Denis E. O’Donnell, MD, FRCPC,FRCPI

Respiratory Investigation Unit

Kingston Health Sciences Centre & Queen’s University

Kingston, Ontario

Canada

Unraveling the Pathophysiology

of Breathlessness in COPD

Conflicts of Interest

I have served on speakers bureaus, consultation

panels and advisory boards for AZ, BI and Novartis.

I have received research funding support from AZ,

BI and Novartis.

Funding from Queens University, Canadian/Ontario

Lung Association, Ontario Ministry of Health and

CIHR

Outline

Definition

Demand/Capacity imbalance

Reducing Inspiratory Neural Drive

Manipulating mechanics

Summary

Definition of Dyspnea (ATS 2012)

“A subjective experience of breathing

discomfort that consists of qualitatively

distinct sensations that vary in intensity.”

Parshall MB, et al; ATS Committee. Am J Respir Crit Care Med 2012; 185:435-52.

Breathlessness:

Demand/Capacity Imbalance

“Breathlessness can be seen to result from the

imbalance between the demand for breathing

and the ability to achieve the demand.”

Norman L. Jones. The Ins and Outs of Breathing 2011.

Efferent-Afferent Dissociation

Mechanistic studies have shown that when the

spontaneous increase in VT is constrained (either

volitionally or by external imposition) in the face of

increased chemostimulation, respiratory discomfort

(ie.air hunger) results.

Wright GW, Branscomb BV. Trans Am Clin Climatol Assoc 1954; 66: 116-25.

Campbell EJM, Howell JB. Br Med Bull 1963; 19: 36-40.

Schwartzstein RM, et al. Am Rev Respir Dis 1989; 139: 1231-7.

Mannning HL, et al. Respir Physiol 1992; 90: 19-30.

Harty HR, et al. J Appl Physiol 1999; 86: 1142-50.

O’Donnell DE, et al. J Appl Physiol 2000; 88: 1859-69.

Evans KC, et al. J Neurophysiol 2002; 88: 1500-11.

Banzett RB, et al. Am J Respir Crit Care Med 2008; 17: 1384-90.

fMRI Shows Limbic Activation during Dyspnea

8

n = 6, p < 0.001 (T > 5.0)

corrected for multiple comparisons

T statistic

Rt

X = 34

4

Z = +8

slice y = +16

Insula

Cingulate

Amygdala

slice y = +4

Evans KC, et al. J Neurophysiol 2002; 88: 1500-11.

The Patient is the Center of Attention

Respiratory Investigation Unit : Established 1990

Dyspnea Intensity-

Work rate Relationships

Quality of Dyspnea

during Exercise

very, very severe

0

1

2

3

4

5

6

7

8

9

10

0 20 40 60 80 100

Work rate (% predicted maximum)

Breathing discomfort

(Borg scale)

very severe

severe

somewhat severe

moderate

slight

maximal

very slight

none

Health

COPD

0 20 40 60 80 100

Increased

Work/Effort

Unsatisfied

Inspiration

Inspiratory

Difficulty

Heavy

Shallow

Rapid

Tight Chest

Expiratory

Difficulty

Selection frequency (% of group)

Health

COPD

* *

*

* p<0.05 vs Health

O’Donnell DE, et al. AJRCCM 1997;155:109-15.

O’Donnell DE. Respiratory Investigation Unit, Kingston, Ontario, Canada.

Measuring respiratory physiology

Drive to

Breathe

Esophageal

pressure

Gastric pressure

Respired flows

EXERCISE REST

“Balloons, Bicycles and Body Boxes”

Plethysmograph

(aka “Body Box”)

Exercise Bike Deadspace

Esophageal

balloon catheter

Chest Strapping

CWS = chest strap to 60% of control VC

DS = 600 mL of added dead space

Chest Wall Restriction & Dead Space Loading in Men

0

1

2

3

4

5

6

7

8

0 20 40 60 80 100

Dysp

nea (

Bo

rg S

cale

)

Work Rate (%predicted maximum)

CWS+DS

CWS

DS Control

10

20

30

40

50

60

0 10 20 30 40 50 60T

ida

l V

olu

me

(%

pre

dic

ted

VC

)

Pes/PImax (%)

Control

CWS+DS

CWS

DS

O’Donnell et al. J Appl Physiol 2000

Increased

CO2 , VT/TI

Bf

Qualitative Aspects of Dyspnea

0 20 40 60 80 100

Increased Work

Inspiratory Difficulty

Unsatisfied Inspiration

Heavy

Shallow

Rapid

Expiratory Difficulty

Hunger

Selection Frequency (%)

Control

CWS+DS

*p<0.05

*

*

*

*

brainstem

Demand/capacity

imbalance

airways

lungs

muscles

pulm

onary

(vagal)

affe

ren

t a

ctivity

Increased drive to

breathe

Impaired Respiratory muscle

action

somatosensory cortex Breathlessness

limbic system Respiratory distress

motor cortex

O’Donnell DE, et al. Respir Physiol Neurobiol 2009;167:116-32.

1

2

Dyspnea and Inspiratory Neural Drive in

COPD and ILD

Faisal A, et al. Am J Respir Crit Care Med 2016

Guenette JA, et al. Eur Respir J 2014; 44: 1177-87.

Elbehairy AF, et al. Eur Respir J 2016; 48: 694-705.

Faisal A, et al. Am J Respir Crit Care Med 2016; 193: 299-309.

Inspiratory Neural Drive during Exercise

Values are means ± SEM. *p<0.05 significantly different from healthy controls at a given work rate.

0

10

20

30

40

50

60

70

80

0 40 80 120 160 200

EM

Gd

i/E

MG

di,m

ax (

%)

Work rate (W)

Healthy Smokers at risk GOLD 1 GOLD 2-3

* *

*

*

Increased Inspiratory Neural Drive:

Mechanisms

Increased VCO2: - Increased physiological dead space

- Earlier metabolic acidosis

Critical arterial O2 desaturation

Increased respiratory muscle loading/weakness

Increased ergoreceptor activation

Increased sympathetic activation

Altered pulmonary reflexes

Estépar SJ, et al. Am J Respir Crit Care Med 2013.

CT measures of pulmonary vascular morphology

in smokers and their clinical implications

Volumetric reconstructions of the pulmonary vasculature

that are colour-coded based on vessel radii:

https://www.youtube.com/watch?v=PtqY3V6Mtqo

Cirio S et al. Respiratory Medicine 118 (2016) 128-132

Ventilatory Inefficiency in GOLD 1 COPD

20

25

30

35

40

45

50

55

60

65

0 40 80 120 160

VE

/VC

O2

Work rate (watt)

Control COPD

* * *

Ofir D, et al. Am J Respir Crit Care Med 2008;177:622-9.

VE/VCO2 = 863 PaCO2 x (1-VD/VT)

. .

Ventilatory Inefficiency during Exercise in COPD

Neder JA, et al. Ann ATS 2017;

P<0.0005

P=0

.00

5

Dyspnea/ ⩒O2 slope

⩒E/⩒CO2

nadir ⩒O2 peak ml/kg/min

DLCO (% predicted)

Inter-relationships between DLCO%predicted, peak VO2,

dyspnea/VO2 slope and VE/VCO2 nadir within smokers

Elbehairy AF, et al. COPD 2017

Reducing Central Chemo-stimulation

in COPD

Elbehairy A et al Respiratory Physiology & Neurobiology 252–253 (2018) 64–71

Bronchodilators do not decrease Wasted Ventilation

Aerobic Exercise

Maltais Pulmonary Rehab Center, Quebec City 2018

Exercise training reduces exercise lactic acidosis and ventilation

Casaburi R, et al. Am Rev Respir Dis 1991.

Treatment Strategies

O2 Therapy

Effects of Hyperoxia on Dyspnea and Exercise Endurance

O’Donnell DE, et al. Am J Respir Crit Care Med 1997;.

0

1

2

3

4

5

6

7

8

0 2 4 6 8 10 12 14

Dys

pn

ea

(B

org

)

Exercise time (min)

Room Air Oxygen

*

*p<0.05 significant reduction in slopes with 50% oxygen vs. room air.

O’Donnell DE, et al. Am J Respir Crit Care Med 1997; 155: 530-5.

Physiological effects of hyperoxia

brainstem

Neuromechanical

dissociation

airways

lungs

muscles

pulm

onary

(vagal)

affere

nt

activity

Ventilatory drive

Respiratory mechanics

somatosensory cortex Dyspnea

limbic system Respiratory distress

? ? Corollary

discharge motor cortex

O’Donnell DE, et al. Respir Physiol Neurobiol 2009;167:116-32.

1

Ventilatory drive

2

Respiratory mechanics

Demand-Capacity Imbalance during

Exercise in COPD

O’Donnell DE, et al. Eur Respir Rev 2016; 25: 333-47.

*

DEMAND

CA

PA

CIT

Y

The lungs of a COPD patient are hyperinflated

compared to age & height matched healthy individuals

IC ~2.5 L TLC 5.2 L

EELV 2.7 L

IC ~1.5 L TLC 6.2 L (120%pr)

EELV 4.7 L (160%pr)

Healthy female Female COPD

patient

Images used with permission from Prof. Denis O’Donnell, Queen’s University and Kingston General Hospital, December 2016

Operating Lung Volume Responses to Exercise

COPD

EELV

TLC

RV

IC IC

IC IC

EELV

TLC

RV

Health exercise ↓

Vo

lum

e

IRV

RV

TLC

EELV

Pressure

IRV

TLC

RV

EELV

∆P

∆V

∆P

∆V

∆P/∆V

15

20

25

30

35

40

45

10 20 30 40 50 60 Ventilation (L/min)

VT

(%

pre

dic

ted

VC

)

16

20

24

28

32

36

10 20 30 40 50 60 Ventilation (L/min)

Fb

(b

reath

s/m

in)

Breathing Pattern during Exercise in COPD (n=427)

O’Donnell DE, et al. Chest 2012;141:753-62.

0

1

2

3

4

5

6

7

8

20 40 60 80 100

VT / IC (%)

Dys

pn

ea

(B

org

sc

ale

)

Q1 Q2 Q3 Q4

‘mild’ ‘severe’ IC %predicted

86

81

69

60

Improving Respiratory Mechanics in

COPD

∆IC = 0.35 L

Pre-dose

0

20

40

60

80

100

120

140

Lu

ng

vo

lum

e

(% p

red

icte

d T

LC

) Post-dose

FRC

TLC

IC

IC pre-dose

IC post-dose

Flo

w

Volume TLC

Isovolume

maximal flow

Pre-dose

Post-dose

Pharmacological Lung Volume Reduction

Responses to Bronchodilators in COPD LABA

LAMA

LABA/LAMA

Langer D, et al. Expert Rev Respir Med 2014; 8(6): 731-49.

0.0 0.1 0.2 0.3 0.4

O'Donnell DE. ERJ 2004a

Man WD. Thorax 2004

O'Donnell DE. Chest 2006

Neder JA. RespirMed 2007

Worth H, RespirMed 2010

O'Donnell DE, Respir Med 2011

Beeh KM, COPD 2011

O'Donnell DE. ERJ 2004b

Maltais F. Chest 2005

O'Donnell DE. JAP 2006

Maltais F. RespirMed 2011

Beeh KM, Int J COPD 2012

Beeh KM, Respir Med 2014

Beeh KM, Respir Med 2014

IC at isotime (L)

(peak)

0 30 60 90 120 150 180

Endurance time (sec)

NS

NS

NS

NS

∆ ∆

NS

Calzetta L, Resp Med, 2017

(n=8)

Reducing Lung Hyperinflation

Improves respiratory muscle function

Improves cardio-circulatory function

Restores Demand /Capacity balance

Delays the onset of severe breathlessness

Improves exercise tolerance

O’Donnell, J Appl Physiol 2006; Travers, Respir Med 2008; Laveneziana, EJAP 2009.

5 L 4.5 L

Bronchodilators

Exercise Training

Endoscopic/ LVRS

Oxygen

Opiates

Heliox

Treatment Strategies

Inspiratory Muscle Training (IMT)

1 2 3 4 5 6 7 8

0

20

40

60

80

100 Intervention

Control

948%

992%

993%

9512%9314%

8817%

100%100%

9511% 9217% 9410% 8725% 976% 992% 100% 100%

Training Week

Trai

ning

Inte

nsit

y

% P

i,max

Bas

elin

e

Inspiratory Muscle Training

Langer D, et al. manuscript in preparation

Increased Inspiratory Muscle Strength

-10

-5

0

5

10

15

20

25

30

MIP at FRC MIP at RV Pes,sniff Pdi,sniff

Ch

an

ge

in

pre

ssu

re (

cm

H2O

)

IMT

Control

*

* * #

#

# #

Langer D, et al. J Appl Physiol 2018 in press

Inspiratory Muscle Training

Reduces Diaphragm Activation

and Dyspnea during Exercise in

COPD Langer D, Journal of Applied Physiology 15

Mar 2018

Key Messages

Dyspnea is a complex multi-dimensional symptom

Increased dyspnea during activity in COPD is related

to increased inspiratory neural drive to the

diaphragm

The distressing sensation of “unsatisfied inspiration”

is linked to neuromechanical dissociation of the

respiratory system – Demand/Capacity imbalance

Some physiological contributors are currently

immutable

Dyspnea Reduction:

A Physiological Rationale

Increase IC to delay dyspnea threshold

Reduce VCO2 and metabolic acidosis

Strengthen the inspiratory muscles

Alter affective dimension

Dyspnea Alleviation in COPD:

Management Strategies

Reduce mechanical load: • Bronchodilators

• Surgical / endoscopic lung volume reduction

• Ventilatory assistance

• Oxygen / heliox / exercise training

Reduce IND: • Oxygen

• Exercise training

• Opiates / anxiolytics

Increase ventilatory muscle strength: • Exercise training

• Specific inspiratory muscle training

Alter Affective Dimension: • Opiates / anxiolytics / oxygen / exercise training

Brief History of Dyspnea

Vagus : Hering-Breuer Reflex [1868]

Hypoxia 1875 [ Tissandier G et al]

Hypercapnia [Haldane 1893]

Psychophysics of Dyspnea [SS Stevens 1960]

Validated Scaling [Borg, 1961]

Length-tension Inappropriateness Theory [EJM

Campbell 1961]

Sense of Increased Effort [KJ Killian 1991]

Indirect Indices of Respiratory Drive

and Demand/Capacity Imbalance

VE/MVC

Respiratory effort (tidal esophageal pressure

relative to maximum inspiratory pressure)

Respiratory neural drive (EMGdi relative to

maximum)

JH Means, Med Monograph 1924, P LeBlanc, ARRD 1986; Jolley, ERJ 2015.

medulla

airways

lungs

muscles

Altere

d a

ffe

rent

activity

Ventilatory drive

Respiratory mechanics

somatosensory cortex

Respiratory discomfort (sensory intensity, quality)

limbic system

Respiratory distress (affective)

Corollary

discharge

motor cortex

central & peripheral

chemoreceptors

Pulmonary ventilation

& gas exchange

PaO2

PaCO2, [H+]

Neuromodulation

by endorphins

O’Donnell DE, Mahler DA. Chest 2015.

O’Donnell DE, et al. Respir Physiol Neurobiol 2009.

1

Ventilatory drive

VCO2, [H+]

VD

PaO2

PaCO2, [H+]

VCO2

[H+]

brainstem

Neuromechanical

dissociation

airways

lungs

muscles

pulm

onary

(vagal)

affere

nt

activity

Ventilatory drive

Respiratory mechanics

somatosensory cortex Dyspnea

limbic system Respiratory distress

? ? Corollary

discharge motor cortex

O’Donnell DE, et al. Respir Physiol Neurobiol 2009;167:116-32.

1

Ventilatory drive

2

Respiratory mechanics

The Dyspnea Challenge Test !

#*@$!!!

The Dyspnea Challenge Test !

#*@$!!!

Bronchodilators reduce the demand-

capacity imbalance during exercise in COPD

O’Donnell DE, et al. J Appl Physiol 2006;101:1025–35.

15

20

25

30

35

10 20 30 40 50 60

VT

(%

pre

dic

ted

VC

)

Pes/PImax (%)

Placebo Tiotropium

IC at end-exercise increased 0.31 L

with tiotropium vs. placebo (p<0.05)

0

10

20

30

40

50

60

70

80

Work/Effort UnsatisfiedInspiration

"Cannot takea deep

breath IN"F

req

ue

nc

y o

f re

sp

on

se

(%

) Placebo

Tiotropium

*

p=0.06

DEMAND

CA

PA

CIT

Y

Inter-relationships at a Standardized Level

of Exercise in COPD

Dyspnea (Borg scale)

Effort / VT ratio p<0.001

IC (EELV)

O’Donnell DE, et al. Am J Respir Crit Care Med 1997; 155: 109-15.

Increasing IC

would be expected

to reduce dyspnea

and decrease

inspiratory effort

Health

IC

EELV

TLC

exercise→

RV

VC

EELV

TLC IC

RV

VC

COPD

The “Dyspnea Threshold”

= Critical ventilatory mechanical constraints (i.e., VT/VE inflection point)

Laveneziana P, et al. Am J Respir Crit Care Med 2011.

Evolution of Dyspnea during Exercise in COPD

0

20

40

60

80

100

0 1 2 3 4 5 6

Exercise time (min)

Descripto

r (%

of

subje

cts

)

Effort IN OUT

Effort = “My breathing requires more work/effort”

IN = “I cannot get enough air in”

OUT = “I cannot get enough air out”

brainstem

Demand/capacity

imbalance

airways

lungs

muscles

pulm

onary

(vagal)

affe

ren

t a

ctivity

Increased drive to

breathe

Impaired Respiratory muscle

action

somatosensory cortex Breathlessness

limbic system Respiratory distress

motor cortex

O’Donnell DE, et al. Respir Physiol Neurobiol 2009;167:116-32.

1

2