Ventilatory system is basically composed of two zones namely Lung respiratory and conducting zones.
Respiratory zone – respiratory bronchioles, alveolar ducts & sacs
Conducting zone – bronchioles, bronchi, trachea
Alveoli is the structural and functional unit of the lungs. Alveoli have largest cross-sectional area
Bronchioles have smooth muscle & cartilage
23 divisions of branches into ever smaller conduits
Protective mechanisms in respiratory system
Mucous-secreting, ciliated cells line conducting zone airways.
Large particles stop at nose, smaller ones caught in cilia, finest particles (like asbestos) make it into alveoli
Gaseous exchange in ventilatory system can be divided into four functional components:
Ventilation – movement of air into lungs (need pump to generate flow, pipes slow down flow – R)
Perfusion – movement and distribution of blood through pulmonary circulation
Diffusion – movement of O2 and CO2 across air-blood barrier or alveolar-capillary membrane
Control of breathing – process of regulation of gas exchange to meet metabolic needs of moment
Respiratory quotient, RQ = CO2produced = 200 ml/min. = 0.8 (average)
CO2consumed 250 ml/min.
Carb RQ = 1, fat RQ = 0.7, protein RQ = 0.8
A = alveolar
a = arterial blood
v = venous blood
Non-respiratory functions of respiratory system:
(upper airway includes nose, paranasal sinuses, naso- and oropharynx, larynx)
1) route for water loss, heat elimination (warms, moistens air so alveoli don’t dry out – oxygen and carbon dioxide can’t diffuse across a dry membrane)
2) enhances venous return (respiratory pump)
3) helps normalize pH by altering amount of CO2 (H+-producing) exhaled
4) enables speech, singing, other vocalization – larynx – vocal cords act as ‘vibrator’
5) defends against inhaled foreign matter (filters particulates or microbes via mucous coat propelled towards larynx by ciliary action, cough reflex, sneeze reflex, immunoglobulins – both locally produced and brought into lung from other sites)
6) removes, activates/deactivates various materials passing through pulmonary circulation (i.e., turns prostaglandins off, angiotensin II on)
7) nose – sense of smell
Lungs contain 300 million alveoli with – 0.3 mm in diameter
total surface area of lungs is about 75 m2(size of tennis court)
Collateral ventilation – airflow between adjacent alveoli (via pores of Kohn)
Pleurisy – inflammation of pleural sac (painful “friction rub”)
atmospheric pressure = 760 mmHg at sea level, decreases as altitude increases
Intra-alveolar pressure (intrapulmonary pressure) will equilibrate with atmospheric pressure
Intrapleural pressure (intrathoracic pressure) = 756 mmHg – vacuum (called ‘-4’); closed cavity
Negative intra-alveolar, intrapleural pressures provide driving force for inhaling/exhaling
transmural pressure – pressure across surface of lungs, = Palveolus – Ppleural space
Two forces hold thoracic walls & lungs in close apposition
thorax cannot be expanded its own without expanding the lungs
1) Intrapleural fluid’s cohesiveness (like water between two slides)
2) Transmural pressure gradient (most important)
intra-alveolar pressure = 760 mmHg, pushes out against intrapleural p. of 756 mmHg
atmospheric pressure = 760 mmHg, pushes in against intrapleural p.
Neither chest wall nor lungs are in their resting position (both are actively pushing against space)
Pleural space has slightly negative pressure because chest is pulling out, lungs are pulling in, and there’s no extra fluid to fill expanded space
Pneumothorax – air enters pleural cavity, pressure equalizes with atmospheric pressure, transmural pressure gradient is gone → lungs collapse, thoracic wall springs out
Before inspiration – respiratory muscles are relaxed, no air is flowing, intra-alveolar p. = atm. p.
Major inspiratory muscles (diaphragm, external intercostals) contract → thoracic cavity enlarges
[Diaphragm is innervated by phrenic nerve; dome-shaped at rest, contracts & pulls down. Responsible for 75% of enlargement of thoracic cavity during inspiration. Contraction of external intercostals enlarges cavity in lateral and AP dimensions (elevate ribs when contracting)]
As lungs expand, pressure decreases (to 759 mmHg) → air flows in
(alveolar pressure is negative during inhalation, positive during exhalation)
Intrapleural pressure drops to 754 mmHg (ensures that lungs will be fully expanded)
Lung expansion is not caused by movement of air into lungs.
With deeper contractions, contract diaphragm and external intercostals more forcefully & contract accessory inspiratory muscles (SCM, scalenes, alae nasi, small muscles of neck/head) to raise sternum & first 2 ribs
At end of inspiration – inspiratory muscles relax, diaphragm is dome-shaped again, rib cage falls because of gravity once external intercostals relax, chest walls & stretched lungs recoil → volume decreases, pressure increases (to 761 mmHg) → air flows out
During quiet breathing, expiration is passive (due to elastic recoil of lungs – no muscular/energy expenditure), whereas inspiration is always active.
During heavy breathing – active expiration – contract abdominal muscles (increase intra-abdominal pressure → pushes diaphragm up → increases intrathoracic pressure), internal intercostal muscles (pull ribs downward, inward) → lungs are emptied more forcefully.
During forceful expiration, intrapleural pressure exceeds atmospheric pressure, but lungs don’t collapse because intra-alveolar pressure increases, too (4 mmHg pressure gradient stays same)
Paralysis of intercostal muscles doesn’t affect breathing much, but paralysis of diaphragm = can’t breathe. Phrenic nerve is C3-C5, so patients with paralysis from neck down can still breathe.
Flow, V = ∆P/R
∆P = pressure gradient between atmosphere and alveoli
R is primarily determined by radius
Resistance of total airways circuit depends on #, length, cross-sectional area of conducting airways. Each terminal bronchiole has greater resistance to flow than trachea, but because of vast cross-sectional area, their overall contribution to total R is less than that of central airways (since bronchioles are arranged in parallel).
In healthy patient, overall respiratory system has extremely low R
Laminar vs. turbulent flow
Flow can be laminar (low flow rate) or turbulent (fast flow rate)
In small airways, flow is usually laminar
For laminar flow, R = 8ηl (Poiseuille’s Law) η = viscosity, l = length
Turbulent flow has different properties – driving pressure is proportional to square of flow (V2)
Turbulence is most likely to occur with high velocity, large diameter.
Volume of inflation of lung has important effect on airway resistance
Pressure = (vol./compliance) + flow * resistance P = pressure required to breathe
Chronic obstructive pulmonary disease (COPD)
Narrowing of lumina of lower airways. When airway R increases, larger ∆P must be present to maintain same airflow. Expiration is more difficult than inspiration – “wheeze” as air is forced out through narrowed passages. In normal patients, smaller airways collapse – further outflow stops only if lung volume is very low (lungs can never be completely emptied)
Chronic bronchitis – triggered by frequent exposure to cigarette smoke, pollution, other allergens. Airway lining thickens, mucous production increases, ciliary mucous elevator is immobilized by irritants. Increased mucous → bacterial infections
Asthma – obstruction due to 1) thickening of walls b/c of inflammation, histamine-induced edema, 2) plugging of airways by very thick mucous, 3) airway hyperresponsiveness – trigger-induced spasms (allergens, irritants, infection). Most common chronic childhood disease.
Emphysema – collapse of smaller airways, breakdown of alveolar walls (irreversible). Can happen because of 1) excessive release of trypsin from alveolar macrophages as defense against cigarette smoke irritants (lungs normally protected by α1-antitrypsin, but can be overwhelmed), 2) genetic inability to produce α1-antitrypsin
(asthma and emphysema start in small airways – difficult to detect – ‘silent airways’)
Amount of inspired air that makes it to alveoli depends on:
**Strength of pump (muscles)
**Airway resistance (frictional resistance, 80% total R)
**Tissue resistance – frictional resistance of lungs and chest wall (20% total R)
**Inertance – energy must be expended to set system in motion
(Need to overcome stiff/elastic recoil, frictional resistance, and inertance)
1) elastic recoil – returning to preinspiratory volume at end of inspiration
2) compliance– measure of distensibility, magnitude of change in volume for given transmural ∆P Defined by slope of pressure-volume curve for lungs – curve is steep in normal operating range (only at very low/high volumes does curve flatten). Normal compliance is 200 cm/ml H2O. Different compliance for expiration/inspiration b/c of surfactant – hysteresis. Static compliance is measured without airflow; dynamic compliance is measured during airflow. (poor compliance = stiff lung, restrictive disease = more work to breathe)
Pulmonary elastic behavior depends on:
1) CT in lungs has lots of elastic fibers (arranged in meshwork)
2) alveolar surface tension
water molecules want to be close together – resist expansion of surface area (the greater the surface tension, the less compliant the lung). If alveoli were lined with water alone, surface tension would be so great, airways would collapse.
pulmonary surfactant (lipid-protein mixture) lowers surface tensionbecause water-surfactant attraction is not as strong as water-water → increases pulmonary compliance, reduces lung’s tendency to recoil. Produced by type II pneumocytes
LaPlace’s Law à P = 2T/r P = inward-directed collapsing pressure, T = surface tension
Smaller airways are more likely to collapse than large ones because of greater surface tension (smaller r), but surfactant is more effective at lowering surface tension in smaller airways (less spread out). Surfactant stabilizes small alveoli.
**Evidence of these two factors of lung elastic recoil is found in differing pressure-volume characteristics of saline-filled vs. air-filled lungs (saline-filled are easier to stretch than air-filled)
You can have separate pressure-volume curves for chest wall, lungs – combine to get one for total respiratory system. Two structures are in series, interdependent – force required to inflate lung equals sum of pressure difference across lung and across chest wall.
Interdependence of neighboring alveoli – surrounding alveoli resist collapse of another alveolus.
Respiratory Distress Syndrome (RDS) – not enough type II cells to make surfactant
Work of Breathing
Normally only required on inspiration
Subdivided into compliance work (to expand lungs against lung/chest wall elastic forces); tissue resistance work (to overcome viscosity of lung/chest wall); airway resistance work
Work = P * V
Measurements of Lung Volumes
3-5% of total energy expended by body goes to breathing (heavy exercise – can increase 50-fold)
in obstructive lung disease, up to 30% of body’s energy expenditure is for breathing – even at rest!
Quiet breathing – 2,200 ml (expiration) – 2,700 ml (inspiration) tidal volume = 500 ml
Tidal volume (TV orVT) – 500 ml at rest. Amount entering/leaving lungs during one breath. As tidal volume increases, intrapleural and intra-alveolar pressures decrease in direct proportion.
Inspiratory reserve volume (IRV) – 3,000 ml. extra air you can breathe in, using inspiratory muscles (beyond normal tidal volume)
Inspiratory capacity (IC) – 3,500 ml. IC = TV + IRV
Expiratory reserve volume (ERV) – 1,200 ml. extra air you can breathe out, using expiratory muscles (beyond normal tidal volume)
Residual volume (RV) – 1,400 ml. amount that can’t be expired from the lungs (can measure with tracer like helium)
Functional residual capacity (FRC) – 2,500 ml. Volume of lungs after normal passive expiration. FRC = ERV + RV
Vital capacity (VC) – 4,600 ml. Maximum volume change possible. VC = IRV + TV + ERV
Total lung capacity (TLC) – 6,000 ml. TLC = VC + RV
Forced vital capacity (FVC) – total volume expired from maximum inspiration to maximum expiration; normal range is 80-120% normal tidal volume.
Forced expiratory volume in 1 second (FEV1) – maximum volume that can be expired in one second. FEV1= 80% VC (normal)
Maximum mid-expiratory flow rate (MMEFR) – FEF25-75 – forced expiratory flow over middle half of the FVC, gives us most information about small airways (<2mm diameter)
Peak expiratory flow rate (PEFR) – FEFmax – highest expiratory flow achieved. Can only be measured from flow/volume curve
Spirometer – air-filled drum floating in water. Breathe into drum – records volume changes on spirogram. Most lung volume subdivisions can be measured directly from spirogram
trapped gas within lung must be measured either by gas dilution method or by body plethysmography. Lung volumes can also be measured by x-ray – planimetry
Spirometry can measure TV, IRV, IC, ERV, VC (others measured indirectly, calculated)
Forced vital capacity (FVC) maneuver – take in deepest breath possible, breathe out as much as possible. Data can be displayed as volume vs. time or as flow vs. volume
if airways resistance is normal, FEV1 > 70%
Obstructive ventilatory defect – decreased air flow through tubes, normal tidal volume. Can be from 1) upper airways disease; 2) peripheral airways disease (from asthma, cystic fibrosis, chronic obstructive bronchitis, bronchiectasis); or 3) pulmonary parenchymal disease (emphysema).
Restrictive ventilatory defect – normal flow, normal R, but small vital capacity, FVC, FEV1 are reduced (in ratio to each other). Can be chest wall, pleural, space-occupying intra-thoracic lesion, extra-thoracic conditions (obesity, pregnancy, ascites), or interstitial lung disease. Reduction in lung volumes below 80% of predicted values.
Examples of lung volumes being smaller than predicted (restrictive defect):
Fibrosing (scarring) – increased elastic recoil
Diseases of chest wall (kyphoscoliosis) – increased elastic recoil
Diseases of the pleural space (pleural effusion) – compress lung
Tests of gas exchange function of lungs
Arterial blood gas determination (ABGs) – measurement of dissolved tensions of CO2 and O2 as well as pH of sample of arterial blood
Pulse oximetry – photometric measurement of saturation of hemoglobin with O2. (non-invasive)
DLCO – diffusing capacity of lung for carbon monoxide, usually done by ‘single breath’ method (DLCOsb). DLCO is affected by factors other than characteristics of gas exchange membrane; membrane thickness and increased surface area reduce DLCO.
Ventilation (V – ventilation, Q – perfusion)
Volume of air breathed in and out in one minute
Respiratory (minute) ventilation, V• = TV (ml/breath) * f, respiratory rate (breaths/min)
At rest: 6,000 ml = 500 * 12 (6 L air breathed in and out per min.)
With exercise, can increase 25-fold, to 150 L/min.
TV is more important than respiratory rate when minute ventilation increases
Dead space (VD) – volume of air-filled space incapable of gas exchange with blood
=Anatomical dead space – 150ml. volume of conducting airways (350ml used for gas exchange)
(equal to individual’s lean body weight in pounds)
Alveolar ventilation, VA• = (TV – VD, dead space) * f, respiratory rate
At rest: 4,200 ml = (500-150) * 12
Alveolar ventilation is about 5 L per minute = cardiac output (excellent transfer of gases)
Normal respiratory rate is 12-15 breaths/minute
**if you breathe deeply & slowly, respiratory ventilation can stay same but alveolar ventilation increases
**if you breathe shallowly & rapidly, respiratory ventilation can stay same but alveolar ventilation decreases (even to zero)
Each tidal breath does not completely fill/empty an alveolus – reservoir of gas ‘stored’ within alveoli that’s only gradually replenished. Volume = 3,000 ml – prevents fluctuation in alveolar gas tensions with each tidal breath.
(alveolar ventilation is more important measurement than respiratory ventilation, since that’s where gas exchange is done)
alveolar gas equation: PAO2 = FiO2 (PB – PH20) – (PACO2/R)
solving for conditions at sea level & R = 0.8: PAO2 = 0.21(760-47) – (40/0.8)
PAO2 = 100
obstructive lung disease – easy to fill lungs, hard to empty
TLC is normal
FRC, RV are increased
VC, FEV1, FEV1/VC% are decreased
restrictive lung disease – lungs are less compliant than normal
TLC, IC, VC are decreased
RV is normal
FEV1/VC% is normal or even increased
Increasing tidal volume is most efficient way to increase alveolar ventilation (increase respiratory rate and alveolar ventilation increases somewhat, but dead space is also increased)
Not all alveoli are equally ventilated with air, perfused with blood → alveolar dead space
(minimal in healthy patients, but can be lethal) ventilated, but don’t participate in gas transfer
physiologic dead space – sum of anatomical & alveolar dead space
Lower regions of lung are better ventilated than upper zones.
Gravity is largely responsible. pleural pressure is more negative at top of thoracic cavity – greater distending pressure for alveoli at top of lungs (top alveoli are larger in size). alveoli on bottom vs. top operate on different parts of a pressure-volume curve
lower regions of lung are better perfused than upper zones.
gravity is primary determinant. hydrostatic pressure gradient from top to bottom b/c lowest point in lung is 30 cm below highest point à pressure gradient of 30 cm water = 23 mmHg (15 mmHg above heart, 8 mmHg below heart)
Perfusion conditions in lung divided into three zones (a=pulm.art, A=intra-alveolar, v-pulm.vein)
Zone 1: Pa < PA collapse of vessel before it crosses alveolus; no forward flow; doesn’t exist in normal lungs – might occur if person has hemorrhaged (BP, intravascular volume are low)
Zone 2: Pa > PA > Pv flow driven by difference between arterial/alveolar pressure; primary area of distension, recruitment of vessels during exercise
Zone 3: Pa > PA, Pv > PA continuous forward flow through distended vessels.
Matching of ventilation to perfusion
there is not perfect matching of ventilation to perfusion in most alveoli. non-uniform distribution of both results in alveolar units with varying ratios of ventilation to perfusion (V/Q)
alveoli at apex are overall poorly ventilated, perfused, but relatively better ventilated than perfused = high V/Q ratio
if no perfusion but good ventilation, alveolar gas tensions will be same as in trachea (PAO2 = 150, PACO2 = 0). No effect on downstream gas tensions – part of dead space. But if there is some degree of perfusion à PAO2will be high, PACO2 will be low
alveoli at base are well ventilated, perfused, but better perfused than ventilated = low V/Q ratio
if no ventilation, but some perfusion, alveolar gas tensions in unit will be same as those in mixed venous blood (no fresh air being added). PAO2will be low, PACO2 will be high (blood exiting capillary will be low in O2, high in CO2)
units with low V/Q ratios have greater effect on overall gas exchange since they receive greater proportion of total pulmonary blood flow.
A high V/Q unit can’t compensate for impact of low V/Q unit because it’s at flat part of S-shaped oxygen-hemoglobin dissociation curve – raises PO2, which results in more dissolved O2, but not much more HbO2
Any rise in PCO2 in arterial blood stimulates respiratory centers to increase alveolar ventilation à removal of CO2 through alveolar units with better V/Q ratios. Overventilation of these units can’t raise PaO2 since they are operating on flat upper portion of oxygen-Hb saturation curve
Measurement of V/Q mismatch
alveolar-arterial gradient – P(A-a)DO2 or A-a gradient – refers to pressure difference for O2 between alveolar conditions and arterial blood. Measurement of inefficiency of oxygen transfer.
**measurement of A-a exists even in normal patients, contributed to by 1) ventilation-perfusion mismatch in normal lung, 2) small amount of shunt caused by bronchial, Thebesian circulations.
**A-a gradient can be calculated using alveolar gas equation to calculate expected ideal PAO2, measure actual PaO2.
**Normal A-a gradient varies with age – rough estimate is 25% of person’s age in years
**If A-a gradient is higher than normal, due to:
increased V/Q mismatch
increased shunt fraction
markedly abnormal diffusion of oxygen – rare clinically b/c of free diffusion of O2, CO2
Venous admixture – proportion of blood flowing through true right-to-left shunts or hypoventilated lungs (units with low V/Q ratios) – measure of wasted perfusion. Calculated from variation of shunt equation:
Qva = CiO2 – CaO2
QT CiO2 – CvO2
Physiologic dead space – proportion of ventilation to both anatomic dead space and hypoperfused lung (high V/Q ratios) – measure of wasted ventilation. Calculated from equation:
VD = PaCO2 – PECO2
Normal VD/VT ratio during resting breathing is 0.2 – 0.35
CO2and O2 are exchanged via simple diffusion – no active transporters – passively move down partial pressure gradients.
When bulk movement of air ceases at terminal bronchioles, oxygen moves towards alveolus by diffusion, carbon dioxide diffuses away from alveolus.
ideal gas law: PV=nRT n = # moles of gas, R = gas constant, T = absolute temperature
Boyle’s Law: as volume of gas increases, pressure decreases
Normal atmospheric air = 79% N2, 21% O2, a little CO2, pollutants, etc.
Total atmospheric air pressure = 760 mmHg, of which 79% is from N2, 21% from O2, etc.
Partial pressure of oxygen, PO2 is normally 160 mmHg (or torr)
PN2is normally 600 mmHg PCO2 is normally 0.03 mmHg
Alveolar PO2 > pulmonary capillary PO2, so more oxygen goes into blood (diffuses until equal).
Alveolar PO2 < atmospheric PO2because 1) air is warmed to 37°C & saturated with water once it enters; water vapor adds 47 mmHg partial pressure, essentially ‘diluting’ partial pressure of other gases, 2) air inspired is mixed with lots of old, “dead” air (FRC). Only 1/7 of total alveolar air is replaced with each breath (<15% alveolar air is “fresh”).
Average alveolar PO2 is 100 mmHg, remains nearly constant throughout cycle (as does blood PO2, as does oxygen in blood available to tissues)
Average alveolar PCO2 is 40 mmHg, also fairly constant
Average arterial PO2 is 100 mmHg, PCO2 is 40 mmHg
Blood entering pulmonary capillaries is systemic venous blood (via pulmonary arteries),
systemic venous blood PO2 = 40 mmHg, PCO2 = 46 mmHg
O2 expelled from lungs = O2 extracted, used by tissues
During exercise, venous blood PO2can drop to 30 → increases ∆P at alveoli → more O2 diffuses from alveoli into blood.
Other factors influencing rate of gas transfer
Partial pressure gradients are the main factor determining rate of gas transfer, but there are others.
during exercise, pulmonary bp increases b/c of increased cardiac output → forces open many of previously closed pulmonary capillaries → increases surface area for gas exchange
emphysema – SA reduced because many alveolar walls are lost – fewer, larger chambers (same when part of lung is collapsed or when part of lung is surgically removed)
pulmonary edema – increased interstitial fluid between alveoli and pulmonary capillaries, caused by pulmonary inflammation or left-sided congestive heart failure
pulmonary fibrosis – replacement of delicate lung tissue with thick fibrous tissue in response to certain irritants
pneumonia – inflammatory fluid accumulation in/around alveoli. (viral/bacterial/aspirating food)
increasing tidal volume increases surface area by stretching alveolar walls, and makes walls thinner.
Clinical measurement of diffusion characteristics of alveolar-capillary membrane done by test called ‘diffusing capacity for carbon monoxide (DLCO).’
Alveolar-capillary membrane has vast surface area (70 m2) with very short distance (0.5 microns) for diffusion. Layers of separation between air and blood:
1) fluid layer lining alveolus, containing surfactant
2) alveolar epithelium – mostly type I cells
3) epithelial basement membrane
4) interstitial space between two basement membranes
5) capillary basement membrane – may be fused with epithelial BM (in which case interstitial space is a potential space)
6) capillary endothelial cell membrane
Rate of gas transfer is proportional to diffusion coefficient, D (related to solubility & MW)
D is proportional to (solubility)/(sq. root MW)
D for CO2 is 20x D for O2 because CO2 is far more soluble in body. Faster diffusion rate is offset by CO2’s smaller ∆P (6 mmHg) than O2 (60 mmHg), so CO2 & O2diffusion more or less equilibrates. In diseased lung, O2 transfer is more seriously impaired than CO2 transfer because of the difference in diffusion coefficient.
Pulmonary caps and systemic caps are only two places in circulation where gas exchange occurs.
Arterial systemic capillary blood: PO2 = 100 mmHg, PCO2 = 40 mmHg
Venous systemic capillary blood: PO2 = 40 mmHg, PCO2 = 46 mmHg (same as tissue conditions)
The more actively the cell is metabolizing, the more cellular PCO2 rises, PO2 drops – more O2diffuses from blood into cells, more CO2 diffuses from cells into blood.
Net diffusion of oxygen is from alveoli into blood, then from blood into tissues (CO2 – opposite)
Oxygen is present in blood in two forms
total O2 content in arterial blood is 20 ml O2/100 ml blood
Physically dissolved in plasma – only 1.5%, because oxygen is not very soluble in body fluids
0.003 ml O2/100ml blood can be dissolved for each mmHg of pressure, so normal dissolved O2 content of blood is 0.3 ml O2/100 ml. Tissue O2 consumption is 250 ml/min at rest, so need extra way to transport O2.
PO2 is related to oxygen dissolved, not oxygen bound to Hb
Chemically bound to hemoglobin (Hb) – 98.5% 19.7 ml O2/100 ml blood
Hb + à HbO2 (reversible)
Reduced hemoglobin oxyhemoglobin
Hb binds reversibly with 1.34 ml O2 per gram of Hb. Normal Hb content = 15 grams
PO2 determines Hb saturation
Each Hb molecule has 4 Fe, is capable of binding to 4 O. “fully saturated” if 4 O are bound.
PO2 of blood is most important factor determining %Hb saturation (related to [O2 dissolved])
Law of mass action
if blood PO2 is increased (i.e., in pulmonary caps), reaction shifts to right, get more HbO2.
if blood PO2 is decreased (i.e., in systemic caps), HbO2 dissociated, releases its oxygen.
O2-Hb dissociation curve is S-shaped, not linear.
at PO2= 100 mmHg, Hb. is 97.5% saturated
even at PO2= 60 mmHg, Hb. is 90% saturated
from 60-760 mmHg PO2, Hb. saturation only changes 10% – provides margin of safety in O2-carrying capacity of blood. Even if PO2falls to 60 mmHg (high altitudes, stuck in a vault, pathological conditions), body can maintain high %Hb saturation. Mixed venous blood carries substantial amount of O2 – reserve which can be unloaded under extreme conditions (exercise).
at PO2 = 40 mmHg, Hb. is 75% saturated (resting systemic capillaries, venous blood)
Hb saturation decreases as cell metabolism increases
from PO2 = 0-60 mmHg, a small drop leads to a steep drop in %Hb saturation.
during strenuous exercise, up to 85% of Hb. gives up its oxygen
pulse oximeter can non-invasively measure Hb saturation
Utilization coefficient – % of Hb that gives up its oxygen as it passes through tissue capillaries. Normal value = 25%, can increase up to 85% during exercise.
Hemoglobin as a storage unit
**Hb. acts as “storage depot” for oxygen – removing oxygen from solution as soon as it enters blood from alveoli. (when oxygen is bound to Hb., it doesn’t count towards PO2). Once Hb is saturated as much as it can be for that PO2, then O2coming into blood increases PO2 until it equilibrates with alveoli.
**Hb. also helps get oxygen into tissues
PO2 of systemic blood (95 torr) is higher than tissue PO2 (40 torr), so O2 diffuses across. PO2 drops → Hb has to release oxygen → PO2 increases. Diffusion continues until Hb can’t unload more oxygen, PvO2= 40 torr until it reaches pulmonary capillary beds.
tissue PO2 is affected by rate of blood flow past tissues & rate of tissue metabolism.
Hb plays role in total quantity of oxygen blood can pick up in lungs or drop off in tissues.
If Hb levels are reduced by 50% (i.e., with anemia), O2-carrying capacity of blood drops by 50%.
Other factors affecting Hb-O2affinity
PO2 is most important factor affecting Hb-O2, but there are others…
↑ PCO2 – shifts O2-Hb curve to right (less HbO2 at a given PO2)
↓ pH (increased acidity) – shifts O2-Hb curve to right CO2 à H2CO3
exercising muscles make more carbonic acid, lactic acid → forces HbO2 to unload more O2 at these tissues
Bohr effect – CO2 & H+ can combine reversibly with Hb at site other than O2 binding site – reduces O2 affinity. Important in enhancing oxygenation of blood in lungs, releasing oxygen at tissues.
↑ temperature – shifts O2-Hb curve to right (exercising muscles generate heat, demand more O2)
**Above three factors are only in systemic capillaries. Hb has higher affinity for oxygen in pulmonary capillaries than in systemic capillaries.
Inside RBCs, 2,3-bisphosphoglycerate (BPG) binds reversibly to Hb and reduces O2 affinity. 2,3-BPG is produced during RBC metabolism. Production gradually increases if Hb is chronically undersaturated (when HbO2 is low – high altitudes, anemia, some circulatory/respiratory diseases)
Since 2,3-BPG is present throughout circulation, it not only increases HbO2’s ability to unload oxygen at the tissues, but it decreases its ability to load O2 from alveoli. (shifts curve to right)
Carbon monoxide poisoning
Hb’s affinity for binding to CO is 240x that for oxygen. HbCO = carboxyhemoglobin
Even small amounts of CO make cells O2-starved.
CO2 is transported in the blood in 3 ways
total CO2 content in arterial blood is 59 ml O2/100 ml blood
1) physically dissolved – depends on PCO2, normal PvCO2 = 45 torr; normal PaCO2= 40 torr. 5% of CO2 in arterial blood is dissolved (10% in venous blood).
2) bound to Hb à HbCO2 = carbaminohemoglobin, 5% of CO2 in arterial blood (30% in venous blood), CO2binds to terminal amine groups of blood proteins – to globin part of Hb, not heme part. Hb has greater affinity for CO2 than HbO2 (HbO2becomes Hb at tissues, picks up CO2)
3) transported as bicarbonate (HCO3–) – 90% in arterial blood (60% in venous blood)
taking place rapidly, in RBCs, with carbonic anhydrase catalyzing first reaction:
CO2 + H20 à H2CO3 à H+ + HCO3–
HCO3– is more soluble in blood than CO2.
RBC has HCO3—Cl–carrier that passively facilitates diffusion of these ions (in opposite directions). Membrane is relatively impermeable to H+, so HCO3– diffuses alone.
HCO3– diffuses out into plasma, Cl– diffuses into RBC = chloride shift
Most H+ that’s left behind binds to Hb (reduced Hb has greater affinity for H+ than HbO2) – Hb helps keep acid-base balance between arterial & venous blood.
Haldane effect – removing O2 from Hb increases its ability to pick up CO2, H+
Bohr effect & Haldane effect feed into one another
↑ CO2, ↑ H+ à ↑ O2 release
↑ O2 release à ↑ CO2, ↑ H+
CO2dissociation curve – depicts relationship between PCO2and total content of CO2 in blood.
curve is much steeper than that for oxygen. 4% volume of CO2 is exchanged during normal transport of CO2 from tissues to lungs.
Respiratory exchange ratio (R) – ratio of CO2 output to O2 uptake.
R = VCO2
Under normal resting conditions, 4ml CO2: 5 ml O2 à 0.8 (80%)
Pulmonary Blood Flow
Physiologic anatomy of pulmonary circulation
high flow (5L/min), low pressure (15 mmHg), low resistance (1-2 mmHg/L/min) circuit
pulmonary artery extends only 5 cm above RV before dividing. Vessels are thin-walled, distensible – can accommodate most of stroke volume of RV.
pulmonary capillaries form a dense network in alveolar walls – air spaces are nearly completely surrounded by flowing blood. (large surface area for gas exchange, short air-blood barrier)
small pulmonary veins collect oxygenated blood from capillaries, run between lobules, form four large pulmonary veins
Pressures in pulmonary circulation
systolic pressure averages 25 mmHg, diastolic pressure averages 8 mmHg,mean pulmonary arterial pressure is 15 mmHg
distribution of blood in lung is not complex – only need enough pressure to lift blood to top of lung
work required of RV is much less than LV à RV is less muscular than LV
pulmonary capillary pressure is estimated using flow-directed pulmonary artery (Swan-Ganz) catheter to measure back pressure from LA. Normal “pulmonary capillary wedge pressure” (PCWP) = 5 mmHg. [helps determine LA filling pressure (would be elevated with stenotic mitral valve, left-sided congestive heart failure)]
pulmonary capillaries are surrounded by gas – subjected to pressure shifts occurring within alveolar spaces during ventilation. Swings in alveolar pressure may affect flow pressure in caps.
if alveolar pressure is higher than pressure in capillary, it will collapse
pressure difference between inside, outside of vessel = transmural pressure
larger pulmonary arteries, veins (“extra-alveolar”) are subjected to much lower pressures than alveolar (smaller) vessels – pulled open as lung expands on inspiration
pulmonary vascular resistance (PVR) = input pressure – output pressure
PVR is about one-tenth that of systemic circulation (1.7 mmHg/L/min). Resistance doesn’t need to be so high since there is no demand to regulate blood flow to various vascular beds/organs.
Lungs have mechanisms to keep pressures low. With exercise, Q through lungs increases several fold, but pressure doesn’t rise because PVR decreases (via recruitment and distension of airways)
as lung inflates, alveolar, extra-alveolar vessels are stretched.
Blood volume of lungs
normal blood volume of lungs is 450 ml (70ml in capillaries)
pulmonary vessels act as reservoir, accommodate up to twice as much blood volume.
volume of blood in lungs varies with intrathoracic p. – high intrathoracic pressure expels blood from lungs; LV failure causes pooling of blood in lungs à rise in pulmonary p.
Factors affecting vascular resistance
Passive changes in vascular resistance
pulmonary arterial pressure (PAP) increase à PVR decreases
LA pressure increases à PVR decreases
blood volume increases à PVR decreases
transpulmonary pressure increases à PVR increases
Active changes in vascular resistance – vessels are reactive because of smooth muscle in walls
alveolar hypoxia – most potent stimulus causing vasoconstriction (adaptive mechanism to match best ventilation with best perfusion) PVR increases
acidemia – PVR increases
humoral substances – histamine, prostaglandin F2a
humoral substances – ACh, prostaglandin E1, nitric oxide, bradykinin
**ANS stimulation has no effect on human PVR
Additional functions of pulmonary circulation
blood volume storage – change from standing to lying posture
filtration – stray blood clots
metabolic – biologic activation (angiotensin I to II by ACE), inactivation (bradykinin, serotonin, PGE1, PGE2, PGF2α)
CONTROL OF RESPIRATION
“Pacemaker” activity for respiration is in respiratory control centers of brain. Neural control of respiration includes:
1) factors responsible for alternating inspiration/expiration rhythm(match body needs)
2) factors that regulate magnitude (rate, depth) of ventilation
3) factors that modify respiratory activity to serve other purposes
both voluntary(i.e., with speech) & involuntary(i.e., sneeze/cough) control.
The medullary respiratory center is the primary respiratory control center; provides output to respiratory muscles. Two other centers, in pons, apneustic center, pneumotaxic center – influence output from primary center.
Cell bodies for neuronal fibers of phrenic, intercostals nerves are in spinal cord. Impulses from medullary centerterminate there à stimulate nerves for inspiratory muscles. When neurons are not firing, inspiratory muscles relax and expiration occurs.
Medullary respiratory center
*Dorsal respiratory group (DRG) – nucleus tractus solitarius; mostly inspiratoryneurons, terminate on motor neurons that supply inspiratory muscles (initial processing station for feedback from peripheral sensors)
*Ventral respiratory group (VRG) – nucleus retroambiguus; both inspiratory & expiratory neurons – both remain inactive during quiet breathing. Called into play by DRG as ‘overdrive’ mechanism. Especially important in active expiration. Only during active expiration do impulses travel to expiratory muscles.
Generation of respiratory rhythm comes from rostral ventromedial medulla, near upper (head) end of VRG. Drives rate at which inspiratory neurons fire. Rhythm starts with latent period of several seconds, followed by APs, which crescendo over a few seconds – leading to ‘ramp’ pattern of inspiratory muscle activity.
Pontine centers exert ‘fine tuning’ influences on medullary center à ensure normal, smooth breathing, influence timing of switching between inspiration & expiration. Pneumotaxic center (upper pons) sends impulses to DRG to ‘turn off’ inspiratory neurons. Apneustic center (lower pons) prevents inspiratory neurons from being turned off. Of the two, the pneumotaxic center dominates. Without pneumotaxic ‘brakes,’ apneusis = prolonged inspiratory gasps with very brief interrupting expirations. (can occur with severe brain damage)
Cortex – involved in voluntary control of respiration
Hypothalamus, limbic system – can alter pattern of breathing, i.e., affective states like fear, rage.
Respiratory effects of brainstem transections (see page 4 of notes for diagram)
*rostral to pons (top) – little effect on spontaneous respiratory rhythm
*mid-pontine– eliminates neurons associated with pontine respiratory group, removing tonic excitation, resulting in slowed frequency, increased tidal volume. Vagusis also transected here – input from lung stretch receptors is lost, resulting in apneusis
*pontomedullary transection – irregular breathing pattern of gasping (loss of vagal afferents has no effect)
*transection of spinal cord – eliminates all descending drive, results in apnea
near ventral surface of medulla in vicinity of exit of 9th and 10th CNs
distinct from respiratory center neurons
bathed in brain ECF, respond to changes in [H+] (composition of ECF determined by CSF, local blood flow, and local metabolism)
CSF contains less protein than blood = poorer buffering capacity. à change in PCO2 will change pH of CSF more than it changes pH of blood.
Carotid bodies (most important), aortic bodies
Respond primarily to decreases in PO2 – less so to decreases in pH, increases in PACO2.
When PaO2 falls below 100 torr, rapid response; below 60 torr– dramatic response
Glomus cells in receptor release catecholamines that stimulate glossopharyngeal nerves
Pulmonary stretch receptors
Airway smooth muscle
Discharge in response to distension of the lung; activity sustained with lung inflation
Impulse travels in vagus
Hering-Breuer reflex – when VT> 1 L (during exercise, etc.), pulmonary stretch receptors in small muscle of airways are activated à APs travel through afferent nerve fibers to medullary center, inhibit inspiratory neurons. (negative feedback to keep lungs from being over-inflated)
Between airway epithelial cells
Stimulated by noxious gases, cold air, particulates
Impulses travel in vagus, leading to bronchoconstriction, hypernea
Juxta-capillary receptors in alveolar-capillary membrane
Impulses travel in vagus à rapid, shallow breathing
Stimulated in interstitial lung disease or pulmonary edema
*Nose and upper airway receptors – respond to mechanical, chemical stimuli (like irritant receptors in lower airways)
*Joint, muscle receptors – impulses from moving limbs may be part of stimulus to increase minute ventilation
*Gamma system – muscle spindles in intercostals, diaphragm that sense elongation of these muscles, strengthen contraction
*Arterial baroreceptors – increased systemic BP can cause reflex hypoventilation, apnea. (decreased BP à hyperventilation)
[H+] in brain ECF is primary regulator of ventilatory magnitude
Arterial blood gases are held very constant in normal range by varying magnitude of ventilation to match body’s needs for oxygen uptake/carbon dioxide removal. Signals sent to medullary respiratory center à sends signals to adjust rate/depth of ventilation.
Decreased arterial oxygen, increased carbon dioxide does stimulate ventilation, but [H+] is more important.
Response to CO2, PaCO2 is most important factor in control of ventilation under normal conditions. PaCO2 is maintained within 3 torr when awake
Ventilatory response to PaCO2is reduced by sleep, increasing age, genetic factors, athletic training.
Central chemoreceptors are main players; peripheral chemoreceptors play minor role
Response to O2 – minor role in control of normal ventilation, except at high altitudes
becomes important in chronic hypoxemia
Response to pH – difficult to separate from response to PCO2
Monitored by peripheral chemoreceptors – carotid/aortic bodies. Not sensitive to modest changes in PO2. Arterial PO2 must be < 60 mmHg (40% reduction) for chemoreceptors to send afferent impulses to medullary inspiratory neurons. (happens with severe pulmonary disease, reduced atmospheric pressure). Until you get to 60 mmHg, you’re still in plateau range of Hb-O2 dissociation curve (safe). If it weren’t for peripheral chemoreceptors, the low PO2 would depress respiratory centers à stop breathing. Chemoreceptors respond to PO2, not oxygen content. Anemia, CO poisoning – PO2is normal, but total O2 is too low.
PCO2 is most important input regulating magnitude of ventilation under restingconditions. Changes in alveolar ventilation have immediate, pronounced effect on arterial PCO2(unlike PO2). Even slight alterations from normal PCO2 induce significant reflex. Increased PCO2 à increased ventilation. Carotid/aortic bodies are only weakly responsive to changes in PCO2. Central chemoreceptors in medulla are sensitive to changes in CO2-induced [H+] (not sensitive to CO2 itself).
BBB is permeable to CO2, so increased arterial PCO2 àincreased brain ECF PCO2 àincreased [H+] àstimulates central chemoreceptors àincreases ventilation by stimulating respiratory centers.
H+can’t permeate BBB – reason central chemoreceptors don’t respond to [H+] in plasma. If you hold your breath > 1 minute, CO2 builds up, [H+] in brain ECF builds up, increased PCO2-H+ stimulant to respiration overrides voluntary input to respiratory centers, and breathing resumes.
Very high CO2 levels directly depress entire brain, including respiratory centers (like low O2 does). If you increase PCO2 up to 70-80 mmHg, ventilation increases to blow it off. Above 80 mmHg, respiratory neurons are depressed à respiratory acidosis. (Reason why, in closed environments like space shuttle/submarine, you need something to remove CO2, pump in O2.)
With some kinds of COPD– prolonged hypoventilation à elevated PCO2 and reduced PO2. Usually synergistic – sum of stimulatory inputs is greater than individual. But in some severe cases, patient loses sensitivity to high PCO2. Prolonged high [H+] in brain ECF allows time for HCO3–to cross BBB and buffer/neutralize H+. Brain ECF [H+] seems normal, and body is unaware of high PCO2. Level of ventilation is unusually low, considering high PCO2. In this case, hypoxic O2 drive to increase ventilation becomes primary respiratory stimulus.
[H+] in arterial blood
Aortic/carotid body chemoreceptors are highly responsive to changes in [H+]. Any change in PCO2leads to change in [H+] (in both arterial blood & brain ECF). Increased [H+] in arterial blood stimulates ventilation, though central chemoreceptors are more important stimulant. Arterial [H+] can change without increased PCO2 – i.e, during diabetes mellitus because of increased keto acids in the blood. The peripheral chemoreceptors’ sensitivity to changes in [H+] serves to regulate the acid-base balance.
Exercise increases ventilation – why?
Alveolar ventilation can increase up to 20-fold with exercise. Yet,
PO2stays the same, or even increases a little,
PCO2stays the same, or even decreases a little
During mild/moderate exercise, [H+] doesn’t increase because CO2 is held constant. With heavy exercise, though, [H+] increases because of lactic acid buildup (from anaerobic metabolism).
Ventilation increases within a few seconds of exercise – not long enough for changes in arterial blood gases to stimulate it. Mechanism for its increase is poorly understood. Possible reasons are:
1) reflexes from body movements – joint/muscle receptors excited during muscle contraction stimulate respiratory centers (reason even passive movement increases ventilation);
2) increased body temperature – energy generated during muscle contraction is converted to heat (same reason increased ventilation accompanies fever);
3) epinephrinerelease from adrenal medulla increases during exercise;
4) impulses from cerebral cortex, especially at onset, to respiratory center & muscles
Ventilation can be influenced by other factors, beyond O2/CO2
*Protective reflexes – sneezing, coughing, govern respiratory activity temporarily.
*Painreflexly stimulates respiratory center.
*Emotional expressions – laughing, crying, sighing, groaning.
*Respiratory system reflexly inhibited during swallowing.
*Cerebral cortex allows for voluntary control of breathing – sends impulses directly to motor neurons in spinal cord that supply respiratory muscles. (You can voluntarily hyper- or hypoventilate to a certain point.)
Local controls on smooth muscle of airways, arterioles
**If alveolus has too much blood compared to air
O2 level in alveolus and surrounding tissues falls below normal (blood is extracting more O2from alveolus). Decreased [O2] → vasoconstriction → reduced blood flow
**If alveolus has too much air compared to blood
Increased [O2] → vasodilation → increased blood flow
(opposite of effect in systemic circulation, where decreased [O2] leads to vasodilation)
As a result of CO2 & O2local controls, little air/blood is wasted → most efficient exchange possible
ANS can modestly adjust airway size
Bronchomotor tone is provided by smooth muscle in airway walls.
Parasympathetic cholinergic neurons on muscarinic receptors (quiet, relaxed situation) promotes bronchoconstriction (via smooth muscle contraction)
ACh, methacholine, humoral substances (histamine), decrease in PACO2
Sympathetic adrenergic neurons on bronchiolar beta receptors cause bronchodilation to ensure maximum airflow with minimum resistance (more oxygen available).
Circulating catecholamines – epinephrine, isoproterenol
β2adrenergic receptors (albuterol – β2 agonist)
Best single predictor of a person’s work capacity is maximum volume of O2 the person can use per minute to oxidize nutrients for energy production, = maximal oxygen consumption, max VO2. Have person exercise until exhausted – measure volume of air, O2, CO2 content. VO2depends on respiratory system, circulatory system, muscles.
Respiratory states with abnormal blood gas levels/abnormal breathing patterns
Asphyxia – oxygen starvation of tissues (lack of O2 in air, respiratory impairment, or inability of tissues to utilize oxygen)
Cyanosis – blueness of skin from insufficiently oxygenated blood in arteries
Eupnea – normal breathing
Hypernea – increased pulmonary ventilation to meet increased metabolic needs (exercise)
Hyperventilation – increased pulmonary ventilation in excess of metabolic needs à
PCO2↓, get respiratory alkalosis (anxiety, fever, aspirin poisoning) voluntary or involuntary
Hypocapnia – below normal CO2 level in arterial blood, caused by hyperventilation
Hypoventilation – underventilation in relation to metabolic requirements à
PCO2↑, get respiratory acidosis
Hypercapnia – excess CO2 in arterial blood, caused by hypoventilation
Hypoxia– insufficient O2 at cellular level, inadequate tissue oxygen delivery; determined by cardiac output, oxygen content of arterial blood, tissue oxygen uptake.
Anemic hypoxia: reduced O2-carrying capacity of blood (decreased RBCs, Hb in RBCs, or CO poisoning) PO2is normal, but O2 content is too low
Circulatory hypoxia: (stagnant hypoxia) too little oxygenated blood delivered to tissues, can be restricted to one area (local vascular spasm/blockage) or generalized (congestive heart failure, circulatory shock) arterial PO2, O2 content normal, but not enough blood reaches cells.
Histotoxic hypoxia: inability of cells to utilize oxygen available to them (cyanide poisoning)
Hypoxic hypoxia: caused by 1) respiratory malfunction involving inadequate gas exchange (normal alveolar PO2, but reduced arterial blood PO2) or 2) exposure to high altitude/suffocating environment(alveolar & arterial PO2 are reduced).
Hypoxemia – reduction in tension of oxygen dissolved in blood (reduced PaO2). If severe enough, leads to Hb desaturation à reduced CaO2
Respiratory arrest – permanent cessation of breathing
Suffocation – O2 deprivation as result of inability to breathe oxygenated air.
Hyperoxia – above normal PO2; impossible if breathing normal atmospheric air at sea level. Breathing supplemental oxygen can increase alveolar and arterial PO2 – total O2content isn’t changed much since Hb was already 97.5% saturated. If PO2 is too high à oxygen toxicity (brain & retinal damage)
Biot’s breathing – a series of breaths of equal depth irregularly alternating with period of apnea (seen most often in meningitis)
Apneustic breathing – prolonged inspiratory gasps (seen in head trauma, neurologic disorders)
Cheyne-Stokes – gradual increase in depth, sometimes rate, to a maximum, followed by gradual decrease, resulting in apnea. Cycles are 30 seconds to 1 minute in length. (seen in severe hypoxemia, at high altitudeswhile asleep, in severe heart diseaseor brain damage)
Apnea – transient cessation of breathing; during sleep, ventilation decreases & central chemoreceptors are less sensitive to arterial PCO2 (especially during REM sleep). Sleep apnea – may stop breathing for a few seconds or up to 1-2 minutes 500 times per night!
Obstructive – cessation of ventilation due to intermittent obstruction of the pharynx by the tongue during sleep. Central controller output is increased.
Central – intermittent cessation of central controller output à cessation of ventilation
Sudden infant death syndrome (SIDS) – 2-4 month old babies, often with poorly developed carotid bodies. Sleeping on stomach, exposure to nicotine increases chances.
Dyspnea – difficult/labored breathing; people have subjective sensation that they are not getting enough air, feel shortness of breath even though their PCO2, PO2 may be normal. Can be from anxiety; increased work of breathing due to restrictive/obstructive factors
Conditions at high & low altitudes
Mountain climbing – At 10,000 feet, PO2 falls into steep part of O2-Hb dissociation curve – Hb saturation rapidly declines as you go above 10,000 feet (not in plateau range anymore). At 18,000 feet, atmospheric pressure = 380 mmHg, PO2 = 45 mmHg. Acute mountain sickness – hypoxic hypoxia, hypocapnia-induced alkalosis (CO2 blown off more rapidly than produced).
Deep sea diving – atmospheric pressure doubles at 30 feet below sea level! More N2dissolves in tissues à nitrogen narcosis (“rapture of the deep”). At 150 feet under – euphoric, drowsy. At 350-400 feet under – lose consciousness (oxygen toxicity).
If you ascend too quickly – decompression sickness (“the bends”). N2 forms bubbles as it quickly converts from solution into gas.