INVITED REVIEW SERIES: IDIOPATHIC INTERSTITIAL PNEUMONIA—PART 3: GENERAL MANAGEMENT ISSUES SERIES EDITORS: TAMERA J CORTE, ATHOL U WELLS AND HAROLD R COLLARD
Exercise pathophysiology and the role of oxygen therapy in idiopathic interstitial pneumonia LAUREN K. TROY,1,2 IVEN H. YOUNG,1,2 EDMUND M.T. LAU1,2 AND TAMERA J. CORTE1,2 1
Department of Respiratory Medicine, Royal Prince Alfred Hospital, and 2Sydney Medical School, University of Sydney, Sydney, Australia
ABSTRACT Exercise limitation is a common feature in idiopathic interstitial pneumonia (IIP). There are multiple contributing pathophysiological mechanisms, including ventilatory mechanical limitation, impaired gas exchange, pulmonary vascular insufficiency and peripheral muscle dysfunction. Progressive exertional dyspnoea and functional incapacity impact significantly on quality of life. Exercise-induced desaturation is frequently observed and is predictive of poorer outcomes. Tests to assess the cardiorespiratory system under stress (e.g. cardiopulmonary exercise testing and the 6-min walk test) can provide important physiologic and prognostic information as adjuncts to resting measurements of lung function. Despite many advances in understanding disease mechanisms, therapies to improve exercise capacity, symptom burden and quality of life are lacking. Exercise training and supplemental oxygen are two potential interventions that require closer evaluation in patients with IIP. Key words: exercise, exercise test, idiopathic interstitial pneumonia, interstitial lung disease, oxygen.
Correspondence: Lauren Troy, Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Missenden Rd Camperdown, Sydney, NSW 2050, Australia. Email: ltroy@ med.usyd.edu.au The Authors: Dr Lauren Troy is a respiratory physician at Royal Prince Alfred Hospital, currently undertaking a PhD in exercise and sleep physiology in the idiopathic interstitial pneumonias. Professor Iven Young is a clinical professor of medicine, Central Clinical School, University of Sydney and the Chair of the Physician Training Council, (Health Education and Training Institute). Dr Edmund Lau is a respiratory physician at Royal Prince Alfred Hospital, recently completing a post-doctoral fellowship in pulmonary vascular disease at Hospital Bicetre, France. A/ProfessorTamera Corte is the Director of the Interstitial Lung Disease Unit, Royal Prince Alfred Hospital, with specialist training and research interest in interstitial lung disease and pulmonary hypertension. Received 18 October 2014; invited to revise 29 January 2015; revised 17 February 2015; accepted 3 August 2015. © 2015 2015Asian AsianPacifi Pacific Society Respirology © c Society ofof Respirology
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Abbreviations: 6MWD, 6-min walk test distance; 6MWT, 6-min walk testing; COPD, chronic obstructive pulmonary disease; CPET, cardiopulmonary exercise testing; CRQ, Chronic Respiratory Disease Questionnaire; DLCO, diffusing capacity for carbon monoxide; ESWT, endurance shuttle walk test; f, breathing frequency; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, heart rate; HRQL, health-related quality of life; HRR, heart rate recovery; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; MIGET, multiple inert gas elimination technique; MVV, maximum voluntary ventilation; NSIP, non-specific interstitial pneumonia; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen; SGRQ, St Georges Respiratory Questionnaire; SpO2, oxyhaemoglobin saturation on pulse oximetry; VA/Q, ventilation-perfusion; VCO2, carbon dioxide output; VD, volume of dead space; VD/VT, dead space to tidal volume ratio; VE, minute ventilation; VE/VCO2, ventilatory equivalent for carbon dioxide production; VO2, oxygen consumption; VT, tidal volume
INTRODUCTION Idiopathic interstitial pneumonia (IIP) comprises a diverse group of fibrotic and inflammatory interstitial lung diseases (ILD) of unknown origin.1–3 Exercise limitation is often the first sign of disease, and may be insidious or more rapid in onset. Exertional dyspnoea can have a substantial impact on quality of life, and with disease progression, even the most fundamental of tasks may pose great challenge for patients. Identifying the contributing causes for effort intolerance, including mechanical, circulatory and gas exchange limitations is key to understanding disease pathogenesis. Detailed evaluation with cardiopulmonary exercise testing (CPET) and 6-min walk testing (6MWT) helps to provide insights into these physiological impairments, as well as explore the effects of interventions such as supplemental oxygen and exercise training. Despite the widespread use of ambulatory oxygen in IIP patients, the evidence is limited, particularly with regard to quality of life and long-term outcomes. Respirology (2015) Respirology (2016) 21, 1005–1014 doi: doi:10.1111/resp.12650 10.1111/resp.12650
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space relative to tidal volume in ILD subjects.6,11 In normal subjects, it is usual for the dead space to tidal volume ratio (VD/VT) to decrease as ventilatory requirements increase during exercise. In ILD subjects, it is not uncommon for the VD/VT to remain the same, or even increase under similar conditions, reducing the ability of the lungs to clear the increasing carbon dioxide production during exercise without a further increase in VE.8,16,17
Early published studies on this subject comprised patients with IIP and non-IIP forms of ILD, including occupational lung disease and chronic hypersensitivity pneumonitis. As many of the principles are common across the ILD group as a whole, this review will focus upon ‘IIP’ within the context of ‘ILD’.
EXERCISE PHYSIOLOGY IN IIP Exercise performance is affected to varying degrees in all forms of IIP, and is thought to be the consequence of altered respiratory mechanics, impaired gas exchange, blunted cardiovascular response and peripheral muscle dysfunction (Fig. 1).4–7
Gas exchange and oxygen desaturation Abnormal gas exchange during exercise is reflected in a widening of the alveolar-arterial oxygen gradient, predominantly due to ventilation-perfusion (VA/Q) inequality.17–19 Diffusion limitation contributes to a lesser degree, as demonstrated with the multiple inert gas elimination technique (MIGET) studies of the 1970s and 1980s.18–20 Reduced mixed venous oxygen content is also seen in exercising ILD patients due to reduced cardiac output and proportionately increased extraction of oxygen by working muscles.17 The combination of these factors often leads to significant arterial oxyhaemoglobin desaturation during exercise—a poor prognostic feature when present.21–24 Despite the impairment of gas exchange and the mechanical constraints, hypercapnia is not typical in patients with ILD. The increased f, and accordingly VE, ensures that eucapnia is maintained.9 Indeed, the ventilatory response to increasing CO2 output (VCO2) during exercise (depicted by the VE/VCO2 relationship) is measurably elevated in exercising ILD subjects, compared with normal.25,26 The VE/VCO2 is an index of the degree of VA/Q inequality in that it is roughly proportionate to the VD/VT as long as PaCO2 is stable.25
Mechanical and ventilatory factors The minute ventilation (VE) of ILD patients is elevated at rest and even more so during exercise.8–11 This increase is largely the effect of an augmented respiratory frequency, f, in the setting of reduced lung compliance and low tidal volumes (VT). The increase in f is thought to be the consequence of increased elastic loading on respiratory muscles and stimulation of peripheral mechanoreceptors.9,12,13 As exercise intensity increases in ILD subjects, tidal volumes account for a greater proportion of the diminished inspiratory capacity, and some will approach, or even exceed, their estimated maximal voluntary ventilation (MVV).8,10 This value is calculated by multiplying baseline forced vital expiratory in 1 s by 40.14 In normal subjects, the peak exercise VE is generally 55 breaths per minute), high VE, sometimes with little or no breathing reserve, a failure to reduce VD/VT, oxygen desaturation and elevated VE/VCO2, as described above. The characteristic CPET findings in IIP and other ILD patients are summarized in Table 1. In ILD patients, diffusing capacity for carbon monoxide (DLCO) and transfer coefficient are predictive of desaturation during CPET and also peak VO2 and VD/VT.17,19,34,46 These resting measurements reflect the degree of diffusion limitation as well as the severity of pulmonary vascular insufficiency, factors that are exacerbated during exercise. Spirometric values and lung volumes also correlate with peak VO2, but less precisely.34 Additionally, a substantial proportion of patients with ILD will have normal resting lung function parameters but abnormal response to exercise.
Six-minute walk testing The 6MWT is a self-paced test that measures the distance a subject can quickly walk in 6 min, on a 30-m track. This provides a simple and practical assessment of functional exercise capacity, with readily accessible standardized guidelines for implementation.47 The 6MWT is used widely in a number of disease states, including chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension and heart failure.48–53 In IIP and other types of ILD, there is a substantive body of evidence for using the 6MWT in prognostic evaluation.21,54–57 The 6MWD has been shown to be highly reliable and reproducible in patients with fibrotic IIP (including IPF and idiopathic NSIP).55 This measurement also correlates well with peak VO2 as measured by CPET, indicating that the exercise intensity achieved during the 6MWT approximates maximal exercise in IIP patients, particular when disease is severe.44,54 Oxygen desaturation during the 6MWT, even in the absence of resting hypoxia, is commonly observed, and can exceed that seen during CPET in the same individuals.44,54 This phenomenon may be explained by greater tolerability of walking than cycling under hypoxic conditions. Because the 6MWT is self-paced, it is considered to be more representative of real-life activity than CPET. Endurance shuttle walk testing The endurance shuttle walk test (ESWT) is an externally paced field test, where a subject walks at a constant rate between two cones on a 10-m track in time to pre-recorded audio signals. The pace is set at 85% of the maximal pace achieved on an incremental shuttle test. The ESWT is well validated for measuring exercise capacity in COPD populations with good repeatability.58,59 In IPF and sarcoidosis patients, distance walked during ESWT correlates well with resting oxyhaemoglobin saturation on pulse oximetry (SpO2), DLCO and peak VO2 as measured with CPET.60,61 The advantage of this test over the 6MWT and CPET is that at 85% maximal intensity, it is arguably a closer approximation to the typical activities of daily living. Although it has been widely applied in ©© 2015 Asian 2015 AsianPacific PacificSociety Societyof of Respirology Respirology
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oxygen in in IIP IIP Exercise and oxygen Table 1
Characteristic CPET results at peak exercise in ILD patients
Exercise Parameter
Normal subjects
ILD patients
Explanation
Peak VO2 (litres/min)
Usually able to exceed 85% predicted Usually able to exceed 85% predicted Usually approaches maximum, that is, no heart rate reserve Preserved
Often below predicted range Often below predicted range May not achieve maximum
Reduced, often 50
Increased, often > 50
VT (litres)
Increases to 50–60% VC
VE (BTPS, litres/min)
Usually 50–80% MVV, that is, breathing reserve of 20–50% Reduced (compared with rest values) 0.25–0.35 (rest) → 0.05–0.20 (peak exercise) Occurs at 50–60% of peak VO2
Increases to a maximum at a relatively low work rate; overall lower than normal Increased > 90% MVV, i.e. breathing reserve
Exercise pathophysiology and the role of oxygen therapy in idiopathic interstitial pneumonia LAUREN K. TROY,1,2 IVEN H. YOUNG,1,2 EDMUND M.T. LAU1,2 AND TAMERA J. CORTE1,2 1
Department of Respiratory Medicine, Royal Prince Alfred Hospital, and 2Sydney Medical School, University of Sydney, Sydney, Australia
ABSTRACT Exercise limitation is a common feature in idiopathic interstitial pneumonia (IIP). There are multiple contributing pathophysiological mechanisms, including ventilatory mechanical limitation, impaired gas exchange, pulmonary vascular insufficiency and peripheral muscle dysfunction. Progressive exertional dyspnoea and functional incapacity impact significantly on quality of life. Exercise-induced desaturation is frequently observed and is predictive of poorer outcomes. Tests to assess the cardiorespiratory system under stress (e.g. cardiopulmonary exercise testing and the 6-min walk test) can provide important physiologic and prognostic information as adjuncts to resting measurements of lung function. Despite many advances in understanding disease mechanisms, therapies to improve exercise capacity, symptom burden and quality of life are lacking. Exercise training and supplemental oxygen are two potential interventions that require closer evaluation in patients with IIP. Key words: exercise, exercise test, idiopathic interstitial pneumonia, interstitial lung disease, oxygen.
Correspondence: Lauren Troy, Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Missenden Rd Camperdown, Sydney, NSW 2050, Australia. Email: ltroy@ med.usyd.edu.au The Authors: Dr Lauren Troy is a respiratory physician at Royal Prince Alfred Hospital, currently undertaking a PhD in exercise and sleep physiology in the idiopathic interstitial pneumonias. Professor Iven Young is a clinical professor of medicine, Central Clinical School, University of Sydney and the Chair of the Physician Training Council, (Health Education and Training Institute). Dr Edmund Lau is a respiratory physician at Royal Prince Alfred Hospital, recently completing a post-doctoral fellowship in pulmonary vascular disease at Hospital Bicetre, France. A/ProfessorTamera Corte is the Director of the Interstitial Lung Disease Unit, Royal Prince Alfred Hospital, with specialist training and research interest in interstitial lung disease and pulmonary hypertension. Received 18 October 2014; invited to revise 29 January 2015; revised 17 February 2015; accepted 3 August 2015. © 2015 2015Asian AsianPacifi Pacific Society Respirology © c Society ofof Respirology
RESP_12650.indd 1005
Abbreviations: 6MWD, 6-min walk test distance; 6MWT, 6-min walk testing; COPD, chronic obstructive pulmonary disease; CPET, cardiopulmonary exercise testing; CRQ, Chronic Respiratory Disease Questionnaire; DLCO, diffusing capacity for carbon monoxide; ESWT, endurance shuttle walk test; f, breathing frequency; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, heart rate; HRQL, health-related quality of life; HRR, heart rate recovery; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; MIGET, multiple inert gas elimination technique; MVV, maximum voluntary ventilation; NSIP, non-specific interstitial pneumonia; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen; SGRQ, St Georges Respiratory Questionnaire; SpO2, oxyhaemoglobin saturation on pulse oximetry; VA/Q, ventilation-perfusion; VCO2, carbon dioxide output; VD, volume of dead space; VD/VT, dead space to tidal volume ratio; VE, minute ventilation; VE/VCO2, ventilatory equivalent for carbon dioxide production; VO2, oxygen consumption; VT, tidal volume
INTRODUCTION Idiopathic interstitial pneumonia (IIP) comprises a diverse group of fibrotic and inflammatory interstitial lung diseases (ILD) of unknown origin.1–3 Exercise limitation is often the first sign of disease, and may be insidious or more rapid in onset. Exertional dyspnoea can have a substantial impact on quality of life, and with disease progression, even the most fundamental of tasks may pose great challenge for patients. Identifying the contributing causes for effort intolerance, including mechanical, circulatory and gas exchange limitations is key to understanding disease pathogenesis. Detailed evaluation with cardiopulmonary exercise testing (CPET) and 6-min walk testing (6MWT) helps to provide insights into these physiological impairments, as well as explore the effects of interventions such as supplemental oxygen and exercise training. Despite the widespread use of ambulatory oxygen in IIP patients, the evidence is limited, particularly with regard to quality of life and long-term outcomes. Respirology (2015) Respirology (2016) 21, 1005–1014 doi: doi:10.1111/resp.12650 10.1111/resp.12650
11/07/16 3:28 PM
2 1006
LK LK Troy Troy et al.
space relative to tidal volume in ILD subjects.6,11 In normal subjects, it is usual for the dead space to tidal volume ratio (VD/VT) to decrease as ventilatory requirements increase during exercise. In ILD subjects, it is not uncommon for the VD/VT to remain the same, or even increase under similar conditions, reducing the ability of the lungs to clear the increasing carbon dioxide production during exercise without a further increase in VE.8,16,17
Early published studies on this subject comprised patients with IIP and non-IIP forms of ILD, including occupational lung disease and chronic hypersensitivity pneumonitis. As many of the principles are common across the ILD group as a whole, this review will focus upon ‘IIP’ within the context of ‘ILD’.
EXERCISE PHYSIOLOGY IN IIP Exercise performance is affected to varying degrees in all forms of IIP, and is thought to be the consequence of altered respiratory mechanics, impaired gas exchange, blunted cardiovascular response and peripheral muscle dysfunction (Fig. 1).4–7
Gas exchange and oxygen desaturation Abnormal gas exchange during exercise is reflected in a widening of the alveolar-arterial oxygen gradient, predominantly due to ventilation-perfusion (VA/Q) inequality.17–19 Diffusion limitation contributes to a lesser degree, as demonstrated with the multiple inert gas elimination technique (MIGET) studies of the 1970s and 1980s.18–20 Reduced mixed venous oxygen content is also seen in exercising ILD patients due to reduced cardiac output and proportionately increased extraction of oxygen by working muscles.17 The combination of these factors often leads to significant arterial oxyhaemoglobin desaturation during exercise—a poor prognostic feature when present.21–24 Despite the impairment of gas exchange and the mechanical constraints, hypercapnia is not typical in patients with ILD. The increased f, and accordingly VE, ensures that eucapnia is maintained.9 Indeed, the ventilatory response to increasing CO2 output (VCO2) during exercise (depicted by the VE/VCO2 relationship) is measurably elevated in exercising ILD subjects, compared with normal.25,26 The VE/VCO2 is an index of the degree of VA/Q inequality in that it is roughly proportionate to the VD/VT as long as PaCO2 is stable.25
Mechanical and ventilatory factors The minute ventilation (VE) of ILD patients is elevated at rest and even more so during exercise.8–11 This increase is largely the effect of an augmented respiratory frequency, f, in the setting of reduced lung compliance and low tidal volumes (VT). The increase in f is thought to be the consequence of increased elastic loading on respiratory muscles and stimulation of peripheral mechanoreceptors.9,12,13 As exercise intensity increases in ILD subjects, tidal volumes account for a greater proportion of the diminished inspiratory capacity, and some will approach, or even exceed, their estimated maximal voluntary ventilation (MVV).8,10 This value is calculated by multiplying baseline forced vital expiratory in 1 s by 40.14 In normal subjects, the peak exercise VE is generally 55 breaths per minute), high VE, sometimes with little or no breathing reserve, a failure to reduce VD/VT, oxygen desaturation and elevated VE/VCO2, as described above. The characteristic CPET findings in IIP and other ILD patients are summarized in Table 1. In ILD patients, diffusing capacity for carbon monoxide (DLCO) and transfer coefficient are predictive of desaturation during CPET and also peak VO2 and VD/VT.17,19,34,46 These resting measurements reflect the degree of diffusion limitation as well as the severity of pulmonary vascular insufficiency, factors that are exacerbated during exercise. Spirometric values and lung volumes also correlate with peak VO2, but less precisely.34 Additionally, a substantial proportion of patients with ILD will have normal resting lung function parameters but abnormal response to exercise.
Six-minute walk testing The 6MWT is a self-paced test that measures the distance a subject can quickly walk in 6 min, on a 30-m track. This provides a simple and practical assessment of functional exercise capacity, with readily accessible standardized guidelines for implementation.47 The 6MWT is used widely in a number of disease states, including chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension and heart failure.48–53 In IIP and other types of ILD, there is a substantive body of evidence for using the 6MWT in prognostic evaluation.21,54–57 The 6MWD has been shown to be highly reliable and reproducible in patients with fibrotic IIP (including IPF and idiopathic NSIP).55 This measurement also correlates well with peak VO2 as measured by CPET, indicating that the exercise intensity achieved during the 6MWT approximates maximal exercise in IIP patients, particular when disease is severe.44,54 Oxygen desaturation during the 6MWT, even in the absence of resting hypoxia, is commonly observed, and can exceed that seen during CPET in the same individuals.44,54 This phenomenon may be explained by greater tolerability of walking than cycling under hypoxic conditions. Because the 6MWT is self-paced, it is considered to be more representative of real-life activity than CPET. Endurance shuttle walk testing The endurance shuttle walk test (ESWT) is an externally paced field test, where a subject walks at a constant rate between two cones on a 10-m track in time to pre-recorded audio signals. The pace is set at 85% of the maximal pace achieved on an incremental shuttle test. The ESWT is well validated for measuring exercise capacity in COPD populations with good repeatability.58,59 In IPF and sarcoidosis patients, distance walked during ESWT correlates well with resting oxyhaemoglobin saturation on pulse oximetry (SpO2), DLCO and peak VO2 as measured with CPET.60,61 The advantage of this test over the 6MWT and CPET is that at 85% maximal intensity, it is arguably a closer approximation to the typical activities of daily living. Although it has been widely applied in ©© 2015 Asian 2015 AsianPacific PacificSociety Societyof of Respirology Respirology
11/07/16 3:28 PM
5 1009
oxygen in in IIP IIP Exercise and oxygen Table 1
Characteristic CPET results at peak exercise in ILD patients
Exercise Parameter
Normal subjects
ILD patients
Explanation
Peak VO2 (litres/min)
Usually able to exceed 85% predicted Usually able to exceed 85% predicted Usually approaches maximum, that is, no heart rate reserve Preserved
Often below predicted range Often below predicted range May not achieve maximum
Reduced, often 50
Increased, often > 50
VT (litres)
Increases to 50–60% VC
VE (BTPS, litres/min)
Usually 50–80% MVV, that is, breathing reserve of 20–50% Reduced (compared with rest values) 0.25–0.35 (rest) → 0.05–0.20 (peak exercise) Occurs at 50–60% of peak VO2
Increases to a maximum at a relatively low work rate; overall lower than normal Increased > 90% MVV, i.e. breathing reserve
