WHAT ARE THE PHYSIOLOGICAL DETERMINANTS OF EXPIRATORY FLOW?

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1 Lung Volume the physiology of breathing: OBSTRUCTIVE LUNG DISORDERS Dr. Andrew Fon MBBS FRACP Respiratory and Sleep Medicine Physician PhD Research Fellow Dept. of Thoracic Medicine, ROYAL ADELAIDE HOSPITAL CME Presentations Boehringer Ingelheim PulmonX Astra Zeneca Mundipharma DECLARATIONS 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 Senior Clinical Lecturer School of Medicine, UNIVERSITY OF ADELAIDE OF EXPIRATORY FLOW? OF EXPIRATORY PRESSURE? PRESSURE FLOW = Lung volume determines elastic RESISTANCE recoil The driving pressure for flow is the lung elastic recoil Resistance is related to properties of the lung and its airways. Determinants of Lung Volume: Height Gender Age Ethnicity OF EXPIRATORY PRESSURE? OF AIRWAY RESISTANCE? 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 Emphysema Normal Pulm. Fibrosis 3 primary factors determine the resistance to flow within a single tube (Hagen-Poiseuille Law) 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 4 th power Pressure Airway calibre is the most important factor

2 WHICH AIRWAYS CREATE THE MOST RESISTANCE? Each lung has 1 main bronchi and 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 OF AIRWAY CALIBRE? 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. OF AIRWAY CALIBRE? OF GAS EXCHANGE? Laryngeal oesophageal afferents Airway wall Airway epithelium Irritant A -fibre Irritants (e.g. cigarette smoke) Allergens Nodose ganglion Cholinergic tone CNS Mast cell Vagus nerve Parasympathetic nerve Parasympathetic ganglion Muscarinic Submucosal gland 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) Adapted from 1. Kistemaker LE et al. Trends Pharmacol Sci 2015;36: Kistemaker LE et al. Life Sci 2012;91: Gosens R et al. Respir Res 2006;7:73. HOW DOES OBSTRUCTIVE DISEASE AFFECT VENTILATION? HOW DOES OBSTRUCTIVE DISEASE AFFECT THE GAS TRANSFER MEMBRANE? 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. IC Emphysema leads to the destruction of alveolar walls and subsequent enlargement of the inter-alveolar spaces. Reduced total surface area available for gas diffusion

3 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 crosssectional area. ANATOMY AFFECTS PHYSIOLOGY All three changes affect the mixed venous oxygen content 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 WHAT ARE THE CLINICAL APPLICATIONS? Treatment goals are to: Minimize disease progression Improve quality of life Reduce exacerbations Improve exercise tolerance Maintain lung function TREATMENT GOALS ARE PATIENT FOCUSSED

4 PHYSIOLOGICAL ADAPTATION Nodose ganglion CNS Laryngeal oesophageal afferents Vagus nerve Parasympathetic nerve Airway wall Irritant Ad-fibre Mast cell Parasympathetic ganglion Muscarinic Submucosal gland Airway epithelium Allergens Irritants (e.g. cigarette smoke) LAMAs / LABAs / SABAs and COPD Inflammation is different in asthma and COPD requiring a different treatment approach: ERJ, Feb % COPD Airway inflammation neutrophils, is largely unresponsive Macrophages, to corticosteroids CD8+ T Cells Asthma Inflammation Mast cells, is responsive Eosinophils, to Inflammatory corticosteroids cytokines UPLIFT - NEJM, Oct 2008 CORTICOSTEROIDS IN COPD CORTICOSTEROIDS IN COPD ISOLDE Trial - BMJ, May 2000 PATHOS - BMJ, May 2013 TORCH - NEJM, Feb 2007 INSPIRE - AJRCCM, Oct 2007 WISDOM - NEJM, Oct 2014 FLAME - NEJM, May 2016

5 CORTICOSTEROIDS IN COPD GSK funded project Only used GSK products LABA/LAMA - Umeclidinium + Vilanterol LABA/ICS - Fluticasone Furoate + Vilanterol LABA/LAMA/ICS - Vilanterol + Umec + FF IMPACT - NEJM, Apr 2018 ~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? REMEMBER: 10-15% CLASS of COPD C & D: patients Initiate will also with have LABA/LAMA asthma Consider ICS FEV1 <50% AND 2 exacerbations per year OR 1 hospitalization CLASS A & B: AND Blood ICS Eosinophil Free Count > 300 cells/ul 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 WISDOM STEROID WEANING: HOW AND WHEN If few/no exacerbations in the past year and low symptom burden: Consider abrupt withdrawal of ICS If concern regarding withdrawal wk wean across each puffer dose decrease EMPHYSEMA: NO ROOM TO BREATHE Three principal factors related to exertional dyspnoea: Ventilatory Abnormalities Pulmonary Gas Exchange Muscle Dysfunction WISDOM - NEJM 2014

6 COPD: NO ROOM TO BREATHE BRONCHOSCOPIC LUNG VOLUME REDUCTION PRE-ELVR POST-ELVR PERI-OPERATIVE MORTALITY ~ 5-20% ONE-WAY VALVE INSERTION Damaged, hyperinflated section of the lungs Healthy, squashed section of the lungs Damaged section of the lungs has collapsed Healthy section of the lungs has expanded BRONCHOSCOPIC LUNG VOLUME REDUCTION TRIAL Size & Follow-up period VENT 4 n=122 (post hoc subset) 6 mo BeLieVeR-HIFi 3 n=50 3 mo STELVIO 2 n=68 6 mo IMPACT 1 n=93 3 mo LIBERATE5 n= mo Lung Function (FEV 1%) MCID = 10%-15% Difference EBV vs Control Groups Exercise Capacity (6MWD) MCID = 26 m Quality of Life (SGRQ) MCID = -4 pts 24.8% 28 m -8.4 pts 20.9%* 33 m* -5.1 pts 17.8%* 74 m* pts 17.0%* 40 m* -9.6 pts* 18.0%* 39 m* -7.1 pts 1. Valipour A et al, AJRCCM : ; 2. Klooster K. et al. N Engl J Med. 2015; 373: Supplementary Appendix; 3. Davey C et al, Lancet. 2015; 386: Supplementary appendix; 4. Scuirba F.C. et al. N Engl J Med. 2010; 363(13): / Herth F. J. et al. Eur. Respir. J. 2012; 39(6): / Ad hoc analysis on file at Pulmonx 5. Criner, G et al, 2018 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