VI.

Ventilation (Alveolar-, Dead Space and Total Ventilation)

What the USMLE expects you to be able to do
1. 2. 3. 4. 5. 6. 7. Describe and contrast the terms total (minute) ventilation, dead space ventilation and alveolar ventilation. Describe, using quantitative terms, minimum (BMR) and maximum oxygen uptake. Define the respiratory quotient (RQ) and respiratory exchange ratio (R); list values for metabolism of fat, carbohydrate, protein. Calculate alveolar PO2 from inspired PO2 and inspired O2 fraction (% O). Calculate alveolar ventilation from CO2 output and PaCO2. Calculate arterial (= alveolar) PCO2 from alveolar ventilation and CO2 production. Diagnose hyperventilation and hypoventilation using arterial blood gases.

Pathway of O2 from airway opening to tissue

Ventilation
inspiratory
O2

O2-Partial pressure

Lung ventilation
alveolar arterial

Lung CO2

CO2

O2

Diffusion Perfusion

Circulation
mixedvenous

Cardiac output

Tissue metabolism
mitochondria 0 40 75 PCO2 (mmHg) CO2 O2

Perfusion Diffusion 0 metabolism 75 PO2 (mmHg) 150

Total-, Alveolar and Dead Space Ventilation

VT = VD + (VT- VD) VT FR = VD FR + (VT-VD) FR VT
Fresh air inspired
Dead space

VE =

VD +

VA

VA = VE - VD
Fresh air

Alveolar gas

VD
Mixing

Fresh air

VT VD = VA

Used alveolar air

VT VD = VA

Alveolus
Inreases by VT Inreases by VT

A. Before inspiration

B. After inspiration

B. After inspiration, just before expiration

Calculation of dead space using the Bohr equation

VT

FA
Fresh air Alveolar gas

FI

VT - VD VD
Mixing

Used alveolar air

VT VD = VA
Inreases by VT

VT

FA
Alveolus

FE
Mixed expiratory

B. After inspiration, just before expiration

C. After expiration

Calculation of dead space using the Bohr equation

VT

FA

FI

(VT VD) FA + VD FI

VT - VD VD
Mixing Alveolar gas

VT

VT FE
Eq. 3

FA
Alveolus

FE
Mixed expiratory

VD VT

FE - FA

FI - FA
O2 PE - PA PI - PA O2

FA - FE FA PA - PE CO2

C. After expiration

VD VT

PA
Eq 4

CO2

Metabolic Rate: the demand for oxygen Uptake

BMR = basal metabolic rate = VO2

250 ml per minute at 37 C (98.6 F)

275 ml per minute at 38 C (100.6 F) 225 ml/min at 36 C (96.6 F)

6.5

Maximum O2 Uptake
4

VO2 (l/min)

VO2 max

0 0 The watt is the SI standard unit of power (energy per unit time, joules/sec). 100 200 300

Work rate (watts)

Respiratory Exchange Ratio (R)

Definition: R = CO2 output/O2 uptake For carbohydrates (glucose):

C6H12O6 + 6O2 6CO2 R= 6O2

6CO2 + 6H2O

=1

For fats, R = 0.7; proteins, R = 0.8

Partial pressure of gases in a gas mixture

Ptotal
Gas-mixture

P1
Dalton's law: Ptotal= P1+ P2+ P3

P2

P2

(Temperature and Volume constant)

Partial pressure of Gases in a Gas-mixture

PB = P1 + P2+ ..... + Pn+ PH2O
Total pressure Partial pressure of (Barometric pressure) Component 2 (for example O2 ) Partial pressure Of H2O

Ideal Gas law :

Px V = Mx R T

..... applied for component x

(PB- PH2O) V = M R T ..... applied for the Sum of dry gases

Division

Px
PB-PH2O

Mx M

= Fx
Fraction of x

Px = Fx ( PB- PH2O )

IV. Clinical Calculations Used in Pulmonary Medicine

A. Inspired PO2: PIO2 = FIO2 x (PB PH2O)

At sea level:
PIO2 = .21 x (74747) = 147mm Hg
O2

At 20,000 feet:
PIO2 = .21 x (347 47) = 63 mm Hg

At 29,035 feet:
PIO2 = .21 x (247 47) = 42 mm Hg

Alveolar PO2 (PAO2)

PIO2

PEO2

If no pulmonary gas exchange:

PACO2 = 0
PAO2 = PIO2
O2

CO2

PvO2

PaO2

Alveolar PO2 (PAO2)

PIO2

PEO2

PAO2 = PIO2 O2

PACO2 R CO2

PvO2

PaO2

Examples

If R = 1:

PAO2 = PIO2 PACO2

PAO2 = 147 40 = 107 mm Hg
O2

If R < 1:

PACO2 PAO2 = PIO2 R 40 PAO2 = 147 = 97 mm Hg 0.8

Alveolar PCO2 (PAO2)

VA

PACO2 =

VCO2

863

VA

VCO2

In tissue produced VCO2

Example:
Patient with normal metabolic rate and depressed brain stem

VCO2 (normal) = 225 ml/min

VA (reduced) = 2250 ml/min

What is the patients alveolar PCO2? PACO2 = 225/2250 x 863 = 86.3 mm Hg

Alveolar Ventilation
PACO2 = VCO2 x 863

VA

VA =

VCO2
PACO2

x 863

From example: VA =

225
86.3

x 863

= 2250 ml/min

Alveolar ventilation and alveolar gas partial pressures

160

PIO2
Quiet ventilation

Alveolar partial pressure, PA (mmHg)

O2
D
120

PAO2

80

40

PACO2

D
0
5 10

CO2
15

PICO2

Alveolar ventilation, VA(lmin-1)

Definition of alveolar ventilation

Normoventilation:

Normal alveolar ventilation e.g. PaCO2 normal (= 40 mmHg)

Hyperventilation:

Alveolar ventilation is increased in excess of metabolic needs, therefore: PaCO2 is reduced below normal (< 40 mmHg)

Hypoventilation:

Opposite of hyperventilation e.g. PaCO2 is above normal (> 40 mmHg)

KEY CONCEPTS 1. Alveolar ventilation is the volume of fresh (nondead space) gas entering the respiratory zone per minute. It can be determined from the alveolar ventilation equation, that is, the CO2 output divided by the fractional concentration of CO2 in the expired gas. 2. The concentration of CO2 (and therefore its partial pressure) in alveolar gas and arterial blood is inversely related to the alveolar ventilation. 3. The anatomic dead space is the volume of the conducting airways. 4. The physiologic dead space is the volume of lung that does not eliminate CO2. It is measured by Bohr's method using arterial and expired CO2. 5. The two dead spaces are almost the same in normal subjects, but the physiologic dead space is increased in many lung diseases.

VII. Pulmonary Gas Exchange

What the USMLE expects you to be able to do
1. Name the factors that affect diffusive transport of a gas between alveolar gas and pulmonary capillary blood (Ficks Law).
2. Describe the kinetics of oxygen transfer from alveolus to capillary and the concept of capillary reserve time (i.e., the portion of the erythrocyte transit time in which no further diffusion of oxygen occurs). 3. Calculate diffusing capacity from carbon monoxide uptake and carbon monoxide partial pressure.

4. Contrast the uptake of O2, CO, and N2O from the lungs to pulmonary capillary blood.
5. Describe why normal subjects at high altitude or patients with lung disease may have a diffusion limitation during exercise.

Alveolo-capillary membrane

Alveolar membrane Erythrocyte

Diffusion law
Diffusion rate, V

Area, A

Thickness, T

Vgas = DL (P1-P2) DL = d a A T

P1
P2
Diffusion capacity

Diffusion coefficient Solubility

DLCO2 ~ ~ 20 DLO2 , because aCO2~ ~ 20 aO2

Diffusion problems may occur for O2 , but not for CO2 !

Diffusing capacity is measured using carbon monoxide gas

DL =
DLCO

V gas

DLCO = PACO - PaCO

PaCO = 0

V CO

50 ml/min = = 25 ml/min/mmHg 2 mmHg

Normal Factors That Influence Diffusing Capacity

Exercise. Diffusing capacity increases = recruitment and distension of pulmonary capillaries & better matching of blood flow and ventilation. Body Position. Supine = increased pulmonary capillary volume and more even distribution of pulmonary blood flow. Body Size. = Lung size = surface area.

Pathological Factors That reduces Diffusing Capacity

Pathology of air-blood barrier ( thickness or surface area) capillary volume hemoglobin.
Examples: COPD, anemia, fibrosis, pulmonary edema, pneumonia.

O2 uptake from alveolar gas into lung capillary blood

Alveolar capillary membrane

PAO2 PvO2
120

Pc'O 2
alveolar (PA) Endcapillary

80

PO

Capillary
2

(Pc')

(mmHg) 40 Mixed venous

Driving Pressure difference

(Pv)
0

Contact distance
or transit time

100%

Diffusion limitation
And alveolar-end capillary O2 Partial pressure difference
Alveolar capillary membrane

PvO2

PAO 2
alveolar (PA)

Pc'O 2
ACDO2 > 0

PO2
(Pv)

(Pc)

1. Advantage for CO2:

PCO2 equality between gas and blood does exist, even if there is no equality for O2 (e.g. interstitial edema with low DO2), Thus, in each alveolus Pc'CO2= PACO2
(Pc)
alveolar (PA) 0 Contact distance 100%

PCO2

(Pv)

CADCO2 = 0

Diffusion limitation
Alveolar
100 normal Diffusion limitation Low DL Extreme Low DL 40

PO2 (mmHg)

exercise 0 0 0.25 0.50

rest 0.75

Transit time (sec)

Effect of low alveolar PO2

Alveolar
50 Normal DL PO2 (mmHg) Low DL 25 Diffusion limitation

exercise 0 0 0.25 0.50 0.75

rest

Time in capillary (sec)

Perfusion limitation
Alveolar
100

PO2 (mmHg)

perfusion limitation PA = PC = No more transfer

40

exercise 0 0 0.25 0.50

rest 0.75

Transit time (sec)

Nitrous oxide transfer is perfusion limited

Start of capillary
Alveolar Partial Pressure perfusion limitation PA = PC = No more transfer

End of capillary

N2O 0 0.25 0.50 0.75

0 Time in capillary (sec)

Carbon monoxide transfer is diffusion limited

Start of capillary Alveolar Partial Pressure End of capillary

CO
0 0 0.25 0.50 0.75 Time in capillary (sec)

Diffusion limitation PA > PC when blood leaves capillary. No more transfer

Diffusion limitation vs. perfusion limitation of gas transfer

Start of capillary Alveolar End of capillary

Perfusion limitation Partial Pressure O2 (normal) O2 (abnormal) N2O CO 0 0 0.25 0.50 0.75 Time in capillary, sec

Diffusion limitation

KEY CONCEPTS 1. Fick's law states that the rate of diffusion of a gas through a tissue sheet is proportional to the area of the sheet and the partial pressure difference across it, and inversely proportional to the thickness of the sheet. 2. Examples of diffusion- and perfusion-limited gases are carbon monoxide and nitrous oxide, respectively. Oxygen transfer is normally perfusion limited, but some diffusion limitation may occur under some conditions, including intense exercise, thickening of the blood-gas barrier, and alveolar hypoxia. 3. The diffusing capacity of the lung is measured using inhaled carbon monoxide. The value increases markedly on exercise. 4. Carbon dioxide transfer into the blood is probably not diffusion limited.

VIII. Pulmonary Circulation

What the USMLE expects you to be able to do
1.

Contrast the systemic and pulmonary circulations with respect to pressures, resistance to blood flow, and vascular response to hypoxia.

2. Describe the normal anatomical shunts that cause reduced arterial PO2. 3. Describe how pulmonary vascular resistance changes with alterations in cardiac output or pulmonary arterial pressure, lung volume, and alveolar hypoxia. 4. Describe the potential causes of pulmonary edema and pleural effusion. 5. Describe the causes of ventilation perfusion mismatch in normal lungs and the compensatory mechanisms to correct V/Q mismatch.

Intravascular pressures in Lung- and systemic circulation

Pressure drop
20/10 (mmHg)

Pulmonary circulation

7,5

6,8

Vein Lung
Right atrium Left atrium

Artery Average pressure: 14

Right ventricle Left ventricle

Artery Average pressure: 100

Heart

Systemic circulation

Vein Tissue
(mmHg)

120/82

20
4

Pressure drop

Control of Pulmonary Vascular Resistance (PVR)

Cardiac output

Mechanisms

Left Atrial Pressure is Measured via a Pulmonary Artery

RA

RV

PA

PAOP wedge pressure

Dependence of pulmonary vascular resistance on lung volume

Low Lung volume

Recoil force

High Lung volume

Alveolus

Residual volume

FRC

alveolar capillary Alveolar septum

Total Pulmonary vascular resistance

alveolar Extra alveolar 0 Lung volume

TLC

Control of Pulmonary Vascular Resistance (PVR)

Good matches V and Q Decreases Shunt effect
Good for fetus Bad after birth Causes pulmonary hypertension
High altitude, hypoVA

Hypoxia
Opposite to systemic circulation where hypoxia vasodilation (see Notes page) Mechanism: hypoxia inhibits Kv Channels, depolarizes, open Ca++ Channels, muscle contracts.

2 agonists dilate
HAPE

Control of Pulmonary Vascular Resistance (PVR)

Good matches V and Q Decreases Shunt effect
Good for fetus Bad after birth Causes pulmonary hypertension
High altitude, hypoVA

Hypoxia
Opposite to systemic circulation where hypoxia vasodilation (see Notes page) Mechanism: hypoxia inhibits Kv Channels, depolarizes, open Ca++ Channels, muscle contracts.

2 agonists dilate
HAPE

Distribution of perfusion in the lung in an upright position

Pressure in Alveolar space (PA) Pressure in pulmonary artery (Ppa) Pressure in pulmonary vein (Ppv)

PA > Ppa > Ppv Zone II

Ppa > PA > Ppv Zone III Ppa > Ppv > PA

Hight

Perfusion

Zone I

Anatomical Shunts Lower Arterial PO2

Normal Anatomical Shunts
AO

PA

O2

Thebesian veins

PV Bronchial veins

Abnormal anatomical shunts

AO PFO PDA PA

O2

VSD

PV

Pulmonary AV fistula

4 examples

KEY CONCEPTS
1. The pressures within the pulmonary circulation are much lower than in the systemic circulation. Also the capillaries are exposed to alveolar pressure, whereas the pressures around the extra-alveolar vessels are lower. 2. Pulmonary vascular resistance is low and falls even more when cardiac output increases because of recruitment and distension of the capillaries. Pulmonary vascular resistance increases at very low or high lung volumes. 3. Blood flow is unevenly distributed in the upright lung. There is a much higher flow at the base than the apex as a result of gravity. If capillary pressure is less than alveolar pressure at the top of the lung, the capillaries collapse and there is no blood flow (zone 1). 4. Hypoxic pulmonary vasoconstriction reduces the blood flow to poorly ventilated regions of the lung. Release of this mechanism is responsible for a large increase in blood flow to the lung at birth. 5. Fluid movement across the capillary endothelium is governed by the Starling equilibrium. 6. The pulmonary circulation has many metabolic functions, notably the conversion of angiotensin I to angiotensin II by angiotensinconverting enzyme.

IX. Gas Transport by the Blood

What the USMLE expects you to be able to do
1. Describe which forms O2 is transported in the blood and be able to analyze the O2 dissociations curve. 2. Identify, using an oxygen dissociation curve, the normal values of saturation, content, and partial pressure of arterial and mixed venous blood. 3. Identify the factors affecting the O2 dissociation curve and describe their effects 3. Compare the effects of carbon monoxide exposure versus anemia on O2 transport. 4. Describe and contrast the processes of oxygenation and oxidation of hemoglobin 4. Describe the forms of CO2 transport from tissues to lungs and the relative importance of each form. 5. Define the Bohr- and Haldane effects and describe their impact on O2 and CO2 exchange in the lungs and tissues

Physically dissolved oxygen

200

O2 Concentration, CO2 (ml STPD l-1)

150

CO2 = a O2 PO2

HENRY`s law

Solubility coefficient
100

50

0
0 75 150

225

300

375

450

O2 Partial pressure, PO2 (mmHg)

O2 Concentration in blood, CO2 (mlSTPD/l)

200 100 150 50

0
0 75

chemically bound (HbO2)

O2 Binding curve of the blood

300 O2 Partial pressure, PO2 (mmHg) 150 225 375

O2- Capaty = Maximal chemically bound oxygen

physically dissolved (aO2 PO2)

Equilibrium between physically dissolved and chemically bound gas

PO2 = PO2
Gas

PO2 > PO2

PO2 = PO2

O2 physically dissolved O2

Adding Hemoglobin Hb

New equilibrium

O2 Binding curve of hemoglobin

1.0 0.98 100 mmHg

O2 Saturation, SO2

0.8

0.75

Hemoglobin

0.6 0.50 0.4

40 mmHg

P0.5 = 27 mmHg 0.2

40

80

120

O2 Partial pressure, PO2 (mmHg)

O2 Binding curve of hemoglobin

O2 Concentration in blood, CO2 (mlSTPD/l)
1.0 200

O2 Binding curve of the blood

physically dissolved (aO2 PO2)
150 225 300 375

0.8

150

0.6 0.50 0.4 P0.5 = 27 mmHg 0.2

100

50

40

80

120

0 0 75

O2 Partial pressure, PO2 (mmHg)

O2 Partial pressure, PO2 (mmHg)

chemically bounded (HbO2)

O2 Saturation , SO

Influences on O2 binding curve of the blood

Increases in affinity = Left shift
1,0

O2 Saturation, SO2

0,5

Decreases in affinity = Right shift 0

40

80

120

O2 Partial pressure, PO2 (mmHg)

Effects of pH and CO2

Effect of pH
H+ H2N

Effect of CO2
NH2 H2N NH-COO-

+ H+
Hemoglobin
100
100

+ O2
H2N
100

+ CO2
NH2

+ O2

NH2 H2N Carbamino hemoglobin

Hemoglobin saturation (%)

80

80

80

PCO2
60

pH
60

PCO2 pH
40 mmHg 7.2 60

PCO2 pH
61 mmHg 7.4 40 mmHg 7.4 40 26 mmHg 7.4

61 mmHg 7.2 40 mmHg 7.4

40 mmHg 7.4
40 40 mmHg 7.6

40

26 mmHg 7.6

20

20

20

0 0 20 40 60 80 100

0 0 20 40 60 80 100

0 0 20 40 60 80 100

PO 2 (mmHg)

PO 2
(mmHg)

PO 2 (mmHg)

BOHR - Effect : H+ impedes O2 binding

O2 O2
Heme
Heme

H+

H+

H+ + HCO3-

CO2+ H2O

Effect of temperature
100
33 80 37

Hemoglobin saturation (%)

60 41 40

20

20

40 60 PO 2 (mmHg)

80

100

a + DPG b

a b

a +4 b

Effect of DPG:
b 100

O2

80

[DPG] Hemoglobin saturation (%)

60

2 mM
4 mM

40

6 mM

20

0 0 20 40

PO

60
2

80

100

(mmHg)

Influences on blood O2 binding curve

Increases in affinity = Left shift
1.0

O2 Saturation, SO2

0.5

H+ concentration Bohr-Effect CO2 concentration Temperature 2,3-BPG concentration

Decreases in affinity = Right shift 0

40

80

120

O2 Partial pressure, PO2 (mmHg)

Carboxyhemoglobin (HbCO)
200 normal blood (0 % HbCO) O2 concentration (ml/l) 150 50 % CO bounded (50 % HbCO) 100

50

Half of O2 capacity (50 % Anemia, 0 % HbCO)

0 0 40 80 O2 partial pressure, PO2 (mmHg) 120

Oxygenation and oxidation of hemoglobin

oxidizing substance

Oxygenation

O2

Oxidation

O2
Fe(II)
Hb (Fe(II)) O2 Oxyhemoglobin Heme

No O2-Binding

O2
Fe(III)

O2-Transport
Hb (Fe(II)) Deoxyhemoglobin

Hb poisoned

Globin

Hb (Fe(III)) Methemoglobin

O2

Deoxygenation

Reduction

Methemoglobin reductase

3 Forms of CO2 in the blood

CO2 + H2O
1. CO2

HCO3- + H+
2. Bicarbonate

CO2 + R-NH2

R-NH- COO- + H+
3. Carbamate

Reactions from CO2 entry into the blood from the tissue, and from CO2 release from the blood in the lung
Tissue or Lung CO2

Plasma

Erythrocyte
O2

CO2

CO2+Hb

-OOC-Hb
+
H+

H2O

+
H2O
Carboanhydrase

HCO3-

HCO3- +H+ ClHbO2

(HaldaneEffect) HHb

+ ClPr-

H+

HPr

CO2 dissociation curve

mixed venous

600

CO2 Concentration (ml/l)

400

200 dissolved

20 40 60 80 CO2 Partial pressure (mm Hg)

arterial

43 ml/l 5 mm Hg

100

Acidification causes CO2 release from binding site

H+ CO2 CCO
2

+ H+

adding

released

PCO 2

H+ + HCO3-

H2O + CO2

H+ + HCO3H+ binding

CO2 + H2O

O2 O2 binding Globin Heme O2 affinity Heme

O2

H+ binding
CO2 binding H+ + HCO3-

A: Bohr effect

CO2 + H2O

B: Haldane effect

KEY CONCEPTS 1. Most of the O2 transported in the blood is bound to hemoglobin. The maximum amount that can be bound is called the O2 capacity. The O2 saturation is the amount combined with hemoglobin divided by the capacity and is equal to the proportion of the binding sites that are occupied by O2. 2. The O2 dissociation curve is shifted to the right (that is, the O2 affinity of the hemoglobin is reduced) by increases in PCO2, H+, temperature, and 2,3-diphosphoglycerate. 3. Most of the CO2 in the blood is in the form of bicarbonate, with smaller amounts as dissolved and carbamino compounds. 4. The CO2 dissociation curve is much steeper and more linear than that for O2. 5. The PO2 in some tissues is less than 5 mm Hg, and the purpose of the much higher PO2 in the capillary blood is to provide an adequate gradient for diffusion. Factors determining O2 delivery to tissues include the blood O2 concentration and the blood flow.

X. Mechanisms of Arterial Hypoxemia

What the USMLE expects you to be able to do 1. Define the 4 types of hypoxia including arterial hypoxemia and
the expected values of blood gases in each type. 2. Describe the 5 causes of arterial hypoxemia and identify those that result in a widened (Alveolar-arterial) PO2 difference.

3. Explain why mismatching of ventilation and perfusion affects arterial PO2 more than arterial PCO2. 4. Describe the effect of gravity on distribution of alveolar ventilation (V ) and blood perfusion (Q) and the ratios (V /Q) in the normal lung.
A A

5. Explain how 100% oxygen can be used to diagnose VA/Q mismatch and shunt.

Types of Hypoxia
1. Tissue Hypoxia:
a) Stagnant hypoxia b) Anemic hypoxia c) Histotoxic hypoxia 2. Arterial hypoxia, or hypoxemia: Judgment parameters: A) Low inspired PO2 (low PIO2) PaCO and (A a) PO 2 2 B) Diffusion limitation C) Hypoventilation D) Alveolar ventilation / perfusion mismatch E) Right to left (venous) shunt

Types of Hypoxia
1. Tissue Hypoxia:
a) Stagnant hypoxia b) Anemic hypoxia c) Histotoxic hypoxia 2. Arterial hypoxia, or hypoxemia: Judgment parameters: A) Low inspired PO2 (low PIO2) PaCO and (A a) PO 2 2 B) Diffusion limitation C) Hypoventilation D) Alveolar ventilation / perfusion mismatch E) Right to left (venous) shunt

Diffusion limitation
Alveolar 50 Normal DL
PO2 (mmHg)

Diffusion limitation

Low DL
25

exercise 0

rest

0.25

0.50

0.75

Time in capillary (sec)

Normoventilation
PIO2 = 150 mmHg PICO2 = 0 mm Hg

PAO2 = 100 mmHg

PACO2 = 40 mm Hg
PVO2 = 40 mmHg PVCO2 = 45 mm Hg

O2

CO2

PaO2 = 90 mmHg PaCO2 = 40 mm Hg

Hypoventilation
PIO2 = 150 mmHg PICO2 = 0 mm Hg Airway obstruction

PAO2 = 80 mmHg

PACO2 = 60 mm Hg
PVO2 = 30 mmHg PVCO2 = 65 mm Hg

O2

CO2

PaO2 = 70 mmHg PaCO2 = 60 mm Hg

Distribution of ventilation and perfusion in the Lung in an upright position

A. Perfusion distribution PO2 PCO2
(mmHg)

B. Ventilation distribution

I I II II III III Perfusion / tissue mass, Q

132 28 100 40 90 42

II

III Ventilation / tissue mass, VA

VA and Q normal

PI VA

PI

VA and/or Q

VA and/or Q
160

PO2
(mmHg)

120

PA = Pa PA

Pa
80

Q Pv
VA Q Pv
: Normal High Low 40

Unequal distribution of Ventilation (VA) and Perfusion (Q)

PO 2 PI
Alveolar region 1

PA
Alveolar region 2

I A1=c'1 A2=c'2 v

Lung:

Alveolar Arterial AaD (Alveolararterial difference)

PA1 = Pc'1 Pv

PA2 = Pc'2 Pa

VA / Q high: Hyperventilated

VA / Q low: Hypoventilated

Right to left shunt (venous shunt)

"Ideal Alveolus PI PA

Alveolar dead space ventilation

PI

PAi Pv Pv Pv Pa

PI

Right to left shunt

Hypoventilated

normo ventilated Average

Hyperventilated

Alveolar dead space

VA / Q =0

VA / Q

VA / Q =

O2 - and CO2 Binding curves

mixed venous

Concentration (ml/l)

arterial

600

43 ml/l 5 mm Hg RQ = mixed venous 43 = 0,86 50 arterial 50 ml/l

400

CO2

200 O2

55 mm Hg

20

40 60 80 100 Partial pressure (mm Hg)

Effects of shunt on arterial PO2 and PCO2

PA

Pc' = PA

Pv
Pv Q

Pa

Shunt 25% of Q

2. Advantage for CO2: Based on very steep slope of CO2 binding curve (in comparison to that of O2), there is practicaly no shunt effects on PCO2. PaiCO2 = PaCO2 ist a reasonable assumption

Causes of hypoxemia and effects of O2 breathing

PaO2 Increases in VA/Q heterogeneity Increases in Right to left shunt
Diffusion problems Hypoventilation Low PIO2 (high altitude)
Unchanged

AaDO2

PaCO2
Normal

aADCO2
( )

PaO2 with 100%O2

Yes

Normal

Unchanged

No

Normal

Unchanged

Yes

Unchanged

Yes, but be careful

Unchanged

Unchanged

Yes

KEY CONCEPTS
1. The four causes of hypoxemia are hypoventilation, diffusion limitation, shunt, and ventilation-perfusion inequality. 2. The two causes of hypercapnia, or CO2 retention, are hypoventilation and possibly ventilation-perfusion inequality . 3. Shunt is the only cause of hypoxemia in which the arterial PO2 does not rise to the expected level when a patient is given 100% O2 to breathe. 4. The ventilation-perfusion ratio determines the PO2 and PCO2 in any lung unit. Because the ratio is high at the top of the lung, PO2 is high there and the PCO2 is low. 5. Ventilation-perfusion inequality reduces the gas exchange efficiency of the lung for all gases. However, many patients with ventilation-perfusion inequality have a normal arterial PCO2. By contrast, the arterial PO2 is always low. The different behavior of the two gases is attributable to the different shapes of the two dissociation curves. In the case of CO2 increased alveolar ventilation contributes additionally in keeping arterial PCO2 normal. 6. The alveolar-arterial PO2 difference is a useful measure of ventilation-perfusion inequality. The alveolar PO2 is calculated from the alveolar gas equation using the arterial PCO2.

XI. Control of Breathing

What the USMLE expects you to be able to do
1. Describe the functions of the neural control centers for breathing including the ventral respiratory group (VRG), dorsal respiratory group (DRG) and pneumotaxic center of the brainstem. 2. Explain how a patient with bilateral paralysis of the diaphragm is able to breathe. 3. Describe the innervation of muscles used for breathing and predict the effects of spinal cord injuries at different levels on the ability of patients to breath; e.g., transection at C2 versus transection at C6. 4. Contrast the primary stimuli, thresholds, nerve pathways, and response times of central and peripheral chemoreceptors. 5. Describe the location and pattern of breathing illicited by irritant and mechanical receptors. 6. Explain why O2 therapy may decrease breathing in a patient with chronic obstructive lung disease; e.g., emphysema. 7. Contrast the acute vs. chronic effects of hypoxia and hypercapnia on ventilation. Describe the functions of the neural control centers for breathing.

Respiratory center & afferent and efferent inputs

Cortex (exercise, voluntary)

Central input

Brainstem (Emotion,Temperature)

Rhythm generator

Efferent output

Afferent input

Respiratory muscles

Mechanoreceptors in lung and thorax Chemoreceptors

Respiratory stimuli:
With feedback Without feedback

Mechanoreceptors in muscloskeletal system

3 groups of neurons control respiration

Inhibitory effects: Off switch of inspiration, control of FR

Pons Medulla
Integration of inputs

Pneumotaxic Center

DRG (NTS)

VRG

Vagus & Glossopharyngeal

Respiratory Motor Paths

Basic rhythm Cardiorespiratory, symp. and parasymp. coupling Basic activity of bronchial muscle cells Extra drive: exercise, high altitude

Basic rhythm

ramp signal

Pulmonary Reflexes: 1. Slowly Adapting Stretch Receptors (HeringBreuer reflex):

Location: Airway smooth muscles, innervated by large myelinated
vagal fibers

Activation:
a) Lung distension (inspiration) b) Breath holding (lack of movement) c) Deflation of the lung below FRC

Functions:
a) Terminates inspiration (prevent the lung from overstretching) b) Terminates large expiration as well

Lung stretch reflex

Rhythm generator (Respiratory center)

+
Inspiratory muscles Lung distension

2. Rapidly Adapting Stretch Receptors (irritant receptors):

Location: Airway epithelium, innervated by myelinated vagal
fibers

Activation:
a) Lung distension b) Irritants

Functions:
a) Cough reflex b) Gasp and bronchoconstriction by high activity

3. C-Fiber or J-Receptors (J = Juxta capillary):

Location: Near capillaries, innervated by non-myelinated vagal
fibers

Activation:
a) Increases in interstitial fluid (congestion or edema) b) Pulmonary embolism

Functions:
a) Rapid shallow breathing b) Bronchoconstriction c) Cardiovascular depression

Peripheral chemoreceptors N.IX

(Glossopharyngial nerve) External carotid artery Internal carotid artery Carotid sinus

Carotid body

N.X (vagus nerve)

Left subclavian artery Common carotid artery Brachiocephalic trunk

Aortic bodies

Aortic arch Pulmonal artery

Peripheral Chemoreceptors Carotid body

(glomus caroticum) Carotid sinus nerve

Capillary

Type I cell

Type II cell

Mechanism of Peripheral Chemoreception

pH PCO 2 O2 pHi Cai2+

K+ Outflux

Action potential

Transmitter release Type I cell

Depolarization

Ca2+ Influx

O2 response curve
40
Minute ventilation (l min-1) At PaCO2 = 40 mmHg 30

20 Value at rest 10 By falling PaCO2

0 0 30 60 90 120 Arterial PO2 (mmHg) 150

Chemical stimuli of breathing

A: CO2 response curve
Minute ventilation (l/min)
80

B: pH response curve C: O2 response curve

60

40
PaCO2 constant PaCO2 constant Normal value PaCO2 falls

20
Normal value

Normal

PaCO2 falls

0 30

45

60

75

7,4

7,3

7,2

30

60

90

120 150

PaCO2 (mmHg)

pHa

PaO2 (mmHg)

Acute vs. chronic hypercapnia PCR & CCR stimulated

Ventilation
CSF and blood pH = HCO3PCO2

Only PCR stimulated

PCO2

Time, days

20

Acute vs. chronic hypoxia

Alkalosis from hyper ventilation inhibits response to hypoxia during first few days

Days

Stimuli for ventilation Voluntary control

Maximum VE response to stimuli
160

Ventilation, L/min

140 120 100 80 60 40 20 0 Rest PO2 pH PCO2 Exer MVV

Regulation of breathing during exercise

Cerebral cortex
sensory motor

"direct stimulation" Rhythm generator Stimulation through feedback"

Respir. muscles

Mechano receptors

working muscles

Musculoskeletal system

Abnormal Patterns of Breathing

Sleep Apnea

Abnormal Patterns of Breathing Cheyne-Stokes Breathing

KEY CONCEPTS
1. The respiratory centers that are responsible for the rhythmic pattern of breathing are located in the pons and medulla of the brainstem. The output of these centers can be overridden by the cortex to some extent. The central chemoreceptors are located near the ventral surface of the medulla and respond to changes in pH of the CSF, which in turn are caused by diffusion of CO2 from brain capillaries. Alterations in the bicarbonate concentration of the CSF modulate the pH and therefore the chemoreceptor response. The peripheral chemoreceptors, chiefly in the carotid bodies, respond to a reduced PO2 and increases in PCO2 and H+ concentration. The response to O2 is small above a PO2 of 60 mm Hg. The response to increased CO2 is less marked than that from the central chemoreceptors but occurs more rapidly. Other receptors (mechano-and irritant receptors) are located in the walls of the airways and alveoli. The PCO2 of the blood is the most important factor controlling ventilation under normal conditions, and most of the control is via the central chemoreceptors. The PO2 (above 60 mm Hg)of the blood does not normally affect ventilation, but it becomes important at high altitude and in some patients with lung disease. Exercise causes a large increase in ventilation, but the cause, especially during moderate exercise, is poorly understood

2.

3.

4.
5.

6.

7.