THE PHYSIOLOGY OF BREATHING DECLARATIONS … · lamas / labas / sabas and copd erj, feb 2004 uplift...

the physiology of breathing:

Dr. Andrew Fon MBBS FRACP

Respiratory and Sleep Medicine Physician

PhD Research Fellow

Dept. of Thoracic Medicine, ROYAL ADELAIDE HOSPITAL

Senior Clinical Lecturer

School of Medicine, UNIVERSITY OF ADELAIDE

OBSTRUCTIVE LUNG DISORDERS

DECLARATIONS

THE PHYSIOLOGY OF BREATHING

• CME Presentations• Boehringer Ingelheim

• PulmonX™

• Astra Zeneca

• Mundipharma

• PhD Research Grants

• University of Adelaide

• PulmonX™

• Thoracic Society of Australia and New Zealand

• Senior Clinical Lecturer• School of Medicine – University of Adelaide

• Access Appointment

• Dept of Thoracic Medicine – Royal Adelaide Hospital

• The driving pressure for flow is the lung elastic

recoil

• Resistance is related to properties of the lung and

its airways.


WHAT ARE THE PHYSIOLOGICAL DETERMINANTS

OF EXPIRATORY FLOW?

△PRESSURE

RESISTANCEFLOW = • Lung volume determines elastic

recoil

• Determinants of Lung Volume:

• Height

• Gender

• Age

• Ethnicity


OF EXPIRATORY PRESSURE?


Emphysema

• Elastic recoil pressure has a

curvilinear relationship with

lung volume

• Different disease processes

will have different effects on

the elastic recoil properties

of the lung



OF EXPIRATORY PRESSURE?

Lung V

olu

me

Pressure

Normal

Pulm. Fibrosis



OF AIRWAY RESISTANCE?

• 3 primary factors determine the resistance to flow within a single tube (Hagen-PoiseuilleLaw)

• Radius (cross sectional area)

• Length

• Viscosity (gas density)

• Resistance is DIRECTLY related to the length of the tube and to the viscosity of the gas.

• Resistance is INVERSELY proportional to the

length of the radius to the 4th power

• Airway calibre is the most important factor

WHICH AIRWAYS CREATE THE MOST RESISTANCE?


• Each lung has 1 main bronchi and 1.5-2 million terminal bronchioles

• The TOTAL cross-sectional area at the terminal airways is much greater that that of the intermediate generations.

• COPD is a SMALL AIRWAYS

DISEASE


• LUNG VOLUME• Increased lung volume pulls the airways apart

• At TLC airway caliber is at its greatest

• AIRWAY COMPLIANCE• Different disease states will affect the

compliance of the airway

• AIRWAY SMOOTH MUSCLE • Throughout the airways from trachea to

terminal bronchioles

• Intra-luminal Content• Inflammation/secretions may contribute to

narrowing of the airway lumen.

WHAT ARE THE PHYSIOLOGICAL DETERMINANTS OF

AIRWAY CALIBRE?

Adapted from 1. Kistemaker LE et al. Trends Pharmacol Sci 2015;36:164–171.

2. Kistemaker LE et al. Life Sci 2012;91:1126–1133. 3. Gosens R et al. Respir Res 2006;7:73.

Vagus nerve

Parasympathetic nerve

Parasympathetic ganglion

Airway

epithelium

Irritants (e.g. cigarette smoke)

Nodose

ganglion

Laryngeal

oesophageal

afferents

C-fibre

A-fibre

Irritantreceptors

C-fibre

receptors

CNS

Airway wall

ACh

ACh

ACh

Muscarinic

receptors

Submucosal

gland

Allergens

Mast cell

“Cholinergic tone”


WHAT ARE THE PHYSIOLOGICAL DETERMINANTS OF

AIRWAY CALIBRE?



OF GAS EXCHANGE?

In the lung, gas exchange is dependent on 3 principal factors:

1. Delivery of gases to and from the pleural membrane (VENTILATION)

2. The physical properties of the gas exchange membrane. (DIFFUSION)

3. Factors affecting supply of blood (PERFUSION)

IC

• Ventilation is limited by expiratory flow

limitation

• Dynamic hyperinflation (DH) causes:

• Increased end expiratory lung volume

(EELV)

• Decreased Inspiratory Capacity (IC)

• DH increases work of breathing:

• Tidal volumes move up the pressure

volume curve

• Increased thoracic volume increases

intrinsic PEEP.


HOW DOES OBSTRUCTIVE DISEASE

AFFECT VENTILATION?


HOW DOES OBSTRUCTIVE DISEASE

AFFECT THE GAS TRANSFER MEMBRANE?

Emphysema leads to the

destruction of alveolar walls

and subsequent enlargement

of the inter-alveolar spaces.

Reduced total surface area

available for gas diffusion

EMPHYSEMA AFFECTS PULMONARY VASCULATURE

• Chronic hypoxia and acidosis leads to vascular remodeling

• Destruction of alveoli and associated structures reduce the number of alveolar capillaries

• Disproportionate hyperinflation causes reduced vascular lumen cross-sectional area.

• All three changes affect the mixed venous oxygen content


ANATOMY AFFECTS PHYSIOLOGY


THE PHYSIOLOGY OF BREATHING THE PHYSIOLOGY OF BREATHING

HOW DOES OBSTRUCTIVE LUNG DISEASE AFFECT

NORMAL RESPIRATORY PHYSIOLOGY?

• LUNG MECHANICS AND VENTILATION

• Loss of elastic recoil

• Increase in airways resistance pressure

• Narrow lumens

• Increased compliance

• GAS DIFFUSION

• Reduced alveolar gas exchange surface area

• PULMONARY CAPILLARY

PERFUSION

• Reduced vasculature - increased

dead space ventilation

• Increased pulmonary capillary

pressures

• Hypoxia induced vasoconstriction

• Reduced capillary perfusion

secondary to cor pulmonale

• CARDIAC CHANGES

• Decreased venous return

• Decreased preload

• Decreased stroke volume

PATHOPHYSIOLOGY DRIVES TREATMENT

• Treatment goals are to:

• Minimize disease progression

• Improve quality of life

• Reduce exacerbations

• Improve exercise tolerance

• Maintain lung function

• TREATMENT GOALS ARE

PATIENT FOCUSSED

THE PHYSIOLOGY OF BREATHINGTHE PHYSIOLOGY OF BREATHING

WHAT ARE THE CLINICAL APPLICATIONS?

PHYSIOLOGICAL ADAPTATION



Vagus nerve

Parasympathetic nerve

Parasympathetic ganglion

Airwayepithelium

Irritants (e.g. cigarette smoke)

Nodoseganglion

Laryngealoesophageal

afferents

C-fibre

Ad-fibre

Irritantreceptors

C-fibrereceptors

CNS

Airway wall

ACh

ACh

ACh

Muscarinicreceptors

Submucosal gland

Allergens

Mast cell



• Inflammation is different in asthma and COPD requiring a different treatment approach:

COPD AsthmaMast cells,

Eosinophils, Inflammatory

cytokines

Inflammation is responsive

to corticosteroidsinflammation is largely

unresponsiveto corticosteroids

Airway neutrophils,

Macrophages, CD8+ T Cells

10%


LAMAs / LABAs / SABAs and COPD

ERJ, Feb 2004

UPLIFT - NEJM, Oct 2008


CORTICOSTEROIDS IN COPD

ISOLDE Trial - BMJ, May 2000

TORCH - NEJM, Feb 2007

INSPIRE - AJRCCM, Oct 2007



PATHOS - BMJ, May 2013

WISDOM - NEJM, Oct 2014


FLAME - NEJM, May 2016


IMPACT - NEJM, Apr 2018


• GSK funded project• Only used GSK products

• LABA/LAMA -

Umeclidinium + Vilanterol• LABA/ICS - Fluticasone

Furoate + Vilanterol• LABA/LAMA/ICS -

Vilanterol + Umec + FF

• ~40% of participants were already on triple therapy at enrolment• 70% of participants were taking an ICS• Patients with a history of asthma were included


WHO SHOULD BE ON WHAT DEVICE?


CLASS A & B:ICS Free

CLASS C & D:Initiate with LABA/LAMA

Consider ICS

REMEMBER:

• 10-15% of COPD patients

will also have asthma

• FEV1 <50%

AND

• ≥ 2 exacerbations per year

OR ≥ 1 hospitalization

AND

• Blood Eosinophil Count >

300 cells/uL

WISDOM - 2014

STEROID WEANING: HOW AND WHEN

• Insufficient data for a definitive plan.

• Patient counselling regarding rationale for withdrawal of ICS

is essential

• Especially important for patients who have been on ICS long-term

• Optimize bronchodilator therapy first

• Consider more frequent follow up in the short term once

withdrawal is started.

• Review at 1 week / 3 weeks / 6 weeks / 3 months / 6 months


• If few/no exacerbations in the past year and low symptom burden:

• Consider abrupt withdrawal of ICS

• If concern regarding withdrawal - 6-12 wk wean across each puffer dose decrease

STEROID WEANING: HOW AND WHEN


WISDOM - NEJM 2014

EMPHYSEMA: NO ROOM TO BREATHE

• Three principal factors related to exertional dyspnoea:

• Ventilatory Abnormalities

• Pulmonary Gas Exchange

• Muscle Dysfunction


COPD: NO ROOM TO BREATHE


PERI-OPERATIVE MORTALITY ~ 5 - 20%

BRONCHOSCOPIC LUNG VOLUME REDUCTION

PRE-ELVR POST-ELVR

ONE-WAY VALVE INSERTION

Damaged, hyperinflated section of the

lungs

Healthy,

squashed

section of the lungs

Healthy section of the lungs

has expanded

Damaged

section of

the lungs has collapsed


BRONCHOSCOPIC LUNG VOLUME REDUCTION

Difference EBV vs Control Groups

TRIALSize & Follow-up

period

Lung Function (FEV1%)

MCID = 10%-15%

Exercise Capacity (6MWD)

MCID = 26 m

Quality of Life (SGRQ)

MCID = -4 pts

VENT4

n=122

(post hoc subset)

6 mo24.8% 28 m -8.4 pts

BeLieVeR-HIFi3n=50

3 mo20.9%* 33 m* -5.1 pts

STELVIO2 n=68

6 mo17.8%* 74 m* -14.7 pts

IMPACT1 n=93

3 mo17.0%* 40 m* -9.6 pts*

LIBERATE5 n= 190

12 mo18.0%* 39 m* -7.1 pts

1. Valipour A et al, AJRCCM 2016. 194: 1073–1082;

2. Klooster K. et al. N Engl J Med. 2015; 373: 2325-2336 + Supplementary Appendix;

3. Davey C et al, Lancet. 2015; 386: 1066-1073 + Supplementary appendix;

4. Scuirba F.C. et al. N Engl J Med. 2010; 363(13): 1233-1244/ Herth F. J. et al. Eur. Respir. J. 2012; 39(6): 1334-1342/ Ad hoc analysis on file at Pulmonx

5. Criner, G et al, 2018

THE PHYSIOLOGY OF BREATHING THE PHYSIOLOGY OF BREATHING

SUMMARY• The physiological basis of disease dictates therapy options in

COPD

• COPD causes loss of elastic recoil, increased small airway resistance, and changes to ventilation and perfusion.

• Focus of therapy is to maximize quality of life and minimize exacerbations and loss of function.

• The majority of patients will not be worse off on LABA/LAMA vs LABA/ICS

• ICS are indicated in the appropriate patient - Efforts to minimize steroid exposure is a must.


REFERENCES

THANK YOU

THE PHYSIOLOGY OF BREATHING DECLARATIONS … · lamas / labas / sabas and copd erj, feb 2004 uplift...

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