in P (PA)/Raw (airway resistance)
what to the segments on the pressure-volume loop represent?
- 0AECD: total mechanical work of inspiration (PxV)
- 0ABCD: inspiratory work to overcome elastic resistance (to stretch the lungs) = potential energy available for passive expiration
- AECB: inspiratory work to overcome non-elastic resistance (airway resistance)
- ABCF: energy required to overcome resistance to airflow during expiration
if ABCF is less than 0ABCD, expiration can be passive (stored energy is enough to expire)
how does restrictive lung disease affect the P-V loop?
ex) pulmonary fibrosis (tissue stiffens)
- decreased compliance
- increased work of breathing
- shallow and faster breathing
how does obstructive lung disease affect the P-V loop?
ex) asthma or bronchitis (inflammed tissue)
- increased resistance
- increased inspiratory work
- increased expiratory work
- deeper and slower breathing
what is Poiseuille’s Law?
airway resistance (Raw) is proportional to viscosity of gas and length of tube, and inversely proportional to the fourth power of radius
Raw = 8nL/pir^4
- for laminar flow
what is the primary site of airway resistance?
large bronchi
- bronchi are in series -> resistance sums
what is Reynold’s number? what is turbulent flow? what is transitional flow?
Re (turbulence) = 2rvd/n
- 2000 < Re < 3000 = transitional flow (generations 1-6)
- Re > 3000 = turbulent flow -> trachea during cough (gen 0, high velocity, large air flow)
what factors influence airway resistance?
- lung volume: decreased volume = increased resistance
- mucus: decreases airway calibre
- edema: decreases airway calibre
- density of the air: increases when diving -> increases turbulence
- smooth muscle contraction/relaxation
- local effects of CO2
- cold/hypoxia
calibre = distensibility
what is the mechanism of bronchodilation?
sympathetic nerves release NA/A onto bronchial membrane
- NA/A bind to B2-adrenergic receptors, activates Gs pathway (increased AC, increased ATP -> cAMP -> activates PKA -> phosphorylates PLB -> disinhibits SERCA -> faster Ca2+ re-uptake -> faster relaxation)
- faster relaxation = bronchodilation
what are the mechanisms of bronchoconstriction?
- histamine is released and binds H1 receptors on bronchial membrane -> activates Gq -> activates PLC -> increases IP3 -> SR Ca2+ release -> bronchoconstriction
- vagus nerve releases ACh on M2-muscarinic receptors on bronchial membrane -> activates Gi -> inhibits AC pathway -> bronchoconstriction
how does CO2 have local effects in the upper airways?
upper airways may have CO2 chemoreceptors
increased upper airway CO2 (hypercapnia):
- increased ventilation
- decreased airway resistance (dilates airways)
decreased upper airway CO2 (hypocapnia):
- increased airway resistance
- particular in asthmatics
how does cold air and hypoxia affect airway resistance?
- increased secretion
- decreased mucociliary clearance
- pulmonary vasoconstriction
- decreased chemosensitivity
- decreased ventilation
- bronchoconstriction
- airway congestion -> increased resistance
what is tidal volume?
amount of air moving in and out during normal quiet breathing
- 500 mL
what is inspiratory reserve volume? what is inspiratory capacity
IRV: amount of air able to be inspired beyond tidal volume
- 3000 mL
IC: TV + IRV
- 3500 mL
what is expiratory reserve volume? what is residual volume?
ERV: amount of air that can be exhaled beyond tidal volume
- 1100 mL
RV: amount of air we can’t breath out
- 1200 mL
what is vital capacity? what is functional residual volume? what is total lung capacity?
VC: normal working range of lungs (everything but residual volume)
- 4600 mL
FRC: ERV + RV
- 3000 mL
TLC: everything
- 6400 mL
how do you calculate minute ventilation? what is a normal volume?
TV (500mL) x frequency of breathing (15 breaths/min) = 7.5 L/min
what volumes can not be measured using spirometry?
- RV
- FRC
- TLC
how can you measure anatomical dead space?
N2 washout:
1) normal quiet inspiration with 100% O2
- fills entire dead space with O2
- some O2 mixes with alveolar air
2) expire through an N2 meter
3) Vdeadspace = blue area x total volume expired/yellow area + blue area = 150 mL
blue area = conducting airways; yellow area = alveoli
what is a normal alveolar ventilation rate?
frequency x (TV - dead space)
12 x (500 - 150) = 4200 mL/min
how can you measure physiological dead space?
comparing arterial and expired CO2
- perfused alveolar PCO2 = arterial PCO2
- mixed expired PCO2 = PCO2 from perfused alveoli diluted by air from non-perfused alveoli
what are the features of a flow-volume loop?
- peak expiratory flow rate (PEFR)
- RV, TLC
- FVC (forced vital capacity - TLC -> RV)
- FEF25, FEF50, FEF75
FEF=forced expiratory flow at 25, 50, 75% of FVC
how does PEFR change with effort? how does VL affect expiratory flow?
- PEFR increases with effort
- first ~20% of expiration is effort independent
- at low VL, expiratory flow rates converge regardless of effort -> expiratory flow is effort independent and flow limited
- caused by increased airway resistance at low VL and positive Pip compressing airways
what is the equal pressure point?
airway pressure = transpulmonary pressure
- moves toward alveoli with low lung volume and increased airway resistance
- increased transpulmonary pressure cannot flow because airway compression matches driving force
- usually in cartilagenous airways
how does emphysema change the flow-volume loop? restrictive lung disease? obstructive lung disease?
- emphysema: shifts loop to the left
- restrictive (ex. pulmonary fibrosis): similar FEV1, reduced volumes
- obstructive (ex. asthma): reduced FEV1, larger lung volumes
what is peak expiratory flow rate? what is it affected by?
peak flow; represents the greatest flow rate during a maximal exhalation - FVC
- age, sex, height, weight
how is perfusion related to cardiac output? what does perfusion depend on?
blood flow through the lungs is equal to CO (CO = SV x HR = MAP/TPR) ; depends on:
- sympathetic, parasympathetic, hormones
- EDV, contractility, compliance, VR
- plasma volume, mean systemic filling pressure
- Poiseuille’s Law (radius) -> alpha and beta adrenergic receptors, ANG II, endothelin, ACh, NO, histamine
how do hydrostatic effects affect perfusion? what are the hydrostatic pressures at the base, middle, and apex of the lungs?
gravity has hydrostatic effects -> when upright, gravity is going to cause increased blood flow to the base of the lungs relative to the apex
- greater resting blood flow at base vs apex
- base: >25/8 mmHg
- middle: 25/8 mmHg
- apex: <25/8 mmHg
what is zone 1 of perfusion?
apex; does not occur in normal physiology (certain conditions ex) hemorrhage)
- PA>Pa>Pv
- capillary blood flow is completely stopped because the alveolar pressure is greater than the arteriolar pressure of the whole capillary
- alveoli is compressing neighbouring capillaries
what is zone 2 of perfusion?
apex to midlung; Pa>PA>Pv; pressures on the arteriole side are still low and pressures on the venular side are still negative
- arteriolar end has positive transpulmonary pressure, causing vessel to dilate
- top of zone 2: pulsatile flow -> systolic capillary pressure is greater than alveolar pressure (not diastolic), therefore flow is only during systole
- bottom of zone 3: target for recruitment -> pressures increase by 1 cm h2o for each cm down towards the base, opening and dilating vessels
what is recruitment? what is an example for a stimulus of recruitment?
the conversion of a closed vessel (or open but not conducting) to a conducting one by increasing Pa and Pv
- stimulus: exercise
what is zone 3 of perfusion?
middle; transpulmonary pressure is positive throughout the vessel, dilating it; Pa>Pv>PA
- top of zone 3: continuous flow
- bottom of zone 3: hydrostatic pressures of Pa and Pv increase -> perfusion increases towards the base of the lung because of increased dilation (distension) of the alveolar vessel, decreasing resistance and increasing flow
what is zone 4 of perfusion?
base; Pa>Pv>PA; contains extra-alveolar vessels
- vessels collapse despite high pressures
- extra-alveolar vessels have a less negative intrapleural pressure -> reduced distension force (less of a suction pulling them open)
decreased flow in extra-alveolar pressures
why is there decreased vascular resistance in pulmonary circulation?
passive changes:
1) recruitment
2) distension
how does recruitment decrease pulmonary vascular resistance?
the greater the perfusion pressure, the more open and conducting vessels there are
- lower flow pathways conduct more blood
- collapsed vessels are forced open with small pressure rises (maintains slow, less resistance flow)
how does distension decrease pulmonary vascular resistance?
once all vessels are open, further decreases in resistance due to vessels dilating (occurs when pressure is already high)
- increases in pressure distend the vessel, occurs with large pressure rises
how does perfusion of alveolar vessels change with the cardiac cycle?
- systole + inspiration: capillary pressure is positive, alveolar pressure is negative -> pulmonary vessels expand during systole
- diastole + expiration: capillary pressure is less positive, alveolar pressure is more positive -> pulmonary vessels are compressed during diastole
how does resistance in alveolar vessels change in response to lung volume?
alveolar vessels are compressed as alveoli expand and lung volume increases
how does resistance in extra-alveolar vessels change in response to lung volume?
with increasing lung volumes, the more negative intrapleural pressure pulls extra-alveolar vessels open
- at the end of inspiration, intrapleural pressure is negative + suction forces will distend in the extra-alveolar vessels and the resistance will decrease
how does hypoxia affect perfusion? how is it different to systemic hypoxia? what is the mechanism behind this?
alveolar hypoxia - PAO2 <70mmHg
- vasoconstricts pulmonary vessels directly adjacent, increases resistance + decreases flow
- opposite to hypoxic effect in systemic vessels
- shuts down flow to under-ventilated alveoli; greater hypoxia = greater vasoconstriction (graded response)
- mechanism may involve chemoreceptors: mitochondrial O2 sensor in VSM; decreased O2 -> decreases H2O2 from mitochondria -> Kv channel inhibition -> depolarizes VSM -> Ca2+ entry -> contraction
how does hypercapnia affect perfusion? how is it different to systemic hypercapnia? what is the mechanism behind this?
- vasoconstricts pulmonary vessels
- opposite to systemic circulation, less potent than hypoxia
- may act by decreasing pH -> local effect on pulmonary VSM
how does the ANS affect perfusion?
- sympathetic = decreased compliance, stiffens vessel wall
- parasympathetic = mild dilation
- small effects on pulmonary vasculature
- large effects on airway resistance (airway smooth muscle) -> bronchioles can bronchiodilate/constrict
how do metabolic factors affect perfusion?
least effective
- NO = vasodilator
- B-adrenergic agonists = dilators
- a-adrenergic agonists = constrictors
what forces in the capillary are for fluid efflux? fluid influx? what is the net force favouring?
efflux forces (29 mmHg):
- capillary hydrostatic P = 7 mmHg
- interstitial hydrostatic P = -8 mmHg
- interstitial fluid oncotic P = -14 mmHg
influx forces (28 mmHg):
- plasma oncotic P = -28 mmHg
net efflux = 1 mmHg
how does the net efflux pressure in pulmonary capillaries regulate capillary fluid exchange in the lung?
net efflux 1 mmHg = 20 mL/hour of fluid leaving capillary
- most enters lymphatics to prevent edema
- little amount enters alveolus to make it moist (evaporates)
what is the total ventilation rate? what is the alveolar ventilation rate?
- Ve = TV x frequency of breathing = 6.0-7.5 L/min
- VA= (TV-Vd) x frequency of breathing = (500mL - 150 mL) x 12 /min = 4.2 L/min
alveolar ventilation rate ~ 70% of total ventilation rate
how can we measure alveolar ventilation rate from alveolar CO2 (PACO2)? what is the alveolar ventilation equation?
- the body produces ~200mL/min CO2 from oxidative metabolism (VCO2), alveolar ventilation removes this CO2
- the relationship between VA and VCO2 is described as the alveolar ventilation equation:
VA = VCO2*k/PACO2
PACO2=PaCO2
what happens when VA is sufficient, insufficient, or in excess?
- sufficient: PaCO2 is normal (40 mmHg)
- insufficient (not enough ventilation): PaCO2 rises (>40 mmHg) -> hypercapnia due to hypoventilation
- excess (too much ventilation): PaCO2 falls (<35 mmHg) -> hypocapnia due to hyperventilation (breathing off too much CO2)
why does exercise have a higher curve, ie have a higher VCO2?
- metabolic rate increases, CO2 production increases, higher PACO2
- more likely to portray hypoventilation b/c not offloading CO2 fast enough to combat rising CO2 levels
how does increasing alveolar ventilation affect PAO2 and PACO2?
as VA increases, PAO2 and PACO2 approach their values of inspired air (PiO2, PiCO2)
how does the alveolar ventilation equation explain the effects of hypoventilation?
200 mL CO2/2.1 L alveolar air x 0.863 = 80 mmHg
- hypoventilation increases PACO2 -> not enough ventilation to offload 200 mL CO2 in sufficient time -> causes respiratory acidosis
how does the alveolar ventilation equation explain the effects of hyperventilation?
200 mL CO2/8.4 L alveolar air x 0.863 = 20 mmHg
- hyperventilation decreases PACO2 -> offloading CO2 too much -> causes respiratory alkalosis
what is Dalton’s Law?
total pressure of gas mixture is equal to the sum of the partial pressures of its constituents
what are the partial pressures of the gases in atmospheric air?
Pb = PCO2 + PO2 + PN2
PO2 = 0.21 x 760 = 160 mmHg
PCO2 = 0.0003 x 760 = 0.23 mmHg
PN2 = 0.78 x 760 = 593 mmHg
how does barometric pressure and saturation of air with water affect partial pressures?
- as barometric pressure decreases (ex. with altitude), partial pressures decrease
- saturated air with water decreases partial pressures of other gases (ex. PO2)
what is the alveolar gas equation? why does it give the value it gives?
PAO2 = PiO2 - PACO2/R
- PiO2 = 150 mmHg
- PACO2 = 40 mmHg (~ PaCO2)
- R = respiratory quotient; ratio of CO2 excreted to O2 consumed, depends on the metabolic substrate (carbs R = 1.0; lipids R = 0.7; usually R = 0.8)
PAO2 = 100 mmHg
how does ventilation change from apex to base? why does this occur?
ventilation increases from apex to base due to gravity and posture
- at FRC, intrapleural pressure less negative at the base so alveoli are underinflated and more compliant
- a given change in intrapleural pressure during inspiration produces a greater change in lung volume near base vs apex
what is the a) ventilation b) flow and c) V-Q ratio of the entire lung?
a) V = 4.2 L/min
b) Q = 5 L/min
c) V-Q = 0.8
how does the V-Q ratio change from base to apex? how do these values change?
V-Q ratio increases from base to apex
- Q has a more dramatic decrease from base to apex than V
- over-ventilation in the apex (high V-Q) ratio -> increased PAO2 and decreased PACO2
what happens when there is no perfusion? how is this compensated for?
due to pulmonary emboli, V-Q is increased (more ventilation, less perfusion)
- alveolar air PO2 rises and PCO2 falls
compensation:
- perfusion to other lung tissue increases
- decreased PCO2 = bronchoconstriction = decreases ventilation
- decreased perfusion = type II alveolar cells decrease surfactant secretion = decreased ventilation
what happens when there is no ventilation? how is this compensated for?
due to obstructed airway, V-Q is decreased (less ventilation)
- alveolar PO2 falls and PCO2 rises
compensation:
- increased ventilation of healthy lung
- hypoxia/hypercapnia = VSM constriction = decreased perfusion of blocked airways
what is Fick’s Law of Diffusion?
Vnet = DL x (P1-P2)
- Vnet = movement of gas
- DL = diffusion capacity of the lungs
- P1-P2 = driving force = Palveolus - Pcapillary)
what are determinants of diffusion capacity?
- Graham’s Law: rate of diffusion of a gas through a liquid is inversely proportional to the square root of its MW
- Henry’s Law
- tissue thickness
- diffusion distance (includes liquid barriers; ex. fluid in the lungs increases diffusion distance)
what is Henry’s Law?
concentration of gas dissolved in a liquid depends on its solubility and partial pressure
- solubility is higher at lower temperatures
- if alveolar capillary temp <37 degrees -> solubility decreases as blood warms deeper in circulation -> air emboli (gas evaporates into circulation)
what cardiopulmonary characteristics promote gas exchange?
- large surface area of alveoli and capillaries in close proximity minimizes diffusion distance
- thin epithelial/endothelial layers to minimize thickness of tissue barrier to diffusion
- substantial partial pressure differences
when and where is diffusion of O2 highly favourable?
- during inspiration -> increases surface area and decreased tissue thickness
- greatest PAO2 at apex of lungs -> largest diffusion gradient
- diffusion is greatest at the beginning of the capillary (arteriolar end) where PO2 is lowest and PCO2 is highest, and decreases along the capillary length
what are the diffusion steps of O2 moving from alveolar air to a RBC?
- alveolar O2 encounters water layer
- diffusion through cytosol of membranes of alveolar type I (pneumocyte) epithelial cell
- cross a thin interstitial space
- diffuses into blood plasma through the endothelial membrane
- diffuses into erythrocyte (RBC) and binds to Hb
how can carbon monoxide be used to determine diffusion capacity?
1) maximum inspiration from residual volume of 0.3% CO
2) hold breath for 10 s (allows Vco to diffuse into blood)
3) expiration
4) measure expired PAco
- the greater the reduction in CO the greater the diffusion capacity
5) calculate DLco
why is nitrous oxide perfusion limited?
equilibriates fast (~10% distance of capillary) because it doesn’t bind Hb
- only requires saturation of plasma and RBC cytosol
- ie fewer N2O molecules required to reach equilibrium
how do we know that O2 is not diffusion limited?
- high diffusion coefficient
- partial pressure gradient is the driving force for O2
why is O2 perfusion limited?
- 1/3 through capillary (within 250 msec) partial pressure of arterial O2 (PaO2) matches the alveolar partial pressure of O2 (PAO2)
- rapid equilibration implies that diffusion does not act as a limiting factor, supporting the classification that O2 exchange perfusion is limited
what is the transit time for RBCs from start to end of capillary?
750 msec
why is carbon monoxide (CO) diffusion limited?
Because capillary PCO fails to reach alveolar PCO at the end (no equilibriation)
- CO entering the RBC binds tightly to Hb
- the [CO]DISSOLVED (and
therefore Pco) hardly changes across the pulmonary capillary
- by the end of the capillary there is still a substantial relative gradient of CO from the alveolar air to the blood (ΔP)
how does exercise limit O2 exchange?
- increased CO -> decreased pulmonary capillary transit time (~250 msec)
- since transit time is decreased, it takes longer for PAO2 to match PaO2 (ie further down the capillary)
- increased CO -> recruitment and distention -> increased surface area -> increased DL
how does altitude limit O2 exchange?
- lower PbO2, decreasing the diffusion gradient of O2 (aka the driving force)
- takes longer for PAO2 to match PaO2 (ie further down the capillary)
what factors influence diffusion/perfusion limitation?
- DL
- Hb concentration
- pulmonary artery gas partial pressure (beginning of capillary)
- CO
- capillary length and diameter
how is oxygen transported? how much of it is delivered? how much is consumed? how much is extracted?
1) dissolved in plasma and RBC cytoplasm (2%)
2) bound to Hb (98%)
- delivered O2 = 1.03 L O2/min
- consumed O2 = 0.2 L O2/min
- extracted O2 = 0.2/1.03 = 20%
what is the structure of hemoglobin?
- iron atom + porphyrin ring = heme group
- 2 a and 2 B globin chains
- histidine residue
- binds up to 4O2
what is sickle hemoglobin (HbS)?
- genetic variation common in subsaharan Africa
- mutation in B globin gene of Hb
- causes polymerization of Hb
- distorts cell into sickle shape -> occlude small vessels (sickle cell crisis)
- prone to hemolysis (destruction of RBCs) -> hemolytic anemia
- sickle cells resistant to parasites (protection from malaria)
what is P50 on the oxyhemoglobin dissociation curve? what are normal values for a) PAO2 b) PaO2 c) PcO2?
- P50 = 27 mmHg
a) PAO2 = 103 mmHg
b) PaO2 = 90-95 mmHg (~98% saturation of Hb)
c) PcO2 = 40 mmHg
what does a right shift of the oxyhemoglobin dissociation curve entail?
greater P50
- higher partial pressures @ 50% binding of Hb at typical PO2 saturation (lower saturation of Hb)
- unloading more of the O2 from Hb into those tissues
- increasing delivery of O2 to tissues, favours offloading
what does a left shift of the oxyhemoglobin dissociation curve entail?
lower P50
- 50% Hb saturation at lower PO2
- high degree of saturation
- Hb still bound to O2
- delivered less O2 to tissues
- disfavours delivery of O2 to tissues
how does pH affect the oxyhemoglobin dissociation curve? how does CO2? what is this called?
decreased pH = RIGHT SHIFT (acidosis)
- reduced Hb saturation at given PO2
- decreased affinity aids O2 release in metabolically active tissue
increased CO2 = RIGHT SHIFT
- reduces Hb saturation
THE BOHR EFFECT: decrease in O2 affinity due to acidosis and increased CO2
how does temperature affect the oxyhemoglobin dissociation curve?
increasing temp = RIGHT SHIFT
- increased O2 released at tissues during exercise
- high temp reduces O2 affinity of Hb
how does diphosphoglycerate (2,3-DPG) affect the oxyhemoglobin dissociation curve? what is it?
increasing 2,3-DPG (exercise, anemia, alkalosis, pregnancy) = RIGHT SHIFT
- metabolic intermediary that accumulates in RBCs due to anaerobic metabolism (RBCs have no mitochondria)
- competes with O2 for heme (reduces Hb affinity for O2)
- binding of 2,3-DPG to Hb destabilizes the interaction of Hb with O2, promoting O2 release
how is CO2 transported in arterial blood?
1) 90% of CO2 is transported as bicarbonate (HCO3-) in RBCs (24 mM)
2) 5% of CO2 is transported dissolved in the plasma and RBC cytoplasm
3) 5% of CO2 is transported as carbamino compounds (ex. carbamino Hb)
how is CO2 transported as HCO3-? what is the chloride shift?
CO2+H2O - carbonic anhydrase -> H2CO3 -> HCO3- + H+
- H+ buffered by plasma proteins or Hb
- buffering is not perfect; venous blood pH = 7.35 (carrying more CO2, shifting eq to right); arterial blood pH = 7.4
- HCO3- leaves cell in exchange for Cl- -> CHLORIDE SHIFT: H2O enters with Cl-, maintaining electrostatic and osmotic equilibrium
how is CO2 transported in venous blood?
- 68% HCO3- (63% coming from tissues into RBC, 5% in plasma)
- 22% carbamino compounds
- 10% dissolved CO2 in RBCs and plasma
what is the Haldane effect?
deoxyHb transports CO2 better than oxyHb
- deoxygenated Hb has a greater affinity for CO2 and more readily forms carbamino Hb
- as Hb releases O2 at the tissues, more likely to pick up CO2
- at the lungs the high PO2 causes CO2 to unload more easily
what factors increase CO2 carrying capacity?
- increased PCO2 (Henry’s Law, increased HCO3-, increased carbamino Hb)
- increased plasma protein concentration (increases pH buffering, drives HCO3- production)
- increased plasma pH (increases HCO3-)
- increased Hb concentration (increased carbamino Hb)
- decreased O2 (increased carbamino Hb)
what is the Henderson-Hasselbach equation? what does it tell us?
pH = 6.1+log([HCO3-]/0.03xPaCO2)
- when pH is disturbed, it is due to a change in [HCO3-] (metabolic) or PaCO2 (respiratory)
what causes respiratory acidosis? how is it compensated for?
- develops when lung gas exchange is impaired (ex. barbiturate drugs or diseases like pneumonia or emphysema)
- increased PaCO2 increases H+ and HCO3-
metabolic compensation: - increases renal H+ secretion, drives renal reabsorption of HCO3-
- PaCO2 still elevated but acid disturbance is compensated
high PaCO2, high HCO3-
what are the mechanisms of renal H+ secretion and HCO3- absorption?
- almost all tubular HCO3- is absorbed; basolateral membrane of nephron is permeable to CO2 which converts to HCO3- and H+ via CA
- H+ moves across apical membrane into tubular fluid (is excreted) by different mechanisms (NHE, H+ pump)
- increased H+ excretion drives HCO3- uptake into the blood (eq shifts to right)
what causes respiratory alkalosis? how is it compensated for?
- develops due to hyperventilation (ex. altitude, anxiety)
- decreased PaCO2 decreases H+ and HCO3-
metabolic compensation: - decreased renal H+ excretion, decreases plasma HCO3-
- PaCO2 is still low but base disturbance has been compensated
low PaCO2, low HCO3-
what causes metabolic acidosis? how is it compensated for?
- due to loss of HCO3- (ketoacidosis, diarrhea)
- decreases HCO3- and increases H+
respiratory compensation: - increased H+ stimulates peripheral (directly) and central (indirectly) chemoreceptors
- stimulates ventilation and resulting hyperventilation reduces PaCO2; brings pH to normal levels
- PaCO2 is low but acid disturbance has been compensated
low PaCO2, low HCO3-
what causes metabolic alkalosis?
- due to loss of H+ (ex. vomiting)
- decreases H+ and increases HCO3-
respiratory compensation: - decreased H+ reduces chemoreceptor stimulation inducing hypoventilation
- causes plasma CO2 retention and pH to fall back to normal
- PaCO2 is high but base disturbance has been compensated
high PaCO2, high HCO3-
what are the 3 main areas of the central controller of ventilation?
1) medullary respiratory centre (essential)
2) apneustic centre (pons, modulatory, less understood)
- lengthens inspiration
3) pneumotaxic centre (pons, modulatory)
- shortens/inhibits respiration
what are the groups of the medullary respiratory centre?
dorsal respiratory group
- nucleus tractus solitarius (NTS)
- process afferent input
- mainly efferent inspiratory neurons
- generate rhythmic activity
ventral respiratory group
- nucleus retroambiguus, retrofacialis, paraambiguous
- coordinate efferent output
- inspiratory and expiratory neurons
how does rhythmicity work in the central control for ventilation?
- inspiration: phrenic n. output to diaphragm over 0.5-2s (allows for smooth lung inflation)
- expiration: after a brief burst, phrenic n. is inactive
where are the central chemoreceptors? what do they do?
- on ventrolateral surface of medulla
- heavily influenced by H+ (sensitive to CO2, not O2)
- neurons stimulated by acidosis tend to be serotonergic (excitatory)
- neurons inhibited by acidosis tend to be GABAergic (inhibitory)
how is ventilation dependent on CSF pH?
- CO2 can cross BBB
- CSF pH modulates ventilation
- acidosis in CSF due to CO2 stimulates ventilation
what are the peripheral chemoreceptors?
aortic and carotid bodies
- contain glomus cells
what are the properties of aortic and carotid bodies?
- high perfusion
- respond to changes in PaO2, PaCO2, pH
- only sensor for O2
- responsible for ~40% of the ventilatory response for CO2
- responsible for ~20% of ventilatory response to exercise
what are the properties of glomus cells?
sense O2, CO2, H+
- increased H+ (CO2) -> K+ channel inhibition
- decreased PO2 causes O2-sensitive K+ channel inhibition
K+ channel inhibition causes depol, releasing NT
- afferent fibres relay to brainstem (carotid sinus n. from carotid body; vagus n. from aortic body)
what is the mechanism of a) low PO2 b) high PCO2 and c) low pH on glomus cells? what is the net effect?
a) low PO2
- heme protein senses hypoxia -> O2 dissociates, reduces probability of K+ channel opening
- increases cAMP, inhibits K+ channel
- increases reduced glutathione, inhibits K+ channel
b) high PCO2 c) low pH
- increases H+ (NHE inactive b/c gradient is less), inhibits K+ channels
** causes depol., NT release onto glossopharyngeal nerve**
what is the integrated response of central and peripheral responses to hypoxia and hypercapnia?
more sensitive to CO2 changes than O2 changes
hypoxia:
- increases ventilation via peripheral chemoreceptors
- increases ventilation changes to acidosis and PCO2
hypercapnia:
- increases ventilation via peripheral and central chemoreceptors
what is the Hering-Breuer inspiratory inhibitory reflex?
negative feedback system that protects lungs from overinflation
- increase in lung volume stimulates bronchial mechanoreceptors -> stretch reflex mediated by vagus nerves
- results in termination of inspiratory drive at the medulla
- inactive during quiet breathing
what is Cheyne-Stokes breathing? what is apneustic breathing?
Cheyne-Stokes:
- changing tidal volume and breathing frequency
- seen with some CNS diseases and in healthy people at altitude
apneustic:
- sustained periods of inspiration with only brief expiration
- due to loss of inspiratory inhibition control with CNS damage
what is sleep apnea?
- unusually prolonged pauses in breathing
- long enough to change PaO2, PaCO2
- either obstructive or central sleep apnea
what is Ondine’s curse?
- no automatic breathing control
- congenital or result of brainstem trauma
- cease ventilation when asleep
- requires nocturnal mechanical ventilation or phrenic n. pacemaker
what defines the extent of damage due to myocardial ischemia?
- vessel affected
- transmural location
- location and extent of block
how can a supply and demand mismatch cause myocardial ischemia?
- anoxia (total O2 deprivation), hypoxia
- decreases FFAs
- decreased glucose
- build up of metabolites (CO2, lactate, K+, H+)
what are the consequences of ischemia?
- decreased beta oxidation due to decreased O2 availability -> decreases ATP production
- decreased glucose oxidation increases pyruvate conversion to lactic acid -> increased lactic acid decreases pH, causing acidosis
- increases CO2 waste increases H+ -> decreases pH and causes acidosis
- peroxidation of lipids (membrane and mito damage)
- hypocontractility and increased incidence of arrhythmia
what are the effects of acidosis and low ATP?
1) electrical remodelling
2) altered Ca2+ handling
3) reduced force of contraction
how does acidosis cause electrical remodelling?
protons inhibit many ion channels; net effect:
- decreased Na+ channel, voltage-gated K+ channel, and Ca2+ channel activity
- altered ion channel activity may be pro-arrhythmogenic, particularly if conduction pathways are affective (ex. bundle branches)
how does acidosis alter calcium handling?
- lowers systolic Ca2+: inhibition of Cav1.2 reduces Ca2+ entry; inhibition of RYR reduces SR Ca2+ release
- increases diastolic Ca2+:
- inhibition of NCX decreases Ca2+ extrusion
- intracellular protons leads to Na/H exchange = increased Na+ = Ca2+ entry via NCX (reversal of NCX)
- inhibition of SERCA reduces SR uptake of Ca2+
net effect: cytoplasmic Ca2+ rises
- but Ca2+ is elevated even during diastole, causing tonic contraction (contraction during diastole)
- elevated Ca2+ activates protease enzymes (ex. Calpain), causing protein breakdown
how does acidosis reduce force of contraction?
hypocontractility (reduced force of contraction):
- decreased myofilament Ca2+ sensitivity - need more Ca2+ to produce contraction (TnC)
- decreased cross-bridge cycling (decreased ATPase activity)
what are the effects of ischemia on Na+ and K+?
decreased Na-K-ATPase activity (decreased ATP and increased H+ - directly reduces ATPase activity)
- extracellular K+ accumulation causes Ek and RMP to become more depolarized
- intracellular Na+ accumulation reverses NCX activity, causing Ca2+ entry
net effect:
- elevated intracellular Na+, elevated extracellular K+, and elevated RMP
- increased excitability - proarrhythmic
