Original Article

Chronic Respiratory Disease

1–9
Six-minute walk distance in patients ª The Author(s) 2015
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with chronic obstructive pulmonary DOI: 10.1177/1479972315575201
crd.sagepub.com
disease: Which reference equations
should we use?

Vasileios Andrianopoulos1, Anne E Holland2,

Sally J Singh3, Frits ME Franssen1,
Herman-Jan Pennings4, Arent J Michels5,
Frank WJM Smeenk6, Ioannis Vogiatzis7,
Emiel FM Wouters1,8 and Martijn A Spruit1

Abstract
The use of different 6-min walk distance (6MWD) reference equations probably results in different predicted
6MWD reference values. We wished to investigate the impact of several 6MWD reference equations for
adults in patients with chronic obstructive pulmonary disease (COPD) and factors accountable for different
6MWD% predicted values. Twenty-two 6MWD reference equations were applied to a data set of 2757
patients with COPD. The predicted 6MWD reference value of Troosters and colleagues was used as the
point of reference. Four out of 21 remaining equations resulted in comparable 6MWD% predicted, 16
equations resulted in significantly higher 6MWD% predicted and 1 equation resulted in a significantly lower
6MWD% predicted. Similar differences in 6MWD% predicted were observed after stratification by sex.
Body mass index and global initiative for chronic obstructive lung disease (GOLD) stage classification
demonstrated varying results within and between the groups; 9 out of 21 equations resulted in comparable
6MWD% predicted in underweight patients but only 1 equation demonstrated comparable result in obese.
Eight equations in GOLD I, whilst 5 out of 21 equations in GOLD IV resulted in comparable 6MWD%
predicted. Existing 6MWD reference equations will give varying results. The choice of 6MWD reference
equation should consider the consistency of 6-min walk test operating procedures and at least be specific
for the country/region of origin.

Keywords
COPD, 6-min walk test, 6MWD reference equations, 6MWD predicted values, exercise capacity

1
Department of Research and Education, CIROþ, Centre of Expertise for Chronic Organ Failure, Hornerheide, Horn, The
Netherlands
2
Department of Physiotherapy, Alfred Health and La Trobe University, Melbourne, Australia
3
Department of Respiratory Medicine, University Hospitals of Leicester NHS Trust, Glenfield Hospital of Leicester Headquarters,
Leicester, UK
4
Department of Respiratory Medicine, Laurentius Hospital, Roermond, The Netherlands
5
Department of Respiratory Medicine, St Anna Hospital, Geldrop, The Netherlands
6
Department of Respiratory Medicine, Catharina Hospital, Eindhoven, The Netherlands
7
Department of Physical Education and Sport Sciences, National and Kapodistrian University of Athens, Athens, Greece
8
Department of Respiratory Medicine, Maastricht University Medical Centre (MUMCþ), Maastricht, The Netherlands

Corresponding author:
Vasileios Andrianopoulos, Department of Research and Education, CIROþ, Centre of Expertise for Chronic Organ Failure,
Hornerheide 1, 6085 Horn, The Netherlands.
Email: vasilisandrianopoulos@ciro-horn.nl

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2 Chronic Respiratory Disease
Introduction
The 6-minute walk test (6MWT) can be used to
assess functional exercise capacity, treatment effi-
cacy and prognosis in chronic respiratory dis-
ease.1–4 New insights of chronic obstructive
pulmonary disease (COPD) affliction, which
include cardiac and peripheral muscle wasting
effects, provide an additional value in the assess-
ment of functional exercise capacity measured by
the 6MWT.5 The 6MWT elicit high but submaxi-
mal cardiorespiratory responses that mimic day life
activities.6 In some clinical situations, the 6-min
walking distance (6MWD) may be a better index of
actual patients’ ability to perform daily activities in
comparison with the peak oxygen uptake.7,8 The
6MWD has been indicated for the prediction of hospi-
talization and mortality in COPD9 and has been also
recognized for its predictive value to post-operative
outcome in candidates for volume reduction
surgery.10
Multiple 6MWD reference equations11–30 were
derived to express the 6MWD as a percentage of these
reference values (% predicted) (see Supplementary
Table 1 for details). Adjusting the measured 6MWD
for physiological variation using the percentage of
walk predicted facilitates the interpretation of the
walked 6MWD and helps to estimate the degree
of exercise tolerance in patients.31 Erroneous selec-
tion of a reference equation may result in misinter-
pretation of the levels of exercise capacity or
improvements of physical performance after partic-
ipation in pulmonary rehabilitation programmes.30
The large number of published 6MWD reference
equations and the fact that those equations are
derived from healthy individuals with different
clinical characteristics and do not consistently
employ the same variables make the choice of
6MWD reference equation often vague.
Several demographic, anthropometric and physio-
logical characteristics can determine the 6MWD in
healthy individuals and in patients with COPD.32
However, the strongest determinants that can inde-
pendently affect the 6MWD in healthy adults seem
to be the age, height, weight, sex and race and these
characteristics have been proposed for clinical
use.15,18,26,33 Muscle strength, true leg length, symp-
toms of depression, health-related quality of life
impairment and other factors such as the standardiza-
tion of the 6MWT can influence the 6MWD.11,34–37
Therefore, it might be anticipated that the use of
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different 6MWD reference equations derived by sev-
eral studies would result in different predicted 6MWD
reference values.
Herein, we report a retrospective analysis in a large
cohort of patients with COPD who were evaluated at
CIROþ between 1 January 2005 and 1 July 2013.38
We assessed the impact of 22 existing 6MWD refer-
ence equations in patients with COPD and investi-
gated the factors accountable for different predicted
6MWD reference values using data from 2757
patients with COPD. Furthermore, we wished to iden-
tify criteria for the choice of 6MWD reference equa-
tion in COPD patients.
Methods
A data set of patients with COPD39 including demo-
graphic, anthropometric characteristics, lung function
evaluation and 6MWT exercise outcomes was ana-
lysed. All patients performed two 6MWTs according
to the American Thoracic Society guidelines,7 includ-
ing a practice walk.40 The 6MWT with the highest
6MWD was used for further analyses.41 During the
6MWTs, transcutaneous oxyhaemoglobin saturation
(SpO2%) and heart rate (HR) were measured using a
pulse oximeter (Nonin 2500; Nonin Medical Inc., Ply-
mouth, Massachusetts, USA). The predicted maxi-
mum HR (HRmax, %) was derived from the formula
HRmax ¼ 220  age in years42 and the D values of
HR (DHR) were calculated by the difference between
the HR at the end of the test minus the baseline HR.
The 6MWD% Troosters et al.26 was used as a point
of reference. These reference values were used in
CIROþ since the last decade, as these reference val-
ues were derived from a Belgian sample of healthy
elderly subjects with a mean 6MWD of 622 + 75
m, which is comparable to the mean 6MWD of Dutch
healthy elderly subjects.43 All available 6MWD refer-
ence equations were applied with the exception of the
alternative equation of Dourado et al.,24 which
required handgrip strength measurement not available
in our data set. All statistical analyses were carried out
using SigmaPlot Version 11 and Statistical Package
for the Social Sciences Version 19.0. Data are pre-
sented as mean (+SD) or proportion, as appropriate.
For parametric data, comparisons were made using a
two-tailed unpaired t-test. The 6MWD% predicted by
Troosters et al.26 was compared with the other refer-
ence values using Dunnett’s multiple comparisons
test. A priori, a two-sided level of significance was set
at p value of <0.05.
Andrianopoulos et al. 3

Table 1. Anthropometric and clinical characteristics of patients with COPD.a

Total sample Men Women
Patients, n (%) 2757 1547 (56) 1210 (44)
Age (years + SD) 67.4 + 9.6 69.4 + 9.2 64.8 + 9.4b
Height (cm) 168 + 9 173 + 7 161 + 6b
Weight (kg) 72 + 18 77 + 17 66 + 16b
BMI (kg/m2) 25.5 + 5.6 25.8 + 5.2 25.2 + 6.1
FFMI (kg/m2) 17.0 + 2.4 18.2 + 2.1 15.6 + 1.8b
FEV1 (L) 1.3 + 0.6 1.4 + 0.6 1.1 + 0.5b
FEV1 (%) 48.0 + 19.7 47.4 + 19.7 48.8 + 19.7
FVC (%) 93.9 + 22.8 92.6 + 32.2 96.7 + 23.5b
Tiffeneau (%) 40.8 + 13.2 39.9 + 13.5 42.0 + 12.8b
TLC (%) 117.8 + 19.2 113.8 + 18.5 123.0 + 18.7b
DLCO (%) 52.8 + 19.4 54.2 + 20.1 50.5 + 18.1b
SpO2 (%) 94.4 + 3.6 94.2 + 4.1 94.6 + 2.6
mMRC (index) 3.4 + 1.1 3.3 + 1.1 3.5 + 1.1b
6MWD (m) 422 + 124 432 + 127 409 + 120b
6MWD (% predicted) 68 + 18 66 + 18 70 + 17b
COPD: chronic obstructive pulmonary disease; BMI: body mass index; FFMI: fat-free mass index; FEV1: volume exhaled at the end of the
first second of forced expiration; FVC: Forced vital capacity; TLC: total lung capacity; DLCO: lung diffusion capacity for carbon mon-
oxide; SpO2: oxyhaemoglobin saturation; mMRC: modified Medical Research Council scale; 6MWD: 6-min walk distance.
a
Characteristics of the studied COPD population and stratified by sex. Data are mean + SD unless specified otherwise.
b
Significant differences (p < 0.05).

Results
A total of 22 reference equations were applied to a
data set of 2757 patients with COPD (age range:
38–92 years). Reference equations encompassed
race/ethnic differences and variety of technical
aspects that can determine the 6MWD (see Supple-
mentary Figure 1 and Table 2). The clinical features
of patients are summarized in Table 1. In brief,
patients generally had moderate to very severe COPD
and an impaired lung diffusion capacity for carbon
monoxide (DLCO). Men were slightly older com-
pared with women and had more impaired Tiffeneau
index and lower total lung capacity, whilst women
had worse DLCO%. On average, the functional exer-
cise capacity was profoundly limited: 422 + 124 m, Figure 1. The frequency distribution of estimated 6MWD
which equals 68 + 18% of the reference values of applying the existing equation of healthy individuals to
Troosters et al.26 (Table 1). Four out of 21 remaining patients with COPD, demonstrated large variation. The
equations resulted in comparable 6MWD% predicted; numbers on the right are mean values per equation.
16 equations resulted in significantly higher 6MWD% 6MWD: 6-min walk distance; COPD: chronic obstructive
predicted (all p < 0.05); and 1 equation resulted in a pulmonary disease.
significantly lower 6MWD% predicted (p < 0.001)
(Figure 1). Similar discrepancies in the 6MWD% pre- remaining reference equations were also observed
dicted among the equations were observed in patients after stratification by body mass index (BMI) and the
stratified by sex (Figure 2). degree of airflow limitation as given by global initiative
Discrepancies between 6MWD expressed as % for chronic obstructive lung disease (GOLD) stages
predicted of the reference values of Troosters et al. within all groups of patients. Furthermore, differences
and the 6MWD expressed as % predicted using the in the number of 6MWD predicted values with

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4 Chronic Respiratory Disease

Figure 2. The frequency distribution of estimated 6MWD, applying reference equations of healthy individuals to patients
with COPD, demonstrated similar impact after stratification by sex. The numbers on the right are mean values per
equation. 6MWD: 6-min walk distance; COPD: chronic obstructive pulmonary disease.

clinically important discrepancies were noticed
between the BMI and between the GOLD stages groups.
Patients with underweight BMI compared those with
obese BMI and patients in GOLD stage I compared
those in GOLD stage IV had a smaller number of discre-
pant 6MWD% predicted values (Figures 3 and 4).
Discussion
Even though a majority of the existing 6MWD refer-
ence equations included similar characteristics, such
as sex, age, height, weight or BMI, clear differences
were found when applying the existing 6MWD refer-
ence equations to a data set of 2757 patients with
COPD (Figure 1). The best choice for the predicted
6MWD reference values probably depends on the
country/region of origin of the healthy subjects that
were used to develop the 6MWD reference equation.
For example, the 6MWD reference equation of Poh
et al.18 resulted in a mean 6MWD of 81% predicted.
This suggests that applying Asian-derived 6MWD%
predicted values to Dutch patients with COPD may
result in an overestimation of their true functional
capacity. As pointed out by authors, one possible
explanation for this discrepancy is the differences in
body stature between Asians and Caucasian. Herein,
it is worth noting that some countries and regions are
very ethnically and racially diverse and reference val-
ues derived from mixed-race populations could be
recommended. When we applied the reference equa-
tion of Enright et al.,11 which is derived from a
mixed-race elderly group (aged: 77 + 4years), true
functional capacity of our patients seems to be overes-
timated compared with the rest of the reference values
(Figure 1). We assume that it could be partly attributed
both to their younger age and to racial differences.
Next to demographic characteristics, a different
operating procedure of 6MWT can also affect on
walking distance and modify the reference values.4
For example, in the study of Troosters et al.,26 the
length of the corridor of used reference equation was
50 m, which can be considered as a long corridor
compared with 20 m corridor of Gibbons et al.28 This
fact can also result in overestimation of 6MWD% pre-
dicted relative to a number of other reference equa-
tions. Accordingly, our triangular track for the
6MWTs of our patients has the characteristics of a
long corridor. Therefore, at CIROþ, the predicted ref-
erence values of Troosters et al.26 are used, who stud-
ied healthy Belgians 50–85 years of age.
Methodological differences in the 6MWT, with
track lengths ranging from 20 m to 50 m, the number
of test repetitions ranging from 1 to 3, test-retest inter-
vals from 30 min to 24 h and variable practices
regarding the given test instructions (i.e. ‘walk at your
own pace’ or ‘walk as far as you can’) and the encour-
agement, may partly account for the observed discre-
pancies in the 6MWD% predicted values. Sciurba

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Andrianopoulos et al. 5

Figure 3. The frequency distribution of estimated 6MWD, applying reference equations of healthy individuals to patients
with COPD, demonstrated less differences in patients with underweight BMI compared with those with normal range or
higher BMI. The numbers on the right are mean values per equation. 6MWD: 6-min walk distance; COPD: chronic
obstructive pulmonary disease; BMI: body mass index.

et al.44 demonstrated that the long compared with
short corridors can increase the 6MWD as the number
of turns is less and thus the physical effort is less.44 In
the study of Alameri et al.,14 healthy individuals
reached a low average of HRmax (45% pred.) when
instructed to walk at their own pace.14 Moreover, the
impact of a learning effect on the walking distance of
6MWT has been investigated in COPD. Steven
et al.45 performed three 6MWTs in 21 COPD patients
on separate days and observed an average increase of
10% in the second test and an additional 3% increase
in walking distance in the third test compared with
first 6MWT.45 Such factors are known to have an
impact on the measured distance (see Supplementary
Table 2).
The health status of the ‘healthy subjects’ may also
have impacts on findings. For example, the study of
Enright et al.11 included participants with risk factors
associated with cardiovascular disease with likely
limitations in functional capacity probably resulting
in an overestimation of the 6MWD% predicted when
applied to individuals with COPD. The physical con-
dition of the volunteers who participated at the several
studies should be considered. The HR recorded at the
end of the 6MWT can vary substantially in moderate
and intense levels of effort in different studies.15,25

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6 Chronic Respiratory Disease

Figure 4. The frequency distribution of estimated 6MWD, applying the reference equations of healthy individuals to
patients with COPD, demonstrated less differences in GOLD stage I across the progress of disease severity. The numbers
on the right are mean values per equation. 6MWD: 6-min walk distance; COPD: chronic obstructive pulmonary disease;
GOLD: global initiative for chronic obstructive lung disease.

These facts indicate that differences in characteristics
of healthy population, 6MWT protocols and/or differ-
ent levels of effort during the 6MWT can result in dif-
ferent 6MWD% predicted values.
On the other side, certain clinical characteristics of
patients’ populations, where the equations are
applied, can also be accountable for the discrepancies
in the 6MWD% predicted values. After stratification
for BMI and the degree of airflow limitation as given
by GOLD stages, the number of discrepant 6MWD
values varied between the groups of BMI and GOLD
stages, respectively (Figures 3 and 4). Applying the
6MWD reference equations to underweight or GOLD
stage I groups of patients leads to more consistent
6MWD% predicted values. Therefore, the choice of
6MWD reference equation in patients with those
characteristics (underweight and/or GOLD stage I)
may be of less importance. BMI and/or disease sever-
ity as given by GOLD stages are major determinants
of exercise performance especially in individuals with
higher BMI and/or worse COPD. The exclusion of
these characteristics from reference equations could
account for the discrepancies in 6MWD% predicted
values and that can be more obvious in obese or

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Andrianopoulos et al.
patients with GOLD stage IV disease. This might
explain the larger number of discrepant 6MWD% pre-
dicted values among the reference equations applied
in the groups of obese and patients with GOLD stage
IV disease compared with the groups of underweight
patients with GOLD stage I disease (Figures 3 and 4).
Recently, Capodaglio et al.30 provided a reference
equation specific for obese population and suggested
that specific predicted reference values may have the
advantage of providing a benchmark for functional
capacity assessment and changes monitoring after
pulmonary rehabilitation.30
Further studies with large cohorts of volunteers in
wide range of age would be necessary in order to cre-
ate a 6MWD reference equation that will be highly
representative and applicable to patients with COPD.
Specifically, a population-based sample, a large num-
ber of healthy subjects in each decade of age, adequate
exclusion criteria for poor health of ‘healthy subjects’
and methodological approach based on American
Thoracic Society guidelines7 should be considered for
the creation of 6MWD reference equations. Anthropo-
metric and demographic characteristics of healthy indi-
viduals recruited for the development of a reference
equation should be ideally matched to the correspond-
ing patients’ characteristics in which the equation is
being applied. Additionally, the 6MWT operating pro-
cedures of studies formulated reference equations
should be in line with those operating procedures fol-
lowed by the population in which the reference equa-
tion is being applied. All of these criteria should be
considered for the development and the choice of
6MWD reference equation that can provide an instant
practical clinical information and interpretation for the
levels of exercise capacity. In summary, existing
6MWD reference equations will give varying results
in patients with COPD. The choice of 6MWD refer-
ence equations should consider the consistency of
6MWT operating procedures and at least be specific
for the country/region of origin. This seems of less
importance in underweight patients with mild COPD.
Authors’ contribution
VA contributed to data acquisition, data and statistical
analysis, figures’ design and drafted the manuscript. AH,
SS and MS contributed to the writing of the manuscript, cri-
tically reviewed the manuscript. FF, HP, AM and FS con-
tributed to patients’ medical assessment, medical
surveillance during exercise tests, critically reviewed the
manuscript. IV and EW critically reviewed the manuscript.
All authors read and approved the final manuscript.
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7
Acknowledgement
VA obtained an ERS Long Term Research Fellowship
(LTRF 63-2012).
Conflict of interest
The authors declare no conflicts of interest.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
Supplemental material
The supplementary material is available at http://crd.
sagepub.com/supplemental
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