Pathophysiology of the respiratory system II –
Pulmonary gas exchange
Physiological principles – alveolar ventilation and alveolar gas equations
Oxygen cascade
Respiratory insufficiency
Hypoxemia – classification of possible causes
(1) hypoventilation / (2) diffusion impairment / (3) shunt / (4) VQ mismatch
Ventilation – perfusion mismatch/(in)equality in detail
Gas exchange in lungs
• main function of respiratory system – gas exchange between blood and
outside environment – is governed by temporally changing requirements of
organism to maintain a stable pH (by excretion CO2) and for O2
– maintained in optimum by regulation of intensity of ventilation (see control of
ventilation further)
• requirements defined mainly by consumption of ATP and its replenishing by
mitochondria
– oxidative phosphorylation
– other O2 consuming processes
• driving force for O2 exchange (and reciprocally for CO2)
is the gradual decrease of its partial pressure, i.e.
concentration gradient between inhaled air, blood
and tissues:
– partial pressure = the pressure that the gas would have
if it alone occupied the same volume at the same temperature
• solubility of the gas matters
– very high for CO2 = there are no biological barriers
in the body to block CO2 diffusion
• tidal volume exchanged by each resting breathing
cycle ads only 0.5L to FRC = meaning
a composition of the alveolar air is more or less
constant
• alveolo-capillary gas exchange takes place
in respiratory zone, i.e. between alveolus
and blood by simple diffusion through
alveolar septum, lung interstitium and
capillary wall
– in the past physiologist believed it was an
active transport
• fish, bird lung
Gas exchange in lungs
Pulmonary gas exchange as an ultimate purpose of breathing
• Alveolar ventilation (VA = VT – VD)
– at rest there is a constant rate of carbon dioxide generation in the body and rate of the
diffusion in the lungs
• while pattern of flow in conductive airways (both upper and lower airways, i.e. dead space) varies
between turbulent / transitional / laminar (depending on Reynolds number – see elsewhere), in
alveoli gas moves across by diffusion
– therefore PACO2 is more or less constant (or fluctuates very little)
• A = alveolar  a = arterial
– all of the CO2 exhaled by the body comes from gas exchanging areas of the lung,
that is ventilated alveoli
• no CO2 comes from a dead space, because there is an atmospheric air there with negligible CO2
content
– the PACO2 is equivalent to the PvCO2 (complete diffusion) and proportional to
PaCO2
• the „excess“ (A-a difference) of CO2 produced is determined by respiratory quotient (RQ)
105
hypothetical perfect lung
PB= 760 mmHg
at sea level
PWV = 47 mmHg
Exchange of gas between the alveolus and the respiratory
bronchiole occurs purely by random diffusion
• There are minimal changes in lung volume between inspirium and expirium
– breathing in and out doesn’t completely replenish the stale air in the lungs
– in fact most of the volume of the lungs stays in the lungs, and each breath dilutes fresh air in
the functional residual capacity (FRC) of the lung
• At rest, with a typical tidal volume VT (the depth of each breath) of around 500 ml, 150
ml is lost in dead space (VD), and the remaining 350 mL is mixed into the much larger
~3,000 mL of existing FRC
– so, it’s not a matter of breathing in, exchanging gases and breathing out
• The process of gas exchange goes on continuously, and breathing is just the
mechanism for removing a little stale air and adding a little fresh stuff
• Therefore, VA is a tidal volume (VT) minus the dead space (VD)
Transport of CO2 in the blood
• CO2 can be considered to be in simple
solution in the plasma, the volume
carried being proportional to its partial
pressure (physically dissolved)
• solubility of carbon dioxide is much
higher (20) than that of oxygen,
therefore physically dissolved CO2 is
much more important than for O2
Blood is in the lungs for less than a second—but that is long enough
to equilibrate the gases (normally!)
• Cardiac Output (CO) of RV equals to that of LV, i.e. CO 5L/min [CO = SV (70mL)  f (72
bpm)]
– the total amount of blood in the lung capillaries is normally about 70 mL (= one stroke volume of the
heart
– at a heart rate of 72 bpm, the blood is in the lungs only 60 s min−1/72 min−1 = 0.83 s
– in literature this value is often 0.75s
• during this short time, venous blood entering the lungs equilibrates nearly completely
with the alveolar air so that the exiting blood has nearly the same PCO2 and PO2 as
alveolar air
– blood actually equilibrates faster than its dwell time, indicating that there is some reserve in the
diffusing capacity to accommodate the increased cardiac output and higher needs for gas exchange
during exercise
the total length of pulmonary capillary
Pulmonary gas exchange as an ultimate purpose of breathing
• Alveolar ventilation (VA = VT – VD)
• at rest there is a constant rate of carbon dioxide generation in the body
and rate of the diffusion in the lungs
– CO2 production can be lowered by cooling the body
– CO2 production increases by exercise or in pathology
• therefore PACO2 is more or less constant (or fluctuates very little)
• all of the CO2 exhaled by the body (V'CO2) comes from gas exchanging
areas of the lung, that is ventilated alveoli (not from a dead space)
• the PACO2 equivalent to the PvCO2 (complete diffusion with very short
equilibration time) and proportional to PaCO2
• (1) The alveolar ventilation equation – describes the
‘mechanics’ = is (alveolar) ventilation sufficient to
maintain gas exchange?
– allows us to calculate alveolar ventilation rate
– V'A = (V'CO2/PaCO2) * K = ~4.2 L/min
• thus the alveolar ventilation is proportional to the rate of carbon
dioxide exhaled by the body (V'CO2) and inversely proportional
to the PaCO2
• instructive in understanding the influence of alveolar ventilation
on the partial pressure of arterial carbon dioxide
– for example, if V'A is doubled, the PaCO2 is halved
– if alveolar ventilation (V'A) is halved, the PaCO2 will double
• (2) The alveolar gas equation – describes the
interdependency of alveolar gases and derives PAO2
– describes the concentration of gases
in the alveolus and demonstrates, that
their dynamic is interconnected
– answers the question: is alveolar oxygen sufficient
and how much is needed to maintain arterial oxygen
normal
• allows to derive an „A-a difference“ as a measure of
diffusion efficiency
– PAO2 = inspired value (= 0.21 x (760 - 47)) – pressure taken by CO2 (=
PaCO2 / RQ (0.8) =  105 mmHg
• basically the two gases (in fact all gases) compete for
partial pressures
– if one increases, others must decrease
– nitrogen irrelevant
• normally PACO2 in mixed venous blood (i.e. in pulmonary
artery is the same as in alveolus) is 45 mmHg and is
proportional to PaCO2
• if PACO2/PaCO2 doubles (e.g. hypoventilation) then PAO2
falls in half, i.e. 50 mmHg
Pulmonary gas exchange as an ultimate purpose of breathing
Example: why I need to be aware of the two equations?
– alveolar gases are very difficult/impossible to measure directly
– on the contrary, we can relatively easily measure arterial blood gases (ABG), i.e. PaO2 and PaCO2
• (1) The alveolar ventilation equation
– is (alveolar) ventilation sufficient to maintain normal gas exchange?
• NO - patient has a two-fold increase of PaCO2 (80 mmHg)  he hypoventilates (VA is inversely related,
therefore halved)
• (2) The alveolar gas equation
– is alveolar oxygen sufficient?
• NO – they are mutually interconnected/dependent
• normally PAO2 = PiO2 (= 0.21 x (760 - 47) = 150) – PACO2 (= PaCO2 40 mmHg/ RQ 0.8 = 45 mmHg) = 105 mmHg
• hypoventilation PAO2 = PiO2 (= 0.21 x (760 - 47) = 150) – PACO2 (= PaCO2 80mmHg / RQ 0.8 = 45 mmHg = 100
mmHg) = 50 mmHg
– and how much is needed to maintain arterial oxygen
• to maintain PAO2 normal, i.e. 105 mmHg we have to change the fractional concentration of O2 in inspired air
– PiO2 (= 0.21 x (760 - 47) has to be 200 mmHg (i.e. SiO2 = 200/(760-47)) = 28%)
• PiO2 (= 0.28 x (760 - 47) = 200) – PACO2 (= PaCO2 80mmHg / RQ 0.8 = 45 mmHg = 100 mmHg) = 100 mmHg
Respiratory insufficiency/failure (= abnormality of pulmonary gas
exchange as an ultimate purpose of breathing)
hypoxemia = PaO2 decreased (<60 mmHg/8.0 kPa)
normocapnia = PaCO2 normal or low (<50 mmHg/6.7 kPa)
PA-aO2 increased
hypoxemia PaO2 decreased (<60 mmHg/8.0 kPa)
hypercapnia PaCO2 increased (>50 mmHg/6.7 kPa)
PA-aO2 normal
pH<7.35
Causes:
(1) low ambient oxygen (e.g. at high altitude)
(2) mild alveolar hypoventilation
(3) diffusion problem
(4) R-L shunt
(5) ventilation-perfusion mismatch leading to pathological dead space
(parts of the lung receive oxygen but not enough blood)
Causes:
(1) severe alveolar hypoventilation
(2) ventilation-perfusion mismatch leading to
pathological shunting (parts of the lung receive blood
but not air – such as in obstructive diseases)
FOUR (4) CAUSES OF HYPOXEMIA (I.E. ABNORMALITY
DEFINING RESPIRATORY FAILURE)
Quantitatively
• (1) inhaled atmospheric air
– 21% O2, 0.03% CO2, 78% N2, water gases 0.6% and the rest
other gases (argon, helium, ..)
• atm. pressure 760 mmHg (101 kPa)
• PO2: 0.21 x 760 = 160 mmHg
• analogically PCO2 = 0.3mmHg
• (2) alveolar air (mixture of inhaled and exhaled air)
– PAO2 = 100mmHg (13.3kPa), PACO2 = 40 mmHg (5.3kPa), Pwater
vapour = 47 mmHg
• PAO2 in alveolus is lower than atmospheric due to higher CO2 content in
alveolus (diffusion from blood)
• (3) arterial blood
– PaO2 = 90mmHg (12kPa), PaCO2 = 45 mmHg
• diffusion of oxygen not 100% and there is also physiological shunt
• (4) venous blood
– PvO2 = 30 - 50mmHg
air (P) alveolar (PA) arterial (Pa) venous (Pv)
O2 21kPa/150mmHg 13.3 kPa/100mmHg 12kPa/90mmHg 5.3kPa/40mmHg
CO2 0.03kPa/0.3mmHg 5.3kPa/40mmHg 5.3kPa/40mmHg 6.0kPa/45mmHg
Oxygen cascade
oxemia any interference with this
physiological cascade (fall
in PAO2/PaO2 will result in
tissue hypoxia
transport of oxygen:
- 98% bound to Hb = measured as Hb saturation
- 2% dissolved = measured as PaO2
Hypoxemia (low PaO2) - classification
• (1) Hypoventilation (low V'A)
– low PaO2 due to low PAO2 with normal atmospheric
pressure and normal FiO2
• (2) Diffusion impairment
– (a) low inspired oxygen or atmospheric pressure
• e.g. high altitude hypoxemia
– low PaO2 due to low PAO2 with low atmospheric pressure and normal
FiO2
• or gas mixture with low FiO2
– (b) shortening of time spent by blood in the capillary
– (c) thickening of alveolo-capillary barrier
• low PaO2 with normal PAO2 with normal atmospheric pressure
and normal FiO2 (increased P(A-a)O2)
• (3) R-L shunt
– low PaO2 with normal PAO2 with normal atmospheric
pressure and normal FiO2 (increased P(A-a)O2)
• (4) Ventilation perfusion inequality
– low PaO2 with variable PAO2 with normal atmospheric
pressure and normal FiO2
(1) Hypoventilation as a cause of hypoxemia
(results in low PaO2 + hypercapnia + normal A-a gradient)
• normally PaCO2 in mixed venous blood (i.e. pulmonary artery) is about 47
mmHg and nearly the same in alveolus (47 mmHg)
• if PaCO2 doubles due to hypoventilation (i.e. VA halves– see alveolar
ventilation equation) then PAO2 falls in half (see alveolar gas equation), i.e.
50 mmHg (more than PaCO2 rise since RQ is 0.8)
• can we restore the PAO2?
– using alveolar gas equation you can calculate what the inspired fraction of oxygen
should be to bring it back to normal
• i.e. PAO2 100 mmHg = (FiO2 ?? x (760 - 47)) - (PaCO2 80 mmHg x 1.25) = 0.28, i.e. 28% oxygen
• examples – typically extra-pulmonary (the lung itself is typically normal)
– respiratory CNS generator
• drug overdose (barbiturates, narcotics, …), CNS trauma, brainstem disease,
metab. alkalosis, encephalitis, congenital apnoea syndromes, …
– neuromuscular
• myasthenia gravis, ALS, Guillain-Barre, muscular dystrophy, cervical spinal
cord injury (phrenic nerve), polio, botulism, …
– chest wall
• deformities, injury (flail chest), obesity, …
– upper airway obstruction
• croup, epiglottitis, OSA,
The opposite situation is bad too: Hyperventilation
• Common causes:
– anxiety, panic attack, nervousness, or stress
• Other causes include:
– bleeding
– use of stimulants/drug overdose (e.g. salicylates - aspirin)
– severe pain
– pregnancy (to increase PaO2)
– lung infection
– lung diseases (COPD or asthma, pulmonary embolism)
– heart conditions (e.g. heart attack)
– diabetic ketoacidosis
– head injuries
– anaemia
– high altitude (over 6,000 feet)
– septic shock
– hyperventilation syndrome
• Symptoms (of PaCO2  pH (respiratory alkalosis)):
– peripheral vasoconstriction incl. brain!!!
– decreased ionised calcium  tetany
• tingling in the lips, hands or feet, headache, weakness, fainting,
and seizures
• in extreme cases carpo-pedal spasms (a flapping and contraction
of the hands and feet)
(2) Diffusion impairment as a cause of hypoxemia
(low PaO2 + normocapnia + large A-a gradient)
• due to
– low inspired oxygen or high
altitude
– shortening of the time blood
spends in pulmonary capillary
– oxygen is normaly perfusion
limited
• extreme exercise
• hyperkinetic circulation
• increased velocity of pulmonary
circulation
– thickened alveolo-capillary
barrier
– oxygen might become
pathologically diffusion limited
• PaO2 typically normal at rest,
but hypoxemia appears in
exercise
Determinants of diffusion
• Fick's Law: V'gas = D * A * ΔP/T
– V'gas = Rate of gas diffusion
across permeable membrane
– D = Diffusion coefficient of that
particular gas for that membrane
– A = Surface Area of the
membrane
– ΔP = Difference in partial
pressure of the gas across the
membrane
– T = Thickness of the membrane
Gases do not diffuse across a homogeneous barrier
Oxygen is normally perfusion-limited
• blood entering the pulmonary capillary has plenty of time to equilibrate
– blood is in the lungs for less than a second—but juts one third of this time is long
enough to equilibrate the oxygen (normally!)
O2 might become diffusion limited- hence the A-a difference importance
• normally 5-15 mmHg
• increases with age
– A-a diff  age/4 + 4, e.g. in 100 yrs/4 + 4  30  age related hypoxemia
• A-a diference
• PAO2 – from alveolar gas equation
– PAO2 = inspired value (= 0.21 x (760 - 47)) – pressure taken by CO2 (= PaCO2 / RQ (0.8) =  105 mmHg
• PaO2 – from ABG
– normal in alveolar hypoventilation
– increased in
• diffusion impairment that is often present in intrinsic restrictive pulmonary disease
– spirometry: FVC, FEV1, FEV1/FVC ratio
– ABG: PaO2,  SaO2 Hb
• A-a difference – high!!!
Examples of disease leading to diffusion impairment
• pathologically oxygen can be diffusion-limited
• typically in interstitial lung diseases
– idiopathic pulmonary fibrosis
– associated with autoimmune diseases
• i.e. rheumatoid arthritis, scleroderma, …
– sarcoidosis
– drug-induced
– acute hypersensitivity pneumonitis
– inhalation of substances and subsequent
scarring = pneumoconiosis
• i.e. silicosis, asbestosis, coal-miner lung, …
• manifest typically with exertional dyspnea,
dry cough and clubbing
• NOTE, very often the diffusion impairment
combines with a dominant V/Q mismatch
– because diffusion impairing diseases are
typically intrinsic restrictive diseases from the
point of view of the ventilation
Idiopathic pulmonary fibrosis (IPF)
• an age-related disease, with the vast majority of
individuals being diagnosed at >60 years of age
• median survival time of 3–5 years after diagnosis
• pathogenesis of IPF not fully understood
– the current hypothesis is that subclinical alveolar
epithelial injury imposed on ageing of epithelial
cells in genetically susceptible individuals leads to
aberrant wound healing, secretion of high levels of
growth factors, cytokines, chemokines,
accumulation of fibroblasts and differentiation into
myofibroblasts, and deposition of the extracellular
matrix (ECM)
– genes – examples
• surfactant protein (SP)-C, mucin 5B, other genes involved
in cell adhesion, integrity and mechano-transduction
Proposed pathophysiological features of IPF: Recurrent epithelial cell injury in genetically susceptible individuals causes senescence of epithelial cells and epithelial mesenchymal transition
(EMT), releasing profibrogenic mediators induces fibrocytes/fibroblasts migration and differentiation into profibrotic macrophages/myofibroblasts, resulting in aberrant matrix deposition
with destructing lung architecture. SNP: single nucleotide polymorphism; TGF: transforming growth factor; HGF: hepatocyte growth factor; PGE2: prostaglandin E2; FGF-1: fibroblast
growth factor-1; FGF-2: fibroblast growth factor-2; CTGF: connective tissue growth factor; PDGF: platelet-derived growth factor; VEGF: vascular endothelial growth factor; MMP: matrix
metalloproteinases; TIMP: tissue inhibitors of metalloproteinases.
(3) Pathological right to left shunt as a cause of hypoxemia
(low PaO2 + normocapnia + large A-a gradient)
• fraction of the RV cardiac output that bypasses pulmonary circulation
(a. pulmonaris capillary network around respiratory airways)
– oxygen-poor blood from the right heart flows in the left heart without passing
through functional, ventilated alveoli
• physiological shunts
– (1) bronchial circulation
• a. bronchialis capillary network around conductive airways – anatomical dead space
– (2) thebesian veins draining coronary vessels into the left ventricle
• majority of the coronary capillary network drains into coronary sinus, a large vein
returning the deoxygenated blood from the heart muscle to the right atrium so that it
can be replenished with oxygen via pulmonary circulation.
lumen of ventricle
(3) Pathological R-L shunts as a cause of hypoxemia
(low PaO2 + normocapnia + large A-a gradient)
• (A) pathological anatomical (pre-existing) shunts aggravating normal
right-to-left shunting
– intrapulmonary: pulmonary arteriovenous malformations (PAVMs)
• usually congenital direct communications between pulmonary artery and vein bypassing
the capillary network
– can be single or multiple, unilateral or bilateral, and simple or complex
– clinical consequences
» hypoxemia
» increased risk of paradoxical embolism (air bubbles, bacteria or clot from systemic
venous blood going to systemic circulation) resulting in stroke or brain abscess
» increased risk of rupture (manifesting as haemoptysis or haemothorax)
– extrapulmonary: right-to-left intra-cardiac shunts
• typically the pressure gradient favours left-to-right shunting, however, when
combined with other conditions increasing resistance, the shunt goes form right-to-
left
– patent ductus arteriosus (PDA)
– atrial septal defect – patent foramen ovale
– ventricular septal defects
• (B) pathological functional (capillary) causes of increased right-toleft
shunting
– fluid-filled alveoli
– atelectasis, ARDS
• (C) shunt-like V/Q mismatch - poorly ventilated alveoli (obstruction)
• Hypoxemia caused by right-left shunts prototypically cannot be
corrected by oxygen therapy
Examples of pathological anatomical shunts
(4) Ventilation-perfusion inequality as a cause of hypoxemia
(low PaO2 + variable normo/hypercapnia)
• Alveolar air composition
– the partial pressures of oxygen and carbon dioxide in any given alveolar unit
are largely determined by the relative rates of ventilation and perfusion of that
alveolus
• For efficient gas exchange it is important that there is a match between
ventilation of the alveoli (VA) and their perfusion (Q)
– in ideal alveolus VA /Q ratio = 1
• However, V'/Q' ratio of alveoli within
even a healthy lung is not uniform
– regional variation within the lung when
an individual is standing upright
– the action of gravity results in a vertical
gradient of both blood flow and ventilation
in the upright lung
• although both blood flow and ventilation are
lowest at the lung apex and highest in the
base, the vertical gradient for blood flow is
wider than that for ventilation
• Ventilation-perfusion mismatch is by far the most common cause of
arterial hypoxaemia, because many lung diseases aggravate the
physiological V/Q mismatch
(VT – VD)  f = VA
(500mL – 150mL)  15 = 5L
SV  f = CO
70mL  75 bpm = 5L
Normal lung - relationship between ventilation and perfusion
• There is a wide variation in the VA/Q ratio to some extent already in healthy subjects, however, it
does not represent a serious health problem in healthy man
– tendency for ventilation not to be matched by perfusion towards the apices, with the reverse occurring at the bases
• kind of physiological dead space in apexes (VA/Q = 3.3)
• kind of physiological shunt in bases (VA/Q = 0.7) – lower PAO2, higher PACO2 and lower pH
• All the blood from various lung regions mixes, however, quantitative contribution of the blood from
bases of the lungs is much greater!
Distribution of VA/Q mismatch largely contributes to the A-a difference
of oxygen
• Blood form various zones mixes with
largest contribution of that from lung
bases
– therefore alveoli with lower VA/Q (from lung
bases with more perfusion) affect the arterial
PaO2 more (PaO2 97 mmHg)
– on the contrary, ventilation does not differ that
much, therefore PO2 in the expired alveolar air
is 100 mmHg
Physiological V/Q inequality contributes to the O2 cascade
V/Q mismatch – causes
additional difference in
PO2 between
pulmonary capillaries
and pulmonary vein
and further systemic
arteries
Effect of the V/Q ratio on Alveolar Gas Tensions
• There are limits in the VA /Q ratio
• The effect of diseases leading to an increased
dead space (VA /Q ratio > 1) can usually be
overcome by a compensatory hyperventilation
of normally perfused alveoli
– alveolar hyperventilation reduces the alveolar
PACO2 and considerable diffusion of CO2 leads to a
proportional fall in the carbon dioxide content of
the blood
• An increased R-L shunting (VA /Q ratio < 1)
results in arterial hypoxaemia that cannot be
effectively compensated for by hyperventilation
• In advanced disease with large VA /Q mismatch
this compensation cannot occur, leading to
increased alveolar and arterial PCO2, together
with hypoxaemia which cannot be
compensated by increasing ventilation
Example of a distribution of ventilation-perfusion ratios
VA and Q measured with the multiple inert gas infusion technique. [Left] healthy subject,
[Middle] COPD type A (i.e. emphysema), [Right] COPD type B (i.e. chronic bronchitis).
Ventilation-perfusion inequality (mismatch)
• VA/Q inequality (mismatch) is significantly
increased in many lung diseases and contributes
to their pathophysiology
–  VA/Q ratio (i.e.  dead space)
• e.g. pulmonary embolism
–  VA/Q ratio (tj.  pulmonary shunt)
• obstructive diseases
• lung collapse
• optimalisation of  VA/Q - vasoconstriction
reflex
– vessels around hypoventilated part of the lung contract
– but!!! see obstructive diseases  development of
pulmonary hypertension
Arterial hypoxemia refractory to supplemental inspired O2
Hypoxemia dif. dg.
Hypoxic pulmonary vasoconstriction (HPV)
• a physiological phenomenon in which small pulmonary arteries
constrict in the presence of alveolar hypoxia (low oxygen levels)
– as in hypoventilation and low VA/Q ratio
• typically in obstructive diseases resistant to compensatory hyperventilation
such as chronic bronchitis
• a homeostatic mechanism that is intrinsic to the pulmonary
vasculature
– intrapulmonary arteries constrict in response to alveolar hypoxia,
diverting blood to better-oxygenated lung segments, thereby
optimizing ventilation/perfusion matching and systemic oxygen
delivery
• chronically happens with low V/Q ratio (and event. in long-lasting
hypoventilation)
• mechanisms
– in response to alveolar hypoxia, a mitochondrial sensor dynamically
changes reactive oxygen species and redox couples in pulmonary artery
smooth muscle cells (PASMC)
– this inhibits potassium channels, depolarizes PASMC, activates voltagegated
calcium channels, and increases cytosolic calcium, causing
vasoconstriction
– sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and
hypoxia-inducible factor (HIF)-1α, leading to adverse pulmonary
vascular remodelling and pulmonary hypertension (PH)
– this pre-capillary PH leads to right heart remodelling – cor pulmonale
• the primary role is in the non-ventilated fetal lung, HPV diverts
blood to the systemic vasculature
Mechanism of HPV The current model of the
cellular mechanism of hypoxic
pulmonary vasoconstriction in
a rat pulmonary artery (PA).
Relevant ion channels are
displayed. Under normoxia,
the membrane potential of
the smooth muscle of the PA
is held at approximately −50
mV because of the TASK-like
background current of a K +
channel. Hypoxic conditions
initially decrease TASK activity.
When combined with TXA 2 ,
activation of NSC induces
membrane depolarization up
to the threshold voltage for
activation of K v channels
(Step 1). In addition to the
NSC activation, hypoxic
inhibition of the K v current
further depolarizes the
membrane potential (Step 2).
As the membrane potential
depolarizes above −40 mV, the
activation of VOCC L
eventually allows for Ca 2+
influx for contraction of
smooth muscles. K v , voltagegated
K + channel; NSC,
nonselective cation channel;
TASK-1, background-type K +
channel with a two-pore
domain (K2P); TXA 2 ,
thromboxane A 2 ; VOCC L ,
voltage-gated L-type Ca 2+
channels.
OXYGEN CASCADE IN THE BODY
What are we breathing?
Oxygen cascade – progressive drop of oxygen content
• reasons for normal gradual decrease of PO2 between air and
blood:
– „competition“ with CO2 in alveoli
• up to the atmospheric pressure
– see alveolar gas equation
– less that 100% diffusion across alveolo-capillary membrane
• irregularity of its thickness and change in the rate of lung perfusion
– diffusion & perfusion limitation
• lower solubility of O2 compared to CO2
– physiological right-left shunt
• mixing of oxygenated and deoxygenated blood
– nutritional supply of large airways by aa. bronchiales and their drainage to v.
pulmonalis
– drainage of vv. coronarie and thebesian veins into left atrium and other chambers
– physiological ventilation-perfusion inequality
• other contributing factors to drop of oxygen content
– physiologically a small fraction of abnormal Hb
• Met-Hb
• COHb
– various oxygen extraction by tissues
• pathological aggravation in any if these steps contributing to drop
of oxygen tension can cause hypoxia
– hypoxic (= hypoxemic!!!!)
– anaemic
– circulatory
– histotoxic
gas atmospheric air alveolar air
nitrogen 78% 79.6%
oxygen 21% 15% (14.8%)
carbon dioxide 0.04% 6% (5.6%)
Oxygen in the body
• there are no significant O2 stores in the body
• available oxygen lasts for  5min
– therefore breathing has to be continuous process
– disruption means
• life-threatening emergency (<5min)
– reversible vision loss in 7s, unconsciousness in 10s
• clinical death (5-7min), event. brain death
• death of the whole organism (>10min)
• 85-90% used in aerobic metabolism coupled with ATP
production
– maintenance of ion gradients
– muscle contraction
– chemical synthetic reactions
• remaining processes are less sensitive to PaO2
– hydroxylation of steroids
– detoxification of xenobiotics in liver
– synthesis of NO ( vasodilation)
– degradation of haem by hemoxygenase
Transport of oxygen in the blood
• CO2 can be considered to be in simple solution in the plasma,
the volume carried being proportional to its partial pressure
(physically dissolved)
• O2 is carried in chemical combination with hemoglobin in the
red blood cells, and the relationship between the volume
carried and the partial pressure (physically dissolved fraction) is
not linear
– in physiological PaO2 (90mmHg/12kPa) and normal hemoglobin there is
nearly 100% Hb saturation
• if PaO2  10kPa/60 mmHg, saturation do not significantly decreases
– advantage when being in high altitude
– saturation measured by pulsion oxymetry
• O2 diffuses to tissues according to demands of mitochondria
– for adequate production of ATP in mitochondria O2 in tissues have to
be > 0.13kPa/1mmHg = critical oxygen tension
• organism needs oxygen:
–  250 mL/min  350 L/day in rest
– much more (10x) during exercise
• total O2 in the blood
– total [O2] = 1.39  [Hb]  % saturation / 100 + 0.003  PO2 = 20.5 ml/dl
Shifting of Hb dissociation curve and the effect of [Hb]
CONTROL OF RESPIRATION
& ITS DISORDERS
46
Control of respiration
• central chemoreceptors in
medulla oblongata
• peripheral chemoreceptors in
aorta and glomus caroticum (via
n. glossopharyngeus and vagus)
– active when PaO2 below 10kPa
– activation supported by
hypercapnia
• pulmonary mechanoreceptors
Central chemoreceptors
48
• sensitive to PaCO2 (and subsequent formation of
H+ in CF)
• H+ cannot go through hematoencephalic barrier
therefore response to other than respiratory
acidosis slower
– increase in [H+] due to metabolic acidosis (e.g. diabetic
ketoacidosis) will subsequently increase ventilation with a
fall in PaCO2 causing deep (Kussmaul) respiration
• very quick adaptation to acute or intermittent
hypercapnia, however, gets adapted to chronic
hypercapnia due to HCO3- in cerebrospinal fluid
– problem in COPD
• they adjust to hypercapnia and hyperventilation ceases
• -in these patients hypoxaemia is the chief stimulus to respiratory
drive
• oxygen treatment may therefore reduce respiratory drive and
lead to a further rise in PaCO2
Peripheral chemoreceptors - oxygen senzors
• Glomus caroticus and aortic bodies - sensitive to change
of PaO2 and pH chgange
– decrease of 02 in these cells closes K+ channels 
depolarization   intracellular Ca2+  excitation 
activation of the respiratory centre
• When hypoxemia is not accompanied with hypercapnia,
activation of this sensors is when PaO27,3 kPa (55 mm
Hg)
Respiratory stimuli
• Coordinated respiratory
movements result from
rhythmical discharges arising
in interconnected neurones in
the reticular substance of the
brainstem (medulla
oblongata), known as the
respiratory centre
– via the phrenic and intercostal
nerves to the respiratory
musculature (principal and
auxiliary respiratory muscles)
- the pulmonary blood flow of 5 L/min carries 11 mmol/min (250 mL/min) of oxygen from the
lungs to the tissues
- ventilation at about 6 L/min carries 9 mmol/min (200 mL/min) of carbon dioxide out of the
body
- normal PaO2 is between 11 and 13 kPa (83 - 98 mmHg)
- normal PaCO2 is 4.8-6.0 kPa (36-45 mmHg)
Respiratory centres
• Respiratory centre is formed by
several groups of neurons:
– The basic automatic rhytm of respiration
is due to activity of Dorsal Respiratory
Group (DRG) — inspiration neurons –
efferent impulses go to diaphragma and
inspiration intercostal muscles
• DRG also obtain afferent stimuli from the
peripheral chemoreceptors and several
pulmonary receptors
– Ventral Respiratory Group (VRG)
contains both inspiration and expiration
neurons
• inactive during to normal ventilation,
increased ventilation leads to their
activation
Higher respiratory centres
• Medulla
– quiet inspiration
– —effort inspiration and forced expiration
• Pons - Pneumotaxic and apneustic
centres can modulate depth of
ventilation and its frequency
– Apneustic centre:
• supports inspiration by the activity of
inspiration neurons
– Pneumotaxic centre:
• antagonises apneustic centre
• inhibition of inspiration
• Ventilation can be modulate by cortex,
limbic systém and hypothalamus
(emotions and diseases).
Apnea
• suspension of external breathing
• causes
– voluntarily achieved (free diving)
– drug-induced (e.g. opiate toxicity)
– during sleep
• mechanically induced (e.g. OSA)
• infants (sudden death)
– central apnea syndromes
• periodical breathing
• Cheyne-Stokes breathing
– patients with cardiac failure
– consequence of neurological disease or
trauma
Obstructive sleep apnea (OSA)
55
• Episodic obstructions of airflow during sleep due to airway
blockade
– breathing pauses can last from a few seconds to minutes
– may occur 30-60 times or more an hour
– typically, normal breathing then starts again, sometimes with a loud
snort or choking sound
• During apnea deep sleep shifts to light sleep
– as a result, the quality of sleep is poor, which makes one tired during
the day (excessive daytime sleepiness)
• Commonly undiagnosed, typically overweight adults
• Risks – due to intermittent hypoxia with significant Hb desaturation
to levels as low as 50%
– changes in the neurons of the hippocampus and
frontal cortex
– hypertension
– coronary artery disease
– type 2 diabetes
– depression
– sleepiness-related accidents
56
RESPIRATORY INSUFFICIENCY
0
10
20
30
40
50
60
70
80
90
0 20 40 60 80 100 120
PaCO2(mmHg)
PaO2 (mmHg)
Respiratory insufficiency (RI)
• the aim of the respiration is to maintain optimal values of blood gases
by way of their exchange with environment, therefore the main
criteria of resp. insufficiency are blood gases values
• RI is defined as PaO2 ≤60 mmHg and event. PaCO2 ≥ 50 mmHg
– ↓PaO2 (hypoxemia) is a constant component of RI
• a dop below 60 mmHg already decrease Hb saturation
– pulsion oxymetry!
– ↑PaCO2 (hypercapnia) sometimes, often normo- or even hypocapnia
• see all 4 causes of hypoxemia and their variable effect on PaCO2
• classification of resp. insufficiency
– type I or partial or hypoxemic
• ↓PaO2 10 kPa and normo or ↓PaCO2)
• failure of oxygenation
– type 2 or global or ventilatory
• ↓PaO2 10kPa and PaCO2 6 kPa)
• failure of mechanical ventilation
– compensated – normal blood pH
» compensatory increase of hydrogen carbonates
– decompensated – decrease of blood pH < 7,36 (respiratory acidosis)
• patterns of blood gas abnormality is different in various types of
disease – for example:
– A - pure hypoventilation
– B - severe V/Q inequality (e.g. bronchial obstruction)
– C - interstitial lung disease with diffusion impairment
– D - R-L shunt
– E - effect of oxygen breathing
A
C
B
D
E
Aetiology and consequences of RI
Respiratory insufficiency (RI)
• extra-pulmonary causes of low paO2
(hypoxemia/hypoxia) are not usually classified as RI
– cardiovascular (heart disease with right-to-left shunt)
– circulation hypoxia
• classification of RI
– latent RI: normal blood gases at rest, abnormal during
exercise
– manifest RI: blood gases pathological in rest
• time course:
– acute: abrupt onset
• aspiration of foreign body, pneumothorax, asthma attack
– chronic: slowly progressing, variable compensation
• COPD, lung fibrosis, cystic fibrosis
– chronic with acute exacerbations:
• COPD
• diagnostics of resp. insufficiency
– examination of blood gases and acidbase
balance (Astrup)
• arterial blood (a. radialis, a. cubitalis, a.
femoralis)
• arterialised blood (ear lobe)
• capillary blood (fingers) – imprecise
– parameters:
• blood pH – normally 7.36-7.44
– i.e.[H+] = 35-44 nM
• paO2 – partial pressure of oxygen
– 10-13 kPa (75-95 mmHg)
• paCO2 – partial pressure of carbon dioxide
– 4.8-6 kPa (36-45 mmHg)
• HCO3 – hydrogen carbonates
– 22,0-26,0 mmol/l
• BE – base excess
– normally 0
• SatO2 – saturation of Hb (normally > 90%)
• Mean PvO2
– 6 kPa (45 mmHg)
• Mean PvCO2
– 6.1 kPa (46 mmHg)
RI is one of the causes of generalized hypoxia
• = deficiency of O2 in the organism (paO2 10kPa/75mm Hg)
• types:
– (1) hypox(em)ic hypoxia =  arterial PO2 - leads to central cyanosis
• causes of hypoxemia
–  PO2 in inspired air (PO2 (high altitude, low FiO2)
– hypoventilation due to damage of respiration center
– diffusion impairment (fibrosis, emphysema)
– anatomical shunting of non-oxygenated blood (heart)
– ventilation-perfusion mismatch
– (2) anemic hypoxia = normal arterial PO2
•  concentration of hemoglobin
– anemia, leukemias
• abnormal hemoglobin with low ability to bind oxygen
– carbonylhemoglogin (COHb )
– methemoglobin
– (3) circulatory hypoxia = normal arterial PO2 – leads to peripheral cyanosis
• decreased cardiac output
• decreased of systemic blood pressure
• (local tissue ischemia)
• microcirculation defects
– (4) histotoxic hypoxia – normal arterial PO2 ,  venous PO2
• Intoxication with cyanides, cobalt, …)
pO2
kidney
erythropoetin
Blood marrow
erytropoesis
Sugar
Lipids
Proteins
cell
+ O2 CO2
CO2
H2O
mitochondria
mitochondria
Histotoxic hypoxia
Hypoxic hypoxia
O2
Circulation hypoxia (ischemic)
Anemic hypoxia
Intermittent, chronic intermittent and chronic hypoxia
• Intermittent hypoxia
– an effective stimulus for evoking the respiratory, cardiovascular, and
metabolic to some extent beneficial
• they may provide protection against disease as well as improve exercise
performance in athletes
• Long-term consequences of chronic intermittent hypoxia (such
as OSA) may have detrimental effects
– hypertension, cerebral and coronary vascular problems
–  right ventricular heart mass, pulmonary
vascular remodeling and pulmonary hypertension
– developmental and neurocognitive deficits and neurodegeneration
• Chronic hypoxia induces proliferation of the vasculature due to
angiogenesis (up-regulation of VEGF) but can also change the
integrity of vessels, leading to changes in vascular
permeability (e.g. contribution to acute mountain sickness)
Hypoxia and gene transcription
• The ability of hypoxia to
promote persistent
adaptations is due in
part to its ability to
induce changes in gene
transcription
• The regulation of the
expression of a wide
variety of genes involved
in hypoxic adaptations is
largely due to activation
of a hypoxia-sensitive
transcription factor,
hypoxia-inducible factor
1 (HIF-1)
– HIF-1 is a heterodimer
of HIF-1 alpha and HIF-1
beta
– oxygen levels directly
regulate the expression
of the HIF-1 component
in a dose-dependent
manner
According to the severity and duration of exposure, intermittent hypoxia (IH) may have either beneficial effects,
involving pre- and postconditioning, or detrimental effects as in sleep apnea. It is not clear whether pre/postconditioning-like
phenomena occur during chronic exposure and contribute to the differential
susceptibility between patients for IH-related consequences and/or to the age-related decline in mortality
observed in sleep apnea patients
Multidimensional classification of lung diseases
• basically each pulmonary disease can be classified un
multiple aspects
– whether it causes a ventilator impairment and of what kind –
spirometry and other kinds of tests
• obstructive (FEV1) vs. restrictive (FVC, TLC)
– whether it causes a gas exchange impairment and of what
kind – blood gas analysis
• 4 causes hypoxemia (hypoventilation, diffusion, R-L shunt, V/Q
mismatch)
– whether it combines with CO2 retention
• hypoxemic (type 1, partial) vs. hypercapnic (type 2, global) RI
– whether it affects ABB and which way - ABG
• respiratory acidosis vs. alkalosis
– what kind of symptoms they produce
• cough / dyspnea / cyanosis / change of breathing pattern