IndoJPMR Vol.

12 - 1st Edition - JUNE 2023 | 1

LITERATURE REVIEW

Exercise Intolerance in COPD:

A Review of the Pathophysiology and Clinical Assessment

Arnengsih Nazir1

1
Department of Physical and Rehabilitation Medicine, Dr. Hasan Sadikin General Hospital/Faculty of
Medicine Padjadjaran University, Bandung, Indonesia

ABSTRACT

Introduction: Chronic obstructive pulmonary disease (COPD) frequently presents with significant
impairments that contribute to reduced functional capacity and exercise intolerance, ultimately leading
to compromised activity performance. Therefore, this study aimed to describe the pathophysiology and
clinical assessment of exercise intolerance in COPD.

Methods: Data used were procured through a thorough search of published literature, conducted using
both PubMed and Google Scholar search engines. Literature was included when published in the last
10 years, written in English, and available in full-text format. The types of literature used were books,
original articles, narrative or systematic reviews, and case reports.

Results: A total of 33 pieces of literature were identified and used to provide explanations for the sub-
topics under discussion. Out of the total pieces, 22 elucidated the pathophysiology of the topic, while the
remaining 12 focused on the clinical assessment.

Conclusion: Shortness of breath and leg fatigue were common symptoms of exercise intolerance
found in COPD. These symptoms were associated with impairment of the body functions such as the
respiratory, cardiovascular, peripheral muscles, neuromuscular, and psychological. Furthermore, physical
inactivity caused worsening exercise intolerance, which could be evaluated using the Borg scale. The
cardiopulmonary exercise test was recommended to assess exercise intolerance in COPD patients and
some field analyses such as walk and step tests could also be carried out.

Keywords: chronic obstructive pulmonary disease, exercise intolerance, functional capacity.

 2 | IndoJPMR Vol.12 - 1ST Edition - June 2023

ABSTRAK

Latar Belakang: Penyakit Paru Obstruksi Kronis (PPOK) sering muncul dengan gangguan fungsional
signifikan yang menghasilkan penurunan kapasitas fungsi dan intoleransi latihan. Ganguan tersebut
menghasilakn tampilan aktivitas yang buruk. Review ini bertujuan untuk menggambarkan patofisiologi
dan penilaian klinis dan intoleransi latihan pada PPOK.

Methods: Data yang digunakan pada ulasan ini dikumpulkan melalui literatur yang telah di kumpulkan
dari dan di cari melalui PubMed and Google Scholar as the search engine. Literature was included if
published in the last 10 years, written in English, and available in full-text format. The type of literature
were books, original articles, narrative or systematic reviews, and case reports.

Hasil: Sembilan puluh enam subjek memenuhi kriteria inklusi dan eksklusi. Kepatuhan memulai program
RJ setinggi 94,6% pada kelompok BPAK dan 100% pada kelompok IKP. Lima puluh subjek (67,56%)
pada kelompok BPAK dan enam belas (72,72%) pada kelompok IKP menjalani sesi latihan sebagaimana
terjadwal. Sebanyak 57 subjek (77,02%) pada kelompok BPAK dan 16 subjek (72,72%) dari kelompok
IKP menyelesaikan 12 sesi latihan, tanpa memandang waktu yang diperlukan untuk menuntaskannya.

Simpulan: Secara keseluruhan, kepatuhan mengikuti program RJ fase II pada kelompok BPAK dan IKP
cukup tinggi. Kepatuhan untuk memulai dan menjalani program RJ fase II pada kelompok IKP lebih
tinggi dari kelompok BPAK.

Kata kunci: bedah pintas arteri koroner, intervensi koroner perkutan, kepatuhan, rehabilitasi jantung.

Correspondent Detail: INTRODUCTION

Arnengsih Nazir
Chronic obstructive pulmonary disease (COPD)
Department of Physical and causes chronic airflow limitation due to
Rehabilitation Medicine, Dr. Hasan Sadikin airway obstruction and parenchymal damage
General Hospital/Faculty of Medicine (emphysema). This disease often appears with
Padjadjaran University, Jl. Pasteur No. 38 significant functional impairments including
Bandung, Indonesia, 40161, shortness of breath, fatigue, and exercise
E-mail: [email protected], intolerance, which can affect a quality of life
Phone: +62-22-2551111, (QoL) and lead to depression or social isolation.
Fax: +62-22-2032216, Furthermore, functional impairments can lead
Mobile Phone: +62-81931222414 to exercise intolerance and decreased activity
performance. 1-3

A study in stable COPD patients found an

association between high dyspnoea scores and
low maximum exercise capacity. Low exercise
 IndoJPMR Vol.12 - 1st Edition - JUNE 2023 | 3

capacity can interfere with daily activities.4 capacity also affects QoL, as an independent
Functional capacity, exercise tolerance, and predictor of increased mortality in patients.9
exercise capacity are often used interchangeably
to describe an ability to perform daily activities The enhancement of exercise tolerance has
requiring aerobic metabolism. Furthermore, become one of the primary objectives of COPD
aerobic metabolism is determined by maximum management since the variable has significant
oxygen uptake (VO2 max) used during muscle ramifications on the physical, psychological, and
contraction, and its impaired functional capacity overall QoL.8 Therefore, this study describes
leads to exercise intolerance.5 exercise intolerance in COPD patients with a
focus on pathophysiology and clinical assessment.
Exercise intolerance refers to the incapability to
attain or maintain the level of exercise intensity
expected for individuals with comparable age, METHODS
body composition, and gender. This impairment
is attributed to the dysfunction of one or more Data utilized for this study were obtained from
major bodily systems, such as the respiratory, literature searched using PubMed and Google
cardiovascular, or peripheral muscular systems. 6, 7 Scholar as the search engine. Literature was
included when published from 2006 to 2021,
A considerable percentage of individuals written in English, and available in full-text
diagnosed with COPD, specifically at least format. Meanwhile, the type of literature were
15%, exhibit diminished functional capacity and original articles, narrative or systematic reviews,
subpar performance in various activities, such and case reports. The results were presented in
as ambulation, quality of sleep, and rest. These the form of text, figures, and tables.
individuals may also struggle with routine tasks
related to home management, recreation, and
other day-to-day activities. Furthermore, basic RESULT
daily activities may even trigger feelings of fatigue
and shortness of breath among individuals with A total of 33 literature were found and used to
moderate to severe COPD. A recent study showed explain sub-topics, where 22 and 12 explained
that 30% of moderately affected individuals pathophysiology and clinical assessment,
were more likely to remain confined to their respectively.
homes, even during stable periods. However,
this percentage increased to nearly 50% during
exacerbations.3

Zamzam et al. reported an association between

decreased QoL and the severity of COPD.
Decreased QoL occurs because patients have
difficulties in socializing, hence, they become
frustrated and angered.8 Decreased exercise
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EXERCISE INTOLERANCE

Pathophysiology of Exercise Intolerance in COPD

Respitory Factors Vascular Factors

Increased Vascular
Respitory Gas Dynamic Decreased Resistance
Inflammation & Oxidative Stress Muscle Exchange Hyperinflation Ventilation
Disfunction Impairment Capacity

Pulmonary
Peripheral Muscle Dysfunction Hypertension
Increased Ventilation Effort

Muscle Fatigue Increased Right

Hypoxia Verticular Afterload

Muscle Hypoperfusion
Exercise Right Ventricular
Intolerance Dysfunction

Increased Sympathetic Activation Psychological

Disorder
Left Ventricular
Inactivity Dysfunction

Figure 1. Pathophysiology of Exercise Intolerance COPD

Central factors causing exercise intolerance in the work of breathing due to increased oxygen
COPD are ventilation, dynamic hyperinflation, demand and blood flow. In intense exercise, there
and shortness of breath, while the peripheral is a decrease in peak oxygen uptake (VO2 peak)
factors include muscle atrophy, weakness, and and premature lactic acidosis causing intolerance.7
fatigue.7,10,11 The pathophysiology of exercise
intolerance is described schematically in Figure Impairment of gas exchange regulation causes
1. 5, 7, 11 alveolar ventilation/perfusion (VA/Q) mismatch,
impaired diffusion, and hypoxemia during
Respiratory Factors exercise causing tissue hypoxia. Meanwhile,
hypoxia directly and indirectly increases
In COPD, ventilation is limited due to airway pulmonary ventilation through peripheral
obstruction and decreased lung compliance.7 chemoreceptor response, and stimulation of lactic
Furthermore, ventilatory limitation causes an acid production leading to lactic academia.7
increase in work of breathing, arterial carbon
dioxide (CO2), metabolic acidosis, and the Lactic acidemia contributes to the failure
burden of ventilation.7,12 Hyperinflation or of muscle to contract and leads to increased
muscle dysfunction also causes the inability of pulmonary ventilation due to CO2 production.7 In
the respiratory system to withstand the workload, severe pulmonary disease patients, arterial oxygen
resulting in shortness of breath.7 (O2) desaturation may occur during exercise.
In addition, low carbon monoxide diffusion
Exercise given to COPD patients can increase capacity can predict the occurrence of arterial
 IndoJPMR Vol.12 - 1st Edition - JUNE 2023 | 5

O2 desaturation and acts as the best predictor of Vascular Factors

exercise capacity.13 Carbon monoxide diffusion
capacity is influenced by diffusion surface area, Vascular factors as the cause of exercise
blood volume in the capillary bed, and distribution intolerance are pulmonary hypertension resulting
of alveolar ventilation. Meanwhile, low diffusion from increased resistance and right ventricular
capacity causes increased ventilation work to dysfunction with an increase of right ventricular
maintain arterial blood gases and acid-base afterload.7,9 Right ventricular hypertrophy can
homeostasis.9, 11, 14 lead to right ventricular failure when untreated.
Furthermore, left ventricular filling is also
Indirect measurement of pulmonary hyperinflation impaired, and the ability of the heart to fulfill
at rest can be conducted by calculating the ratio of exercise requirements is reduced. The occurrence
inspiratory capacity to total lung. In large-scale of left and right ventricular dysfunction results
population studies, this ratio has been observed to in the limitation of physical activity. Myocardial
predict all-cause mortality, respiratory mortality, dilatation and hypertrophy can also cause
and the severity of the risk of exacerbations. tachyarrhythmias. In addition, Faludi et al.
In contrast, serial measurement of dynamic showed that right ventricular diastolic function
hyperinflation can be achieved by assessing the and its filling pressure affected functional capacity
changes in inspiratory capacity from resting and led to impairment of oxygen delivery as well
values.6 as metabolic acidosis.7, 9, 16-18

Hyperinflation causes excessive expansion of Peripheral Muscle Dysfunction

the thoracic cavity, resulting in overstretching
of the respiratory muscles. Mechanically, this Many factors considered a potential cause of
is caused by the inability of the muscles to peripheral muscle dysfunction are cigarette
increase their output following the increase in smoking, muscle disuse, drugs, oxidative
neurological signals. The consequences of these stress, systemic muscle inflammation, hypoxia,
pathological changes are muscle weakness and hypercapnea. Table 1 summarizes the
causing hypercapnea, shortness of breath, arterial structural abnormalities of skeletal muscles
O2 desaturation, and exercise intolerance. During in COPD patients.19 Furthermore, peripheral
exercise, the maximal inspiratory pressure muscle dysfunction causes fatigue which is
is increased due to the respiratory muscles’ characterized by the inability to perform work at
workload.7, 15 a certain intensity, or maintain the force required
during contraction to meet the needs of physical
Another respiratory muscle dysfunction that activity. Decreased muscle endurance is mainly
causes exercise intolerance is an increase in found in patients with advanced COPD. Serres et
systemic vascular resistance in diaphragmatic al. also reported a positive relationship between
workload. This causes a “stealing” effect of blood muscle endurance and COPD severity.19-22
from the peripheral muscles, even though there
are no convincing data to confirm this theory.7
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Table 1. Structural Abnormalities of Skeletal Muscles in COPD Patients

Structural Abnormalities of Skeletal Muscles in COPD

• Low mitochondrial density and synthesis
• High mitochondrial degradation
• Low oxidative enzyme activity
• A shift of muscle fiber type (towards a more glycolytic profile)
• Low muscle capillary
• An imbalance between muscle protein synthesis and breakdown
• Muscle atrophy

During exercise, peripheral muscles are Malnutrition causes a decrease in enzyme capacity
very sensitive to any changes in O2 delivery. and the availability of energy substrates in muscle.
Metabolites such as hydrogen ions (H+), About 30% of COPD patients in outpatient
inorganic phosphate, and lactic acid accumulate clinics experienced weight loss due to decreased
more quickly when the supply of O2 is reduced caloric intake and chronic inflammatory effects.
and caused impaired contractility. Furthermore, Similarly, the use of corticosteroids, specifically
insufficient O2 transport during exercise during exacerbations, affects skeletal muscle
causes muscles to tire easily.22 There is also the through decreased contractile protein, increased
manifestation of deoxyribonucleic acid damage protein breakdown, decreased growth factors,
and reduced mitochondria due to oxidative stress decreased glycolytic activity, and sarcomere
in COPD. Decreased physical activity is caused atrophy.7
by changes in the distribution of fibers and a
reduction in capillary density that cause muscles Neuromuscular Factors
susceptible to fatigue in performing an exercise
with high- intensity.7, 11, 12 In COPD, there is an increase in sympathetic
activity in the muscles, resulting in negative
Peripheral muscle fatigue is also caused by effects such as inflammation, anabolic catabolic
increased degradation due to inflammation imbalance, apoptosis, cardiomyocyte injury,
which leads to wasting.20 Meanwhile, chronic decreased number of type 1 muscle fibers,
inflammation increases muscle oxidative stress impaired endothelial function, and dyspnea.
by increasing reactive oxygen species, directly Excessive sympathetic outflow results in muscle
causing damage and degradation of protein. The hypoperfusion leading to hypoxia. Meanwhile,
study by Couillard et al found that oxidative sympathetic muscle activity at rest is negatively
stress occurred in the quadriceps muscle correlated with the VO2 peak. In healthy muscles,
characterized by an increase in lipid and protein vasoconstrictive activity can be overcome,
peroxidation.23 and when there is a sympathovagal imbalance,
 IndoJPMR Vol.12 - 1st Edition - JUNE 2023 | 7

vasoconstriction of blood vessels increases and sweats, dizziness, and leg fatigue before, during,
causes a decrease in blood flow and non-oxidative and after exercise. The occurrence of exercise
metabolism.24, 25 intolerance during training or testing indicates
termination. It also determines risk stratification,
Psychological Factors which is the cardiovascular events during
exercise training or testing.7
Anxiety and depression are reported in about
40% and 20% of COPD patients. These variables Borg Scale
cause an increase in shortness of breath symptoms
that worsen hyperinflation and decrease exercise Dyspnea and fatigue are the two main symptoms
tolerance and QoL.7 There is also a relationship in COPD patients assessed through recall or
between depression and admission rate due real-time. A real-time evaluation of symptoms
to COPD exacerbations. Exacerbations also only answers the question of how hard the
affect physical activity levels, but the study dyspnea or fatigue was experienced during the
cannot be concluded. Hormonal changes such test. The visual analog and Borg scales are the
as over-activity of the hypothalamic-pituitary- most commonly used tools to assess dyspnea or
adrenocortical axis or dysregulation of the fatigue during the test.7
autonomic nervous system also occur during
depression.26 The Borg scale is a very simple numerical list
used to assess the Rating of Perceived Exertion
Physical Inactivity (RPE). Patients are asked to rate exertion
during the activity by combining all sensations
Physical inactivity due to shortness of breath, of physical stress and fatigue. They are told
fatigue, peripheral muscle dysfunction, and to ignore other factors such as shortness of
psychological factors caused the worsening of breath or leg fatigue, by trying to focus on the
exercise intolerance. Mazzarin et al. reported sensations of exertion and this scale ranges
that there is a relationship between inactivity as from 6-20, as shown in Figure 2. Compared to
measured by the number of steps per day and other linear scales as the visual analog, the RPE
the exercise capacity of COPD patients.23 The shows the same sensitivity and reproducibility
incidence of exacerbations in moderate-grade of results (29). The Borg scale is also used to
COPD patients caused patients to become more assess shortness of breath and limb fatigue in
inactive.27, 28 a Category Ratio (CR) of 1-10 and is referred
to as the Borg CR10, as shown in Figure 2. 30, 31
Clinical Assessment of Exercise Intolerance in
COPD

Symptoms and signs of exercise intolerance

include chest pain, shortness of breath, cold
 8 | IndoJPMR Vol.12 - 1ST Edition - June 2023

Borg RPE Borg CR10 Scale

Score Score
Level of Exertion Level of Exertion
6 No exertion et all 0 No exertion et all
7 0.5 Very, very slight (just noticeable)
7.5 Extremely light 1 Very slight
8 2 Slight
9 Very light 3 Moderate
10 4 Somewhat severe
11 Light 5 Severe
12 6
13 Somewhat hard 7 Very severe
14 8
15 Hard (heavy) 9 Very, very severe (almost maximal)
16 10 Maximal
17 Very hard
18
19 Extremely hard
20 Maximal exertion
RPE indicates Rating of Perceived Exertion, and CR10 indicates Category Ratio 10.

Figure 2. Borg RPE and Borg CR10 Scale

Cardiopulmonary Exercise Testing (CPET) The variable used to assess exercise capacity with
CPET is peak O2 uptake (VO2 peak). The VO2
The level of exercise capacity and intolerance peak value is the highest value obtained at the end
is clinically determined by the CPET test, of the exercise test until exhaustion. In this state,
which is a non-invasive technique to evaluate no O2 uptake can be identified (plateau VO2) and
the integrative functions of the cardiovascular, the VO2 peak is considered the maximum (VO2
respiratory, hematopoietic, metabolic, and max). Meanwhile, a VO2 max of less than 85%
neuropsychological systems during maximal of the predicted value is considered abnormal.
exercise. This test is considered a gold standard Another variable to predict exercise intolerance
to assess exercise capacity and objectively with CPET is the inspiratory capacity (IC), which
determine intolerance. Furthermore, it allows the is the maximum amount of air exhaled after
evaluation of metabolic and cardiorespiratory normal breathing. The decrease occurred due to
responses during maximal or peak exercise.7, 32 dynamic hyperinflation and increasing in end
respiratory lung volume during exercise.15, 32
 IndoJPMR Vol.12 - 1st Edition - JUNE 2023 | 9

Field Test compared to survived subjects with more than

1 year (22 meters) without a parallel change in
Field tests such as the 6-minute walk (6MWT), forced expiratory volume of 1 second (FEV1).
three-minute step (3MStepT), and sit-to-stand can The distance covered in this test is considered a
also be used to determine exercise capacity. There good predictor of mortality. Meanwhile, distances
are numerous benefits to these tests, including of less than 350 meters are associated with
their ease of administration, minimal equipment increased mortality in COPD.29, 34
requirements, non-laboratory setting, and ability
to accurately assess pulmonary rehabilitation Three-Minute Step Test (3MStepT)
progress.7, 33
This test is performed by stepping up and down
Six-Minute Walk Test (6MWT) on the platform for 3 minutes. Beaumont et al.
found a correlation between 6MWD and 3MstepT
This test is recommended to assess functional and concluded that 3MstepT was valid to measure
capacity and evaluate treatment response in a exercise capacity in COPD patients. After the
COPD rehabilitation program. Previous studies 3MstepT, there is a higher heart rate and greater
reported that 6MWT results were reliable in leg fatigue observed, while a lower oxygen
patients with severe and very severe cases.29,34 saturation is noted in 6MWT. The advantages of
The 6MWT offers several advantages, such as field tests include their ease of administration,
its cost-effectiveness, ease of administration, minimal space requirements, relatively short
and suitability for evaluating exercise tolerance duration, and simple equipment needs (such as
levels. The test has some drawbacks, such as a 15 cm high platform). Moreover, 6MWT is
the inability to objectively determine the precise typically well tolerated by COPD patients.33
cause of exercise limitations, the need for prior
familiarization, the relatively long time required Sit to Stand Test (STST)
to complete the test, and the need for a 30-meter
corridor. However, monitoring of blood pressure, Versions of STST are varied, ranging from a few
heart rate, and oxygen saturation before and after seconds to several minutes. All STST versions
the test can provide an index of functional capacity. have been tested in COPD patients, and the most
A walking distance of 6 minutes (6MWD) is used frequently used is the 1-min STST.36 Furthermore,
to determine the functional capacity.35 Janssens et al. found that the value of the
5R-STST in COPD patients was lower than in
There is a strong association between 6MWD healthy subjects of the same age.37 The 5R-STST
and COPD clinical outcomes because the test can identifies impairment of exercise capacity and
describe both pulmonary and extra-pulmonary mobility. Another study by Puhan et al. reported
manifestations of the complication. A study of a lower 1- minute STST performance in subjects
longitudinal changes in subjects with severe who died within 2 years than in survivors.
COPD for over 2 years, found an increase in Meanwhile, subjects that cannot conduct more
survival. In subjects who did not survive, there than 12 repetitions in 1 minute have a lower
was a significant decrease in 6MWD by 40 meters metabolic power and can predict the risk of
 10 | IndoJPMR Vol.12 - 1ST Edition - June 2023

death.38 The shorter, medium, and longer version 2. Djibo DA, Goldstein J, Ford JG. Prevalence
of the STST provides information on leg strength of disability among adults with chronic
and coordination, muscle endurance, and exercise obstructive pulmonary disease, Behavioral
capacity and tolerance, respectively.36 Risk Factor Surveillance System 2016–
2017. PLoS One. 2020;15(2):e0229404.
3. Belfer MH, Reardon JZ. Improving exercise
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4. Crisafulli E, Aiello M, Tzani P, Ielpo A,
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Longo C, Alfieri V, et al. A high degree of
with the same condition. Shortness of breath
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and leg fatigue are common symptoms of
exercise capacity in subjects with COPD with
exercise intolerance found in COPD. In addition,
the same severity of air-flow obstruction.
respiratory dysfunctions such as impaired
Respir Care. 2019;64(4):390-7.
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5. Arena R, Myers J, Williams MA, Gulati M,
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Kligfield P, Balady GJ, et al. Assessment of
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settings: a scientific statement from the
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American Heart Association Committee on
changes in the muscles can cause patients
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