The Chemoreflex

Control of
Breathing
James Duffin
Respiratory Research
Group
Departments of Anaesthesia
& Physiology
University of Toronto

Regulation of Respiration
Metabolic
Carbon Dioxide
Production

Pulmonary
Ventilation

Oxygen
stores

Po2

Metabolic
Oxygen
Consumption

Carbon Dioxide
stores

Pulmonary
Ventilation

Pco2

Respiratory Control System

EFFERENT

AFFERENT

Medullary
Respiratory
Neurons

Central
Chemoreceptors
(medulla)

Upper
Airway
Muscles

Peripheral
Chemoreceptors
(carotid bodies)

Muscle
Receptors
Respiratory
Muscles

Airway
Smooth
Muscle

IX

Spinal
Respiratory
Motoneurons

Pulmonary
Ventilation

Airway and
Lung
Receptors

Po2 and [H+] /Pco2

Central Respiratory Control System

Chemosensitive Areas

Inspiratory & Expiratory Neurons

PRG

DRG
XII
VRG

Ventral Aspect

Dorsal Aspect

Cross-section

Other Respiratory Drives

Voluntary Control
(motor cortex)
Cough
Sneeze etc.
(medulla)

Emotions
(forebrain)
Posture
(cerebellum)
Rhythm
Generator
(medulla)

Limbic
System

Reticular
Formation

Respiratory Motoneurons
(spinal cord)

Sensory
Stimuli
(pain, startle)

Respiratory Negative Feedback Regulator

Gas Exchange

Ventilation

Po2

Other

Chemoreflexes

[H+]

[PO4-]

Pco2

AcidBase

[SID]

[Alb]

Chemosensitive Areas

M
S
L

Ventral Aspect

Central Chemoreceptors
midline
VRG

ROb
RPa
ce
a
f
r
u
al s
r
t
n
Ve

TTX

ace
f
r
su
l
a
tr
n
e
V

Cd2+

Dr. Yasumasu Okada, Department of Medicine, Keio University, Japan

Central Chemoreceptors

Richerson, G. B., 2004. Serotonergic neurons as carbon dioxide sensors that

maintain pH homeostasis. Nat Rev Neurosci 5, 449-61.

Central Chemoreceptors

Richerson, G. B., 2004. Serotonergic neurons as carbon dioxide sensors that

maintain pH homeostasis. Nat Rev Neurosci 5, 449-61.

Central Chemoreceptors
Mulkey, D., Stornetta, R.,
Weston, M., Simmons, J.,
Parker, A., Bayliss, D.,
Guyenet, P. Respiratory control
by ventral surface
chemoreceptor neurons in rats.
Nat Neurosci. 2004
Dec;7(12):1360-9

Guyenet, P. G., Stornetta, R. L., Bayliss,

D. A., Mulkey, D. K., 2005.
Retrotrapezoid nucleus: a litmus test for
the identification of central
chemoreceptors. Experimental Physiology
90, 247-253.

The Central Chemoreceptor Response

Central Drive to Breathe (L/min)

50
40

30

20

10

30

40

central chemoreceptor
threshold

60
50
central [H+] (nM/L)

Aspects of The Central Chemoreflex

1) Blood-brain barrier for polar solutes
Consequently: brain tissue & central chemoreceptors
may have a different [H+] than arterial blood during acidbase disturbances.
2) Chemoreceptors located in brain tissue
Consequently: central chemoreceptors respond slowly to
increases in inspired CO2: after a blood transport delay
there is an exponential rise with a time constant of ~100 s.

Peripheral
Chemoreceptors

Petrosal
Ganglion

Nodose
Ganglion

Carotid sinus nerve

Chemoreceptor
cells

Carotid
body
Superior
cervical
ganglion

Capillaries

Common
carotid artery

Sustenticular
cells

Is Hypoxia an Independent
Chemoreflex Stimulus to Breathing?

Ventilatory
Response to
Carbon Dioxide &
Hypoxia
Nielsen, M., Smith, H., 1952.
Studies on the regulation of
respiration in acute hypoxia. Acta
Physiol. Scand. 24, 293-313.

1) Linear response to CO2

above a threshold.
2) Hypoxia sensitizes the
carotid body to CO2.
3) Hypoxia is an
independent stimulus

Modified Rebreathing Responses

100
subject
2

60

60
80

40

22 100

Ventilation (L/min)

Ventilation (L/min)

End-tidal Po2
(mmHg)
40

40

45

50

55

End-tidal Pco2 (mmHg)

60

100

60

20

40

80

60

80

20

35

40

subject
3

80

30

End-tidal Po2 (mmHg)

100

30

35

40

45

50

55

End-tidal Pco2 (mmHg)

Mohan, R., and Duffin, J. 1997. The effect of hypoxia on the ventilatory
response to carbon dioxide in man. Respiration Physiology 108: 101-15.

60

Response to Hypoxia below Threshold

N=9

Rapanos, T., Duffin, J., 1997. The ventilatory response to hypoxia below the
carbon dioxide threshold. Can. J. Appl. Physiol. 22, 23-36.

The carotid body is not a dreary little

CO2 receptor that is brought to life by
hypoxia: it is a very excitable CO2
receptor that is calmed down by oxygen.
R.W. Torrance
St. Johns College
Oxford

The Peripheral Chemoreceptor Response

40
40

Peripheral Drive to Breathe (L/min)

50

30

20

)
g
H
m
(m
Po 2 50

10

100

200

30

40

peripheral chemoreceptor
threshold

60
50
arterial [H+] (nM/L)

The Peripheral Chemoreceptor Response

Sensitivity to [H+] (L/min/nM/L)

1.2
Asymptotic to Po2 = 30 mmHg

1.0
0.8
0.6

Asymptotic to zero sensitivity

0.4
0.2
0
0

30

50

100

Po2 (mmHg)

150

200

Aspects of The Peripheral Chemoreflex

1) Responds to Pco2 with a sensitivity controlled by Po2
Consequently: when Po2 is high (hyperoxia) the
peripheral chemoreceptors do not respond to Pco2

2) There is a threshold for the Pco2 response

Consequently: when Pco2 is below threshold (hypocapnic)
the peripheral chemoreceptors do not respond to hypoxia.

50
40

ventilatory
recruitment
thresholds

30
35
20

50
150
arterial Po2
(mmHg)

30
20

0
chemoreflex
drive
threshold

10
0

30

10

35

assumed a-c Pco2

difference of 6 mmHg

40
45
50
+
arterial [H ] (nM/L)

55

60

Ventilation (L/min)

Central + Peripheral Drives to Ventilation

(L/min)

The Summed Chemoreceptors Response

Controlled System
Central chemoreceptors
BRAIN

Pco2 in brain
Ventilation

Peripheral chemoreceptors
LUNGS

Cardiac output

TISSUES

Pco2 at carotid
body

Input Pco2 at
mouth
time

The Metabolic Hyperbola

(CO2 Elimination) (Alveolar Ventilation) X (Alveolar Pco2)

(Alveolar Ventilation)

(CO2 Elimination)
(Alveolar Pco2)

y = constant
x

The Metabolic Hyperbola

30

Ventilation L/min

25
20
15
10
5
0
0

10

20

30

40

50

60

Arterial Pco2 mmHg

70

80

The Chemoreflex Graphical Model: Awake

arterial Po2 (mmHg)
50
equilibrium
points

40
Ventilation (L/min)

50

35

150

30
metabolic hyperbola
for 0.3 L/min carbon
dioxide production

20
10

wakefulness drive = 7 L/min

0

30

35

assumed a-c Pco2

difference of 6 mmHg

40
45
50
arterial Pco2 (mmHg)

55

60

The Chemoreflex Control of Breathing

50
normal resting
equilibrium point

Ventilation L/min

40

100
100
60 100
100

40
40
40

>150
Arterial Po2
mmHg

30

20

ion
s
s
e
pr
e
d
etic
h
t
s
e
an a
exercise metabolic hyperbola

exercise
drive

10
resting metabolic hyperbola

wakefulness
drive

35

40

45

Arterial Pco2 mmHg

50

55

The Chemoreflex Graphical Model: Sleeping

arterial Po2 (mmHg)
35

50

Slope =
sensitivity

equilibrium
points

40
Ventilation (L/min)

50

150
30
20

metabolic hyperbola
for 0.3 L/min carbon
dioxide production

10
0

30

apnoea thresholds

35

40
45
50
arterial Pco2 (mmHg)

55

assumed a-c Pco2 difference of 6 mmHg

60

Can the control system become

unstable?

Altitude acclimatization and sleep

Respiratory System Stability: Loop Gain

Oscillations

Plant Gain

Ventilation

Other

Pco2 Po2

Chemoreflexes

Ventilation

Gas Exchange

time
Feedback Gain

Loop Gain
Too large and
instability results

Khoo, M. C. K., 2000. Determinants of

ventilatory instability and variability. Respir.
Physiol. 122, 167-182.

Respiratory System Stability: CO2 Reserve

An increase in loop gain causes
swings in Pco2 above and below
the chemoreflex threshold
promoting episodes of apnoea

Ventilation

Ventilation

Apnoeas

time

Pco2

Dempsey, J. A., Smith, C. A.,

Przybylowski, T., Chenuel, B., Xie, A.,
Nakayama, H., Skatrud, J. B., 2004. The
ventilatory responsiveness to CO2 below
eupnoea as a determinant of ventilatory
stability in sleep. J Physiol (Lond) 560, 111.

What can go wrong during sleep?

Obstructive Sleep Apnoea

Repeated airway obstructions during sleep
decrease pulmonary ventilation causing:
1) hypoxia
2) hypercapnia
3) arousal

Loop Gain & OSA

Greater the severity of OSA, the greater the Loop Gain
YOUNES, M., OSTROWSKI, M., THOMPSON, W., LESLIE, C. & SHEWCHUK,
W. (2001). Chemical control stability in patients with obstructive sleep apnea. Am
J Respir Crit Care Med 163, 1181-1190.

OSA patients have higher chemoreflex sensitivity than

patients without OSA; Loop Gain is greater
MAHAMED, S., HANLY, P. J., GABOR, J., BEECROFT, J. & DUFFIN, J. (2005).
Overnight changes of chemoreflex control in obstructive sleep apnoea patients.
Respiratory Physiology & Neurobiology 146, 279-290.

End-stage renal disease patients with OSA have higher

chemoreflex sensitivity than those without OSA; Loop
Gain is greater.
BEECROFT, J., DUFFIN, J., PIERRATOS, A., CHAN, C. T., MCFARLANE, P. &
HANLY, P. J. (2006). Enhanced chemo-responsiveness in patients with sleep
apnoea and end-stage renal disease. Eur Respir J.

How might Loop Gain change?

Loop Gain Changes: Threshold Decreases

Loop Gain Decreases
Plant Gain - Decreases

Feedback Gain - No Change

For the same Pco2
increase, ventilation
increases the same

Ventilation

Ventilation

For the same ventilation

increase, Pco2 decreases
less

Pco2

Pco2

Loop Gain Changes: Metabolism Decreases

Loop Gain Increases

For the same

ventilation increase,
Pco2 decreases more

Pco2

Feedback Gain - No Change

Ventilation

Ventilation

Plant Gain - Increases

For the same Pco2

increase, ventilation
increases the same

Pco2

Loop Gain Changes: Sensitivity Increases

Loop Gain Increases

For the same

ventilation increase,
Pco2 decreases less

Pco2

Feedback Gain - Increases

Ventilation

Ventilation

Plant Gain - Decreases

For the same Pco2

increase, ventilation
increases more

Pco2

Do the chemoreflexes change during a

night of sleep?

OSA & Overnight Changes in Chemoreflexes

Mahamed S, Hanly PJ, Gabor J, Beecroft J,

and Duffin J. Overnight changes of chemoreflex
control in obstructive sleep apnoea patients.
Respiration Physiology & Neurobiology 146:
279-290, 2005.

Hypothesis
We hypothesized that the numerous episodes of hypoxia,
hypercapnia and arousal experienced by OSA patients
induce overnight changes in respiratory chemoreflexes.
Two modified rebreathing tests:
hyperoxic for central
hypoxic for central & peripheral

evening

morning
Overnight sleep assessment for OSA

Protocol
500 patients were screened after being referred to the St.
Michaels Hospital Sleep Laboratory for OSA assessment.
35 volunteered to participate in this study. All were nonsmokers, medication free, with no history of cardiorespiratory disease, and with a BMI less than 40.
These 35 patients were separated into non-OSA and OSA
groups based on their apnoea-hypopnoea indices (AHI);
non-OSA patients had AHIs < 10
OSA patients had AHIs > 30
those between these limits were excluded.

Chemoreflex Overnight Changes

Basal (non-chemoreflex) ventilation
no change in either group
Rate of rise of Pco2 (metabolism)
decreased in both groups
Chemoreflex Threshold
decreased in non-OSA group
Chemoreflex Sensitivity
increased in OSA group

Consequences for Stability: Loop Gain

Non-OSA
Decreased threshold
counteracts effect of
metabolism decrease

OSA
Increased sensitivity
adds to the effect of
metabolism decrease
Plant & feedback
gain increased in
the morning

morning
evening

Pco2

Ventilation

Ventilation

Plant & feedback

gain no change

morning
evening

Pco2

Conclusions: Overnight Changes in Stability

In both groups the decreased metabolism
decreases stability.
In the OSA group, the increased chemoreflex
sensitivity decreases stability.
In the non-OSA group, the decreased
chemoreflex threshold increases stability and
offsets the effect of metabolism.

Relevance: Overnight Changes in Stability

These findings may therefore explain why a number of
studies have shown that apnea severity increases from the
beginning to the end of the night independent of other factors
such as sleep stage.
Charbonneau M, Marin JM, Olha A, Kimoff RJ, Levy RD and Cosio MG.
Changes in obstructive sleep apnea characteristics through the night. Chest 106:
1695-1701, 1994.
Cala SJ, Sliwinski P, Cosio MG and Kimoff RJ. Effect of topical upper
airway anesthesia on apnea duration through the night in obstructive sleep
apnea. J Appl Physiol 81: 2618-2626, 1996.
Fanfulla F, Patruno V, Bruschi C and Rampulla C. Obstructive sleep apnoea
syndrome: is the "half-night polysomnography" an adequate method for
evaluating sleep profile and respiratory events?
Eur Respir J 10: 1725-1729, 1997.
Sforza E, Krieger J and Petiau C. Nocturnal evolution of respiratory effort in
obstructive sleep apnoea syndrome: influence on arousal threshold. Eur Respir
J 12: 1257-1263, 1998.

Acknowledgements
Funded by The Ontario
Thoracic Society.
Special thanks to my
former students.

For additional information on the Respiratory Research Group visit:

http://www.utoronto.ca/respgrp/