Non-Invasive Ventilation During Exercise Training For People With Chronic Obstructive Pulmonary Disease (Review)

Cochrane Database of Systematic Reviews
Non-invasive ventilation during exercise training for people

with chronic obstructive pulmonary disease (Review)
Menadue C, Piper AJ, van ’t Hul AJ, Wong KK
Menadue C, Piper AJ, van ’t Hul AJ, Wong KK.

Non-invasive ventilation during exercise training for people with chronic obstructive pulmonary disease.
Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD007714.
DOI: 10.1002/14651858.CD007714.pub2.
www.cochranelibrary.com
Non-invasive ventilation during exercise training for people with chronic obstructive pulmonary disease (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Analysis 1.1. Comparison 1 Non-invasive ventilation during exercise training versus exercise training alone or exercise
training with sham non-invasive ventilation, Outcome 1 Exercise capacity: peak cycle work rate (watts). . . . 51
training with sham non-invasive ventilation, Outcome 2 Exercise capacity: peak VO2 (L/min). . . . . . . 52
training with sham non-invasive ventilation, Outcome 3 Exercise capacity: percentage change. . . . . . . 53
training with sham non-invasive ventilation, Outcome 4 Exercise capacity: constant work rate cycle endurance time
(minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
training with sham non-invasive ventilation, Outcome 5 Health-related quality of life: St George’s Respiratory
Questionnaire. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
training with sham non-invasive ventilation, Outcome 6 Training intensity: final training session (% baseline peak
work capacity). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
training with sham non-invasive ventilation, Outcome 7 Physiological outcomes: isoload lactate (mmol/L). . 57
training with sham non-invasive ventilation, Outcome 8 Physiological outcomes: peak exercise lactate (mmol/L). 58
training with sham non-invasive ventilation, Outcome 9 Physiological outcomes: isotime exercise minute ventilation
(L/min). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
training with sham non-invasive ventilation, Outcome 10 Physiological outcomes: peak exercise minute ventilation
(L/min). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
training with sham non-invasive ventilation, Outcome 11 Physiological outcomes: change in VO2 at anaerobic
threshold (L/min). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
training with sham non-invasive ventilation, Outcome 12 Dyspnoea: isotime exercise dyspnoea (Borg scale). . 62
Non-invasive ventilation during exercise training for people with chronic obstructive pulmonary disease (Review) i
training with sham non-invasive ventilation, Outcome 13 Dropouts. . . . . . . . . . . . . . . . 63
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 71
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Non-invasive ventilation during exercise training for people with chronic obstructive pulmonary disease (Review) ii
[Intervention Review]
Non-invasive ventilation during exercise training for people

with chronic obstructive pulmonary disease
Collette Menadue1 , Amanda J Piper1,2 , Alex J van ’t Hul3 , Keith K Wong1,2
1 Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, Australia. 2 Woolcock Institute of Medical
Research, Glebe, Australia. 3 Department of Pulmonary Diseases, UMC St Radboud, Nijmegen, Netherlands
Contact address: Collette Menadue, Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road,
Camperdown, NSW, 2050, Australia. collette.menadue@sswahs.nsw.gov.au.
Editorial group: Cochrane Airways Group.

Publication status and date: New, published in Issue 5, 2014.
Citation: Menadue C, Piper AJ, van ’t Hul AJ, Wong KK. Non-invasive ventilation during exercise training for people with
chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD007714. DOI:
10.1002/14651858.CD007714.pub2.
ABSTRACT
Background
Exercise training as a component of pulmonary rehabilitation improves health-related quality of life (HRQL) and exercise capacity in
people with chronic obstructive pulmonary disease (COPD). However, some individuals may have difficulty performing exercise at an
adequate intensity. Non-invasive ventilation (NIV) during exercise improves exercise capacity and dyspnoea during a single exercise
session. Consequently, NIV during exercise training may allow individuals to exercise at a higher intensity, which could lead to greater
improvement in exercise capacity, HRQL and physical activity.
Objectives
To determine whether NIV during exercise training (as part of pulmonary rehabilitation) affects exercise capacity, HRQL and physical
activity in people with COPD compared with exercise training alone or exercise training with sham NIV.
Search methods
We searched the following databases between January 1987 and November 2013 inclusive: The Cochrane Airways Group specialised
register of trials, AMED, CENTRAL, CINAHL, EMBASE, LILACS, MEDLINE, PEDro, PsycINFO and PubMed.
Selection criteria
Randomised controlled trials that compared NIV during exercise training versus exercise training alone or exercise training with sham
NIV in people with COPD were considered for inclusion in this review.
Data collection and analysis
Two review authors independently selected trials for inclusion in the review, extracted data and assessed risk of bias. Primary outcomes
were exercise capacity, HRQL and physical activity; secondary outcomes were training intensity, physiological changes related to exercise
training, dyspnoea, dropouts, adverse events and cost.
Non-invasive ventilation during exercise training for people with chronic obstructive pulmonary disease (Review) 1
Main results
Six studies involving 126 participants who completed the study protocols were included. Most studies recruited participants with
severe to very severe COPD (mean forced expiratory volume in one second (FEV1 ) ranged from 26% to 48% predicted). There was
an increase in percentage change peak and endurance exercise capacity with NIV during training (mean difference in peak exercise
capacity 17%, 95% confidence interval (CI) 7% to 27%, 60 participants, low-quality evidence; mean difference in endurance exercise
capacity 59%, 95% CI 4% to 114%, 48 participants, low-quality evidence). However, there was no clear evidence of a difference
between interventions for all other measures of exercise capacity. The results for HRQL assessed using the St George’s Respiratory
Questionnaire do not rule out an effect of NIV (total score mean 2.5 points, 95% CI -2.3 to 7.2, 48 participants, moderate-quality
evidence). Physical activity was not assessed in any study. There was an increase in training intensity with NIV during training of 13%
(95% CI 1% to 27%, 67 participants, moderate-quality evidence), and isoload lactate was lower with NIV (mean difference -0.97
mmol/L, 95% CI -1.58mmol/L to -0.36 mmol/L, 37 participants, moderate-quality evidence). The effect of NIV on dyspnoea or the
number of dropouts between interventions was uncertain, although again results were imprecise. No adverse events and no information
regarding cost were reported. Only one study blinded participants, whereas three studies used blinded assessors. Adequate allocation
concealment was reported in four studies.
Authors’ conclusions
The small number of included studies with small numbers of participants, as well as the high risk of bias within some of the included
studies, limited our ability to draw strong evidence-based conclusions. Although NIV during lower limb exercise training may allow
people with COPD to exercise at a higher training intensity and to achieve a greater physiological training effect compared with exercise
training alone or exercise training with sham NIV, the effect on exercise capacity is unclear. Some evidence suggests that NIV during
exercise training improves the percentage change in peak and endurance exercise capacity; however, these findings are not consistent
across other measures of exercise capacity. There is no clear evidence that HRQL is better or worse with NIV during training. It is
currently unknown whether the demonstrated benefits of NIV during exercise training are clinically worthwhile or cost-effective.
PLAIN LANGUAGE SUMMARY

Breathing support via a mask during exercise training for people with chronic obstructive pulmonary disease
Background: Quality of life and exercise tolerance are commonly reduced in people with chronic obstructive pulmonary disease
(COPD). In addition, physical activity levels are lower compared with those of healthy people of a similar age. Exercise training as a
part of a formal rehabilitation programme is an important component of management for people with COPD and has been shown to
improve both quality of life and exercise tolerance. However, some individuals may have difficulty performing exercise at an adequate
training intensity. Non-invasive ventilation (NIV) is a method of providing breathing support using a machine called a ventilator.
Breathing support is delivered via a mask that is worn over the nose, mouth or both, or via a mouthpiece. During a single exercise
session, NIV has been shown to improve exercise tolerance and reduce breathlessness. Consequently, NIV used over multiple exercise
sessions (during exercise training) may allow people with COPD to exercise at a higher intensity and potentially to achieve greater
improvement in exercise tolerance, quality of life and physical activity.
Review question: We conducted a review to determine whether NIV during exercise training affects exercise tolerance, quality of life
and physical activity compared with exercise training alone or exercise training with sham NIV (placebo) in people with COPD.
Study characteristics: The evidence is current to November 2013. We included six studies involving 126 participants who completed
the study protocols. Most studies recruited participants with severe to very severe COPD. The average age of participants ranged from
63 to 71 years. Cycling or treadmill exercise training was performed in the studies. The duration of exercise training programmes ranged
from six to twelve weeks.
Key results: The percentage change in peak exercise capacity increased by an average of 17% in three studies, and the percentage change
in endurance exercise capacity by an average of 59% in two studies that provided NIV during training compared with training without
NIV or training with sham NIV. However, these improvements in exercise capacity were not consistent findings as there was no clear
evidence that NIV improved all other measures of exercise capacity. The results for quality of life were uncertain and our analysis did
not exclude there being an effect with NIV during exercise training in two studies. Physical activity was not assessed in any of the
studies. Non-invasive ventilation allowed participants to exercise at a higher training intensity (average of 13% higher) in three studies,
and evidence of a greater training effect on the muscles was found in two studies, as a marker in the blood (isoload blood lactate)
was significantly lower by an average of 0.97 mmol/L. No information regarding adverse events or cost was reported. It is currently
unknown whether demonstrated benefits of NIV during exercise training are clinically worthwhile or cost-effective.
Quality of the evidence: This review was generally limited by the small number of included studies and the small numbers of
participants within the included studies. The quality of the evidence was low for exercise capacity outcomes, largely because of issues
with study design. Consequently, the effect of NIV during exercise training on exercise capacity is uncertain. The quality of the evidence
for quality of life, training intensity and isoload blood lactate was moderate, and these findings can be interpreted with a greater degree
of confidence.
Non-invasive ventilation during exercise training for people with chronic obstructive pulmonary disease (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Non- invasive ventilation during exercise training versus exercise training alone or exercise training with sham non- invasive ventilation for people with chronic obstructive
pulmonary disease
Patient or population: people with chronic obstructive pulm onary disease

Settings: outpatient
Intervention: non-invasive ventilation during exercise training
Comparison: exercise training alone or exercise training with sham non-invasive ventilation
Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Exercise training alone Non- invasive ventila-

or exercise training tion during exercise
with sham non- inva- training
sive ventilation
Exercise capacity: per- Exercise capacity: per- M ean exercise capac- 17% (7% to 27%) 60 ⊕⊕
centage change in peak centage change in peak ity: percentage change (3 studies) lowa
work rate work rate in the control in peak work rate in
Increm ental cycle or groups ranged f rom a the intervention groups
increm ental treadm ill m ean of was
test 9% to 38% 17% higher
Follow-up: 6 to 8 weeks (7% to 27% higher)
Exercise capacity: per- Exercise capacity: per- M ean exercise capac- 59% (4% to 114%) 48 ⊕⊕ M ean change exceeds
centage change con- centage change con- ity: percentage change (2 studies) lowb,c m inim al im portant dif -
stant work rate en- stant work rate en- constant work rate en- f erence of 34%
durance time durance tim e in the con- durance tim e in the in-
Constant work rate cy- trol groups ranged f rom tervention groups was
cle endurance test a m ean of 59% higher
Follow-up: 6 to 8 weeks 74% to 88% (4% to 114% higher)
4
Exercise capacity: en- Exercise capacity: en- M ean exercise capac- 3.62 m inutes (-0.17 to 48 ⊕⊕ CI crosses zero but
durance time (minutes) durance tim e (m inutes) ity: endurance tim e 7.41 m inutes) (2 studies) lowb,d does not rule out an ef -
Constant work rate cy- in the control groups (m inutes) in the inter- f ect
cle endurance test ranged f rom a m ean of vention groups was
Follow-up: 6 to 8 weeks 3.9 to 13.0 minutes 3.62 minutes higher
(0.17 lower to 7.41
higher)
Health- related quality M ean health- 2.45 points (-2.3 to 7.2 48 ⊕⊕⊕ CI crosses zero but
of life related quality of lif e in points) (2 studies) moderate e does not rule out an ef -
Change in total score the intervention groups f ect
of St George’s Res- was
piratory Questionnaire. 2.45 points higher
Scale f rom 0 to 100 (2.3 lower to 7.2 higher)
Follow-up: 6 to 8 weeks
Physical activity: not See com m ent See com m ent Not estim able - See com m ent This outcom e was not
m easured reported in any of the
included studies
Training intensity: fI- Training M ean training intensity: 13% (1% to 27%) 67 ⊕⊕⊕ Heterogeneity between
nal training session (% intensity: change f rom change f rom baseline (3 studies) moderate f studies was explained
baseline peak work ca- baseline (%) in the con- (%) in the intervention by one study that
pacity) trol groups ranged f rom groups was recruited participants
Follow-up: 6 to 8 weeks a m ean of 13% higher with m ilder disease
75% to 93% (1% to 27% higher) com pared with other
studies in the analysis
Physiolog- Physiolog- M ean physiolog- -0.97 m m ol/ L (-1.58 to 37 ⊕⊕⊕

ical outcomes: isoload ical outcom es: isoload ical outcom es: isoload -0.36 m m ol/ L) (2 studies) moderate g
blood lactate (mmol/ L) blood lactate (m m ol/ L) blood lactate (m m ol/
Follow-up: 6 to 12 in the control groups L) in the intervention
weeks ranged f rom a m ean of groups was
2.50 to 2.61 mmol/ L 0.97 mmol/ L lower
(1.58 to 0.36 lower)
5
* The basis f or the assumed risk (e.g. the m edian control group risk across studies) is provided in f ootnotes. The corresponding risk (and its 95% conf idence interval) is
based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI).
CI: Conf idence interval.
GRADE Working Group grades of evidence.

High quality: Further research is very unlikely to change our conf idence in the estim ate of ef f ect.
M oderate quality: Further research is likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and m ay change the estim ate.
Low quality: Further research is very likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and is likely to change the estim ate.
Very low quality: We are very uncertain about the estim ate.
a -2 f or risk of bias: None of the studies blinded participants or trainers, and only one study used a blinded assessor. It was
unclear whether allocation concealm ent was adequate in two of the studies. Also, one study reported signif icant between-
group dif f erences in baseline peak exercise capacity.
b -1 f or risk of bias: One study did not blind participants or use a blinded assessor.
c
-1 f or im precision: wide 95% conf idence interval.
d
-1 f or im precision: 95% conf idence interval includes no ef f ect, and upper conf idence lim it crosses the m inim al im portant
dif f erence f or benef it.
e -1 f or risk of bias: Participants were not blinded in one study.
f -1 f or risk of bias: Participants were not blinded in two of the studies, and trainers were not blinded in any of the studies.
g -1 f or risk of bias: None of the studies blinded participants or trainers, which m ay have resulted in perf orm ance bias and
could have indirectly af f ected this outcom e.

6
BACKGROUND How the intervention might work
In people with COPD, the use of NIV during a single session of
lower limb exercise was shown in a systematic review (van’t Hul
Description of the condition 2002) to increase exercise endurance and reduce dyspnoea com-
pared with exercise without NIV or exercise with sham NIV. Un-
Chronic obstructive pulmonary disease (COPD) is a preventable
loading of both inspiratory and expiratory components of the res-
but not curable disease that is generally progressive in nature (Viegi
piratory muscle pump has been observed with NIV during exercise
2007). In 2010, COPD was one of the leading causes of mortality
(Kyroussis 2000), with the reduction in dyspnoea being propor-
worldwide (Lozano 2012). Although variability between countries
tional to respiratory muscle unloading (Maltais 1995). Improve-
has been noted, it is estimated that the prevalence of COPD at
ment in pattern of breathing (Maltais 1995; van’t Hul 2004) and
GOLD (Global Initiative for Chronic Obstructive Lung Disease)
in gas exchange (Dreher 2007; Hernandez 2001) was also noted.
stage II or higher (GOLD 2013) is 10.1% globally (Buist 2007).
In addition, several extrapulmonary effects have been reported
The economic and social costs of COPD are substantial (Pauwels
with NIV during exercise, including improved locomotor muscle
2004), and acute exacerbations of COPD that require admission
perfusion (Borghi-Silva 2008), decreased exercise-induced lactic
to hospital are some of the largest contributors to direct healthcare
acidosis (Borghi-Silva 2008; Polkey 2000) and associated reduc-
costs (Viegi 2007). The number of years that people are living
tion in symptoms of muscle fatigue (Bianchi 1998; Borghi-Silva
with disability due to COPD is also rising (Vos 2012).
2008).
Chronic obstructive pulmonary disease is characterised by expira-
tory flow limitation that is not fully reversible (O’Donnell 2006).
In addition to pulmonary disease and dysfunction, COPD has
a number of associated systemic manifestations including skele- Why it is important to do this review
tal muscle dysfunction, weight loss and systemic inflammation
Given the benefit of NIV during a single session of exercise, ap-
(Agusti 2003). Dyspnoea is the hallmark symptom of COPD
plication of NIV over multiple sessions of exercise, that is, dur-
(Viegi 2007) and is more common in severe disease (Killian 1992).
ing exercise training, may allow people with COPD to exercise
Dyspnoea can lead to a cycle of activity avoidance, deconditioning
at a higher intensity for a greater duration. Therefore, exercise
and reduced participation in society. Exercise capacity and health-
training with NIV could potentially lead to greater improvement
related quality of life (HRQL) are commonly reduced in people
in exercise capacity compared with exercise training alone. Such
with COPD (Garrod 2006), and physical activity levels are lower
improvement in exercise capacity may also improve HRQL and
than those of age-matched healthy individuals (Pitta 2005).
increase physical activity levels in people with COPD.
Description of the intervention

Exercise training as a component of pulmonary rehabilitation is OBJECTIVES
supported by high-level evidence as one of the few effective inter-
ventions in the management of COPD (Rabe 2007; Ries 2007). To determine whether NIV during exercise training (as part of
Pulmonary rehabilitation has been shown to improve exercise ca- pulmonary rehabilitation) affects exercise capacity, HRQL and
pacity (Cambach 1999; Troosters 2000), HRQL and symptoms physical activity in people with COPD compared with exercise
(Lacasse 2006), and to reduce the frequency of hospital admissions training alone or exercise training with sham NIV.
in those with a recent exacerbation (Puhan 2011). However, the
effect of pulmonary rehabilitation on physical activity appears to
be small (Ng 2012). High-intensity exercise training may produce METHODS
greater physiological improvement compared with lower-intensity
exercise training in people with COPD (Casaburi 1991; Gimenez
2000). However, some individuals may have difficulty performing
exercise at an adequate intensity for the required duration (Maltais Criteria for considering studies for this review
1997) and may not achieve the same benefit from exercise training
as those without a significant ventilatory limitation to exercise,
particularly if peripheral muscle strength is relatively preserved Types of studies
(Garrod 2006; Plankeel 2005; Troosters 2001). Consequently, a We included in this review randomised controlled trials (RCTs)
number of adjuncts to exercise have been proposed, including non- comparing NIV during exercise training versus exercise training
invasive ventilation (NIV), a type of breathing support delivered alone, or exercise training with sham NIV (control group). Ran-
via a mask or mouthpiece. domised cross-over trials were also considered for inclusion. Quasi-
RCTs, for example, those with alternate randomisation, were ex- Exclusion
cluded. Studies that used continuous positive airway pressure as the active
treatment during exercise training were excluded.
Types of participants
Types of outcome measures
Primary outcomes
Inclusion 1. Exercise capacity (defined as peak exercise capacity, constant
work rate (endurance) exercise capacity or functional exercise
We considered studies with participants with stable COPD for
capacity measured post exercise training, without NIV).
inclusion. Participants were considered to be stable if no history
2. Health-related quality of life (measured using disease-
of an exacerbation was reported over the past month (Rabe 2007).
specific or generic HRQL instruments).
The definition of COPD was based on:
3. Physical activity: direct measurement (e.g. metabolic
1. a clinical diagnosis of COPD; and
equivalents (METS), step count).
2. a best recorded ratio of forced expiratory volume during
one second (FEV1 ) over forced vital capacity (FVC) < 70% and a
best recorded FEV1 < 80% predicted for individual study Secondary outcomes
participants (equivalent to GOLD stage II to IV) (GOLD 2013). 1. Training intensity (e.g. peak training intensity, final session
training intensity).
2. Physiological changes related to exercise training (e.g. blood
lactate levels, minute ventilation).
Exclusion 3. Dyspnoea (e.g. Borg score, visual analogue scale score).
We excluded studies that included participants with non-COPD 4. Dropouts.
respiratory disease or participants with concomitant neuromuscu- 5. Adverse events.
lar disease, a restrictive thoracic disorder, significant cardiac failure 6. Cost.
or cardiac disease if data from participants with COPD could not
be analysed separately.
Search methods for identification of studies
Types of interventions
Electronic searches
We identified trials with assistance provided by the Cochrane Air-
ways Group Trials Search Co-ordinator using the Cochrane Air-
ways Group Specialised Register of trials. This Register was de-
Inclusion
rived from systematic searches of bibliographic databases includ-
The intervention for the active group consisted of the applica- ing the Cochrane Central Register of Controlled Trials (CEN-
tion of NIV (including bilevel, inspiratory pressure support and TRAL), MEDLINE, EMBASE, Cumulative Index to Nursing
proportional assist ventilation) delivered via a mask or mouth- and Allied Health Literature (CINAHL), Allied and Complemen-
piece during all supervised exercise training sessions. The inter- tary Medicine Database (AMED) and PsycINFO, and from hand-
vention for the control group was exercise training with or without searching of respiratory journals and meeting abstracts, including
sham NIV during all supervised exercise training sessions. Studies annual meetings of the American Thoracic Society, the European
that involved the delivery of supplemental oxygen during exercise Respiratory Society and the British Thoracic Society. All records
training in one group (e.g. exercise training with NIV and supple- in the Specialised Register coded as ’COPD’ between 1 January
mental oxygen) were included provided that supplemental oxygen 1987 and 24 November 2013 were searched using the following
was also delivered to the alternative group (e.g. exercise training terms: (exercis* or physical* or train* or rehabilitat* or condition-
with supplemental oxygen). Similarly, studies that involved the use ing or ergometry or treadmill or endurance or “upper limb”) AND
of nocturnal NIV were included only if both the actively treated (non-invasive* or noninvasive* or “non invasive*” or NIV or “pos-
group and the control group received nocturnal NIV. Training itive pressure” or NIPPV or NPPV or “pressure support” or IPS or
had to include lower limb and/or upper limb endurance exercise “assist* ventilation” or PAV or “ventilatory support” or bilevel or
and had to comprise four or more weeks with a minimum of two BVS or “mechanical ventilation” or “artificial ventilation” or “arti-
supervised sessions per week. ficial respiration” or mask* or BiPAP or IPAP or EPAP or nasal* or
“positive airway*”). The search commenced from 1 January 1987, inclusion from the initial selection of full papers (from titles and
as the first reports in the literature of NIV delivered via a mask abstracts) and from the second selection of included studies (from
were dated 1987 (Ellis 1987; Kerby 1987). full papers).
To reduce the risk of missing eligible studies, separate
searches were conducted on the following databases across
Data extraction and management
the same time period: AMED, CENTRAL, CINAHL, EM-
BASE, Latin American and Caribbean Health Science Infor- Two review authors (CM and AJP) independently extracted data
mation Database (LILACS), MEDLINE, Physiotherapy Ev- from the included studies onto a predesigned form. We recorded
idence Database (PEDro), PsycINFO and PubMed. See the following information: study methods; participant character-
Appendix 1 for a list of search strategies for each database. istics; interventions; outcomes; and results. Although NIV was
Several clinical trials registers and search engines were also used during exercise training in the actively treated groups, post-
screened: Australian New Zealand Clinical Trials Register ( training primary and secondary outcome data were extracted only
www.anzctr.org.au); ClinicalTrials.gov (www.ClinicalTrials.gov); when study participants were evaluated while off NIV (e.g. unas-
International Standard Randomised Controlled Trial Number sisted test of exercise capacity). Discrepancies in the extracted
Register (www.controlled-trials.com/isrctn/); Netherlands Trial data were resolved by consensus. If data were not presented
Register (www.trialregister.nl/trialreg/index.asp); University hos- numerically, a software programme (Engauge Digitizer, http://
pital Medical Information Network (UMIN) (www.umin.ac.jp/ digitizer.sourceforge.net/) was used by one review author (KKW)
ctr/index/); Google Scholar (http://scholar.google.com.au/); and to convert graphical images to numerical data. Two other review
Web of Science (http://thomsonreuters.com/web-of-science/). authors (CM and AJP) independently manually extracted numer-
ical data from each graph using enlarged copies of the images. Dis-
crepancies were resolved by consensus. Authors of included stud-
Searching other resources ies were contacted and were asked to provide missing information
We screened reference lists of included studies and of review arti- when applicable.
cles obtained from the initial search for additional studies that po-
tentially met the inclusion criteria. Authors of the included trials Assessment of risk of bias in included studies
and international experts in the field of NIV were contacted and
Two review authors (CM and AJP) independently assessed the in-
were asked to identify any other published or unpublished stud-
ternal validity of the included studies. The strategy recommended
ies involving NIV during exercise training in COPD. Four of the
in the Cochrane Handbook for Systematic Reviews of Interventions
six authors of included trials responded (Bianchi 2002; Hawkins
(Higgins 2011) was used and included assessment of randomisa-
2002; Toledo 2007; van ’t Hul 2006), and 11 of the 18 experts
tion sequence generation; allocation concealment; blinding; com-
responded. No additional trials were identified. We also screened
pleteness of outcome assessment; selective outcome reporting; and
conference abstracts from the following meetings: American Col-
other potential sources of bias. Unblinded studies were included
lege of Chest Physicians, Asia Pacific Society of Respirology, Ger-
in this review. Each item was graded as high, low or unclear risk
man Society for Pneumology and Respiratory Medicine and the
of bias. Disagreements were resolved by consensus. Study authors
Thoracic Society of Australia and New Zealand. Abstracts were
were contacted to provide additional information when needed.
included in this review, and no language restrictions were applied.
Studies with multiple treatment groups
Data collection and analysis One study (Johnson 2002) consisted of two intervention groups
and one control group. Data were extracted only from the inter-
vention group that used NIV during exercise training and from
Selection of studies the control group, which performed exercise training alone.
Two review authors (CM and AJP) independently selected studies

for inclusion in the review. Initially, titles and abstracts were re- Measures of treatment effect
viewed, and studies that obviously did not fit the inclusion criteria We recorded mean postintervention values and mean changes from
were discarded. Full papers of the remaining studies were obtained baseline values and standard deviations (SDs) for continuous vari-
for closer evaluation. Studies that met the inclusion criteria were ables from both groups within each study. The mean difference
selected. A list of excluded trials compiled from the group of full pa- (MD) and the 95% confidence interval (CI) were used when con-
pers included the primary reason for exclusion (see Characteristics tinuous data measured on the same scale were combined. The stan-
of excluded studies for details). Disagreements in study selection dardised mean difference (SMD) was used when studies reported
were resolved by consensus. We calculated a kappa coefficient to data measured on different scales that could not be calculated back
determine agreement between the two review authors on study to a common scale. When possible, estimates of treatment effect
and confidence limits were related to the minimal important dif- in future updates of this review, the following subgroup analyses
ference (MID) for each outcome. When dichotomous data were will be considered if I2 indicates a moderate or higher level of het-
combined, the treatment effect was defined as the odds ratio (OR) erogeneity (I2 > 30%).
with 95% CI. 1. Study population (e.g. moderate vs severe to very severe
disease (GOLD 2013)).
2. Blinding versus no blinding.
Unit of analysis issues
3. Type of exercise (e.g. treadmill vs cycling training, upper
The unit of analysis was the participant. limb vs lower limb training).
4. Ventilatory settings (e.g. low- vs high-level ventilatory
Dealing with missing data assistance, mode of ventilation).
5. With versus without the use of supplemental oxygen during
If the number of dropouts was large (> 15%), and results from
exercise training.
intention-to-treat analyses (ITT) and per-protocol analyses were
6. Duration of the training programme (e.g. standard vs long).
reported, data were extracted from ITT analyses. If ITT analyses
7. Primary limitation to peak exercise (e.g. ventilatory limited
were not reported, data from the per-protocol analyses were ex-
vs limited by leg fatigue).
tracted for use in the meta-analysis. If incomplete statistical re-
sults were reported in an included study for a given outcome (e.g.
point estimate but no measure of variability), we contacted the Sensitivity analysis
study author and asked for the missing data. If the missing data
We performed sensitivity analyses to determine the effects of the
were not provided, data were not extracted from the study for that
following on results: methodological design (blinding and allo-
particular outcome.
cation concealment), participant characteristics (disease severity),
characteristics of the intervention (programme duration) and be-
Assessment of heterogeneity tween-group differences at baseline. Sensitivity analyses were lim-
The effect of heterogeneity was quantified using the I2 statistic. ited to outcomes that included data from three or more studies in
The I2 statistic indicates the percentage of the total variation in the initial analysis.
observed intervention effects across studies that is due to hetero-
geneity rather than to chance alone (Deeks 2011). The following
thresholds have been suggested to guide the interpretation of I2 :
0% to 40% might not be important; 30% to 60% may indicate RESULTS
moderate heterogeneity; 50% to 90% may indicate substantial
heterogeneity; and 75% to 100% represents considerable hetero-
geneity (Deeks 2011).
Description of studies
Assessment of reporting biases See Characteristics of included studies and Characteristics of
excluded studies.
As a result of the small number of included trials, we were not
able to produce meaningful funnel plots to assess the likelihood
of publication bias (Sterne 2011). Results of the search
The initial search of electronic databases identified 12,392 poten-
Data synthesis tially relevant reports of studies. Of these, we excluded 12,299
When the included studies were clinically homogeneous, data were by title and abstract. Full papers of the remaining 93 publica-
combined using Review Manager 5 software (RevMan 2012), and tions were retrieved for closer inspection. Substantial agreement
forest plots were generated. We used a fixed-effect model for all was reported (Landis 1977) between the two review authors in
analyses unless a moderate or greater degree of heterogeneity was selection of publications for retrieval of full papers and closer in-
detected (I2 > 30%), in which case we used a random-effects spection (kappa = 0.78). After the full papers were examined, an
model. additional article was identified from the study reference lists and
was retrieved for detailed evaluation. Of the 94 full papers, six
met the inclusion criteria of the present review. Perfect agreement
Subgroup analysis and investigation of heterogeneity was noted between the two review authors for final selection of
The small number of studies included in this review precluded included studies (kappa = 1.0). A flow chart of the study selec-
the investigation of heterogeneity between studies and the perfor- tion process is displayed in Figure 1. The latest search was run 24
mance of subgroup analyses. However, if more studies are included November 2013.
Figure 1. Study flow diagram.
NIV.
Included studies
All studies used exercise capacity to evaluate treatment effects, and
In total, six RCTs were included in the review (Bianchi 2002; two studies evaluated HRQL. None of the studies used physical
Hawkins 2002; Johnson 2002; Reuveny 2005; Toledo 2007; van activity as an outcome measure. We attempted to contact authors
’t Hul 2006). Details of each included study are outlined in from all six trials to obtain additional information about study
Characteristics of included studies, and a summary is provided in design, outcomes or funding support for the study. Three study
Appendix 2. All trials used a parallel-group design and were pub- authors provided the requested information, one gave a partial
lished in English. When all studies were combined, data from a response and two did not respond.
total of 126 participants who completed the study protocols (i.e.
excluding dropouts) were analysed (control: N = 63; NIV during
exercise training: N = 63). Individual study sample sizes ranged Excluded studies
from 18 to 29 participants. Studies were conducted in Italy, the A list of studies excluded (N = 88) during the second round of
United Kingdom, the United States of America, Israel, Brazil and selection (i.e. from the list of full papers that were evaluated in
The Netherlands. The mean age of participants ranged from 63 detail) and reasons for exclusion are presented in Characteristics
to 71 years. Most participants were male (n = 93 of 108 partici- of excluded studies. The primary reasons for exclusion included
pants from five studies; one study did not report the sex of par- the following: not an RCT (N = 38); exercise training not eval-
ticipants). Most studies recruited participants with severe to very uated (N = 37); no COPD (N = 6); NIV not used during exer-
severe COPD (mean FEV1 26% to 41% predicted), and one study cise (N = 4); wrong comparison (N = 2); no stable COPD (N
recruited participants with moderate to severe COPD (Bianchi = 1). Of the excluded trials in which the wrong comparison was
2002). made, one study (Pires Di Lorenzo 2003) compared nocturnal
Exercise training programmes were conducted in the outpatient NIV plus exercise training versus NIV during exercise training
setting: two were hospital based (Bianchi 2002; Hawkins 2002); without nocturnal NIV. This study was excluded because noctur-
four were based in non-hospital centres (Johnson 2002; Reuveny nal NIV has been shown to augment the benefits of pulmonary
2005; Toledo 2007; van ’t Hul 2006). Exercise training pro- rehabilitation (Duiverman 2008; Garrod 2000; Kohnlein 2009),
grammes were similar between studies; most were conducted over and this could have confounded the results. The second study
six to eight weeks, with two to three sessions per week of 30 to (Borghi-Silva 2010) compared supplemental oxygen during exer-
45 minutes of exercise training per session at a moderately high cise training versus NIV during exercise training. This study was
intensity. One study (Johnson 2002) encouraged participants to excluded because supplemental oxygen during exercise training
perform additional unsupervised exercise at home (without NIV). has been shown to increase both training intensity and exercise
Based on log book records, this resulted in an average of two extra capacity in people with COPD compared with exercise training
exercise sessions per week. All studies involved lower limb exercise alone (Emtner 2003), which also could have confounded the re-
training. None of the studies assessed upper limb training. sults. Four excluded studies were written in Portuguese, three in
A variety of modes of NIV were used during exercise training, in- German, one in Russian, one in French and one in Norwegian.
cluding bilevel, proportional assist ventilation (PAV) and inspira- The abstract and method sections of these studies were translated
tory pressure support (IPS), with low to moderate levels of ventila- before exclusion. The remaining studies were published in En-
tory support. Only one study compared exercise training with NIV glish.
versus exercise training with sham NIV (van ’t Hul 2006). The
remaining studies used exercise training without NIV as the con-
trol intervention. Three studies used supplemental oxygen during
Risk of bias in included studies
exercise training (Hawkins 2002; Johnson 2002; Reuveny 2005). Details of the review authors’ judgements on risk of bias for each
Delivery of oxygen was reported as equivalent between groups. included study can be seen in Figure 2, Figure 3 and Characteristics
None of the studies included participants receiving domiciliary of included studies.
Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Allocation
have an equivalent effect on exercise performance as unassisted
The method of randomisation sequence generation was described exercise in people with severe COPD (van’t Hul 2004). Half of the
and was judged to be adequate in half of the studies (Bianchi studies (Reuveny 2005; Toledo 2007; van ’t Hul 2006) reported
2002; Hawkins 2002; van ’t Hul 2006). The remaining three stud- using blinded assessors to evaluate clinical outcomes. Two stud-
ies did not report randomisation sequence generation (Johnson ies (Bianchi 2002; Hawkins 2002) did not use blinded assessors
2002; Reuveny 2005; Toledo 2007), and inability to contact study and were judged as having high risk of detection bias. One study
authors prevented a conclusive assessment of bias in two stud- (Johnson 2002) did not report whether outcome assessors were
ies (Johnson 2002; Reuveny 2005). However, despite the use of blinded, and the study author could not be contacted to provide
sealed, opaque envelopes to conceal group allocation, it may have clarification.
been possible to predict group allocation for a small number of
participants (4/29) in the study by (Hawkins 2002), as randomisa-
tion blocks were of a fixed size, the study was performed at a single Incomplete outcome data
centre and investigators were not blinded to group allocation. Five studies reported the number of dropouts and the reasons for
dropping out, and one study (Toledo 2007) did not report the
number of dropouts. Intolerance of NIV was reported as a reason
Blinding for dropping out in two studies: In one study (Reuveny 2005),
Personnel who trained participants were not blinded to group allo- all dropouts from the NIV during training group (n = 3/12 or
cation in any of the studies. Similarly, participants were not blinded 25%) were due to NIV intolerance; in the other study (Bianchi
in most of the studies; this may have introduced bias for outcomes 2002), 28% of participants (n = 5/18) dropped out as the result of
such as exercise capacity and HRQL, whereas physiological out- NIV intolerance. An ITT analysis was performed in two studies
comes were less likely to be affected. Consequently, high risk of (Bianchi 2002; van ’t Hul 2006). The study authors stated that
performance bias was observed for five of the six studies. Lack of the results did not differ from per-protocol analyses, although data
blinding of participants largely reflects the difficulty of providing from ITT analyses were not reported.
an adequate sham intervention for NIV during exercise training.
However, one study (van ’t Hul 2006) did blind participants using
Selective reporting
sham NIV (IPS 5 cmH2 O), which previously has been shown to
Although most studies were free from selective outcome reporting, Peak exercise capacity
two studies (Reuveny 2005; Toledo 2007) did not report results for
between-group comparisons for exercise capacity or for a number
of physiological variables despite reporting post-training within-
group differences.
All six trials included in the review reported the effects of NIV
during exercise training on peak exercise capacity. Three studies
Other potential sources of bias (Bianchi 2002; Hawkins 2002; Reuveny 2005) assessed peak ex-
In one study (Johnson 2002), the results may have been con- ercise capacity using an incremental cycle ergometer test in a com-
founded by contamination, as the group randomly assigned to bined total of 28 participants who trained with NIV and 29 par-
exercise training with NIV also performed unsupervised exercise ticipants who trained without NIV. No clear evidence of a dif-
training without NIV for an average of two sessions per week. In ference was found between training with or without NIV (MD
addition, the same study (Johnson 2002) reported significant be- 6.34 watts; 95% CI -1.66 to 14.34; Analysis 1.1). Two studies
tween-group differences in baseline exercise capacity, which may evaluated peak exercise capacity using incremental treadmill tests.
have affected the response to NIV during exercise training. The One study (Johnson 2002) used a protocol that increased walking
efficacy of the control intervention (unassisted exercise training) speed and incline, with performance measured in METS, and the
was questionable in one study (Reuveny 2005), as within-group other study (Toledo 2007) used a protocol that increased walk-
improvement in exercise capacity did not occur. The group that ing speed only, while performance was measured in kilometres per
trained with NIV did improve. However, as trainers and partic- hour. Although both studies used incremental treadmill tests to as-
ipants were not blinded to the intervention, bias cannot be ex- sess peak exercise capacity, results were not combined, as different
cluded. However, the progression of training intensity was stan- constructs were measured (one protocol measured peak work, the
dardised, which should have helped to ensure that participants other measured peak walking speed) (Table 1). Peak oxygen con-
were exposed to the same training programme. sumption during an incremental treadmill test was also reported
in two studies (Reuveny 2005; Toledo 2007). No clear evidence of
a difference was found between exercise training with or without
Effects of interventions
NIV (MD 0.12 L/min; 95% CI -0.08 to 0.31; Analysis 1.2). The
See: Summary of findings for the main comparison Non- remaining study (van ’t Hul 2006) measured peak exercise capac-
invasive ventilation during exercise training versus exercise training ity using the incremental shuttle walk test (ISWT) (Singh 1992).
alone or exercise training with sham non-invasive ventilation for The individual study effect size of 17.0 metres (95% CI - 2.4 to
people with chronic obstructive pulmonary disease 36.4) was lower than the reported MID of 47.5 metres (95% CI
See Summary of findings for the main comparison. 38.6 to 56.8) for this test (Singh 2008) (Table 1). A significant
difference in peak exercise capacity in favour of training with NIV
was observed when the percentage change in peak work rate was
Primary outcomes assessed in three studies (Hawkins 2002; Johnson 2002; Reuveny
2005) in a combined total of 30 participants who received NIV
during exercise training and 30 participants who received exercise
Exercise capacity
training alone (MD 17%; 95% CI 7 to 27; Figure 4; Analysis 1.3).
Figure 4. Forest plot of comparison: 1 Non-invasive ventilation during exercise training versus exercise
training alone or exercise training with sham non-invasive ventilation, outcome: 1.3 Exercise capacity:
percentage change.
Three sensitivity analyses were also performed (Table 2). The anal-
ysis for peak work rate (watts) was re-run first after exclusion of endurance of 34% (95% CI 29 to 39) (Puente-Maestu 2009), the
data from one study (Bianchi 2002) that recruited participants lower limit of the confidence interval was less than the MID.
with milder disease severity, and second after exclusion of data
from another study (Reuveny 2005) that did not report adequate
Functional exercise capacity
allocation concealment. No change in effect size was observed in
either case. Finally, the analysis for percentage change in peak work Functional exercise capacity was measured in one study (Bianchi
rate was rerun without data from one study (Johnson 2002) with 2002) by the six-minute walk test (6MWT). The MID for the
significant between-group differences in exercise capacity at base- 6MWT in people with COPD is 25 metres (95% CI 20 to 61)
line. Similarly, no differences in effect size were observed. (Holland 2010). Individual study results demonstrated no statisti-
cally or clinically significant difference between training with NIV
Endurance exercise capacity
and exercise training alone (MD 4.3 metres; 95% CI -64.1 to
Endurance exercise capacity was assessed with a constant work rate 72.7) (Table 1).
cycle ergometer test in two studies (Hawkins 2002; van ’t Hul
2006) in a combined total of 25 participants who trained with
NIV and 23 participants who performed exercise training alone Health-related quality of life
or with sham NIV. The reported MID for the constant work rate Health-related quality of life was measured in two studies (Bianchi
cycle endurance test (performed at 75% peak work capacity) is 101 2002; van ’t Hul 2006) with the St George’s Respiratory Question-
seconds (95% CI 86 to 116) (Puente-Maestu 2009). A trend for naire (SGRQ) in a total of 24 participants who trained with NIV
increased exercise endurance was found to favour exercise training and 24 participants who trained without NIV or with sham NIV.
with NIV (MD 3.62 minutes; 95% CI -0.17 to 7.41; Analysis A reduction of four points in the SGRQ total score represents a
1.4). However, the lower limit of the confidence interval crossed clinically worthwhile improvement in HRQL (Jones 2002). No
zero. When the summary effect for each study was expressed as the clear evidence of an effect on HRQL was found for the SGRQ
percentage change from baseline, rather than as post-intervention total score (MD 2.5 points; 95% CI -2.3 to 7.2). Similar results
values, a significant effect in favour of exercise training with NIV were found for the three subscales of the SGRQ: symptoms (MD
was observed when the results were combined (MD 59%; 95% 0.9 points; 95% CI -10.2 to 11.9); activity (MD 0.1 points; 95%
CI 4 to 114; Figure 4; Analysis 1.3). Although the mean effect CI -14.9 to 15.0); and impacts (MD 0.1 points; 95% CI -6.8 to
size for percentage change in endurance time was greater than the 7.1) (Figure 5; Analysis 1.5). Heterogeneity between studies was
reported MID for percentage change in constant work rate cycle considerable (I2 = 77%) for the activity subsection of the SGRQ.
training alone or exercise training with sham non-invasive ventilation, outcome: 1.5 Health-related quality of
life: St George’s Respiratory Questionnaire.
Three studies (Bianchi 2002; Hawkins 2002; van ’t Hul 2006)

Physical activity
reported the training intensity achieved during the final training
None of the included studies reported physical activity as an out- session (expressed as a percentage of baseline peak work capacity)
come. in a combined total of 34 participants who trained with NIV and
33 participants who performed exercise training alone or with
sham NIV. A significant effect on training intensity was found to
Secondary outcomes
favour training with NIV during exercise (MD 13%; 95% CI 1
to 27; Figure 6; Analysis 1.6). However, heterogeneity between
studies was substantial (I2 = 72%).
Training intensity
training alone or exercise training with sham non-invasive ventilation, outcome: 1.6 Training intensity: Final
training session (% baseline peak work capacity).
Two sensitivity analyses were conducted (Table 2). First, the anal-
ysis was rerun without data from one study (Bianchi 2002) that A significant decrease in isoload blood lactate was observed to
recruited participants with milder disease. The effect size increased favour training with NIV when data from two studies (Hawkins
to a mean of 20% (95% CI 12 to 28), and heterogeneity was re- 2002; Toledo 2007) with 19 participants who trained with NIV
duced to 0%. Second, the analysis was rerun without data from and 18 participants who trained without NIV (MD -0.97 mmol/
one study (van ’t Hul 2006) that blinded participants to determine L; 95% CI -1.58 to -0.36; Figure 7; Analysis 1.7) were combined.
whether the effect size was different (e.g. overestimated) if only There was no clear evidence of an effect between exercise training
studies with unblinded participants were included. The effect size with NIV and exercise training alone or exercise training with
was slightly reduced and the 95% CI widened, with the lower sham NIV for peak exercise blood lactate, isotime exercise minute
limit of the 95% CI crossing zero (MD 10%; 95% CI -9 to 28). ventilation (VE), post-training peak exercise VE, or change in
Heterogeneity also increased to I2 = 83%. oxygen consumption at the anaerobic threshold (Analysis 1.8;
Analysis 1.9; Analysis 1.10; Analysis 1.11). A moderate level of
Physiological outcomes
heterogeneity between studies was found for the analysis of peak
exercise blood lactate (I2 = 59%).
training alone or exercise training with sham non-invasive ventilation, outcome: 1.7 Physiological outcomes:
Isoload lactate (mmol/L).
Several sensitivity analyses were conducted (Table 2). First, anal-

yses for isotime exercise VE and for peak exercise VE were rerun did not change substantially. Analyses for peak exercise blood lac-
without data from one study (Bianchi 2002) that recruited partic- tate and peak exercise VE were also rerun with data excluded from
ipants with milder disease. For each outcome, the effect size did one study (Reuveny 2005) that did not report adequate allocation
not change. The analysis for isotime exercise VE was rerun with- concealment. A slight increase in effect size was noted for peak
out data from one study (van ’t Hul 2006), which blinded par- exercise blood lactate from -0.35 mmol/L (95% CI -1.10 to 0.41)
ticipants to determine whether the effect size was different if only in the initial analysis to -0.62 mmol/L (95% CI -1.22 to -0.01),
studies with unblinded participants were included. The effect size and heterogeneity between studies did not change. The effect size
for peak exercise VE was not altered. Finally, the effect size for COPD, with demonstrated improvement in exercise capacity,
peak exercise blood lactate was mildly reduced to 0.04 mmol/L HRQL and dyspnoea (Lacasse 2006). The aim of this systematic
(95% CI -0.55 to 0.62) when the analysis was repeated without review was to determine whether NIV during exercise training
data from one study (Toledo 2007) with a programme duration could provide benefit for exercise capacity, HRQL and physical ac-
approximately twice as long as that of other studies included in tivity above that of exercise training alone in people with COPD.
the review, and heterogeneity between studies decreased to 0%. The current review showed that NIV during exercise training al-
lowed participants to achieve a greater percentage improvement
Dyspnoea in lower limb peak and endurance exercise capacity, to exercise
at a higher training intensity and to gain a greater physiological
Post-training isotime exercise dyspnoea was measured in three
training effect compared with exercise training alone or exercise
studies (Bianchi 2002; Hawkins 2002; Toledo 2007) in a total of
training with sham NIV. There was no clear evidence that HRQL
28 participants who trained with NIV and 28 participants who
was better or worse with NIV during exercise training, and the
performed exercise training alone. No significant effect on dysp-
effect of NIV during exercise training on physical activity is un-
noea, as measured on the Borg scale, was noted between partici-
known, as none of the included studies reported this outcome.
pants performing exercise training with and without NIV (MD -
Results for the effect of NIV during exercise training on exercise
0.18; 95% CI -1.09 to 0.72; Analysis 1.12). A sensitivity analysis
capacity should be interpreted with caution, as differences were
that excluded data from one study (Bianchi 2002), which recruited
found only when percentage change from baseline values rather
participants with milder disease, did not change the size of the
than post-intervention values were used in analyses. One possible
effect. Similarly, a sensitivity analysis that excluded data from one
explanation for the difference in results is that if large interindi-
study (Toledo 2007) with a longer programme duration did not
vidual or intergroup baseline differences were present, the use of
alter the effect size (Table 2).
change from baseline values rather than postintervention values
would provide greater statistical power to detect treatment effects.
Dropouts In addition, the overall quality of the evidence for percentage
change in peak and endurance exercise capacity was judged as low
Dropouts were reported in five studies (Bianchi 2002; Hawkins
(see Summary of findings for the main comparison). The clinical
2002; Johnson 2002; Reuveny 2005; van ’t Hul 2006) from a
significance of the treatment effect for percentage change in peak
total of 151 participants (78 participants who were randomly as-
exercise capacity is unknown, and the effect size may have been
signed to exercise training with NIV and 73 participants who
exaggerated because of the high risk of bias of studies included in
were randomly assigned to exercise training without NIV or with
the analysis. Endurance exercise capacity may be more relevant to
sham NIV). There was no evidence of a clear effect on dropouts
people with COPD than peak exercise capacity, given that most
with NIV during exercise training compared with exercise train-
daily activities are performed at a submaximal level (Pitta 2005).
ing alone, or exercise training with sham NIV (OR 1.26; 95% CI
However, interpretation of the clinical significance of the effect
0.61 to 2.59; Analysis 1.13). A sensitivity analysis that excluded
size for percentage change in endurance exercise capacity is also
data from one study (Bianchi 2002), which recruited participants
unclear. Although the mean effect of 59% was above the reported
with milder disease, did not change the magnitude of the effect
MID of 34% (Puente-Maestu 2009), the 95% CI was very wide,
(Table 2).
with the lower limit of the CI (4%) considerably below the MID.
The finding of an improvement in some aspects of exercise capacity
Adverse events with NIV during exercise training compared with exercise training
alone or exercise training with sham NIV may relate to the fact
Adverse events were not reported in any of the studies.
that NIV during exercise training permits higher-intensity exercise
training and results in a greater physiological training effect, as
Cost reflected by lower isoload blood lactate levels. It is interesting to
note that although isoload lactate was reduced with NIV during
Cost was not reported in any of the studies.
exercise training, no evidence was found of a significant reduction
in isotime VE or isotime dyspnoea. Although overall assessments
of the quality of the evidence for training intensity and isoload
lactate were moderate (see Summary of findings for the main
DISCUSSION comparison), it is unknown whether the size of the treatment
effects is clinically meaningful.
Summary of main results As no cure for COPD is known, treatment aims to relieve symp-
toms, slow disease progression, optimise function and overall
Pulmonary rehabilitation, with exercise training as a key com-
health and prevent and treat exacerbations (GOLD 2013). As
ponent, is well established as a standard of care for people with
such, HRQL is an important outcome for people living with report the number of patients screened during the recruitment
COPD. Although the overall quality of the evidence for HRQL process. Of those studies that did report the number of patients
was judged as moderate (see Summary of findings for the main screened during the recruitment process (Bianchi 2002; Hawkins
comparison), only two of the studies included in this review as- 2002; Johnson 2002), no information was provided regarding the
sessed HRQL. In addition, significant heterogeneity was found number of patients who declined to take part because of the in-
across studies for the activity subsection of the SGRQ and could tervention (NIV). Subsequently, the potential for participants to
not be investigated further because of the small number of stud- have been highly selected cannot be excluded. In addition, two
ies included in the analysis. As a result, the effect of NIV during studies reported dropouts due to poor tolerance of NIV (Bianchi
exercise training on this domain remains uncertain. The effect of 2002; Reuveny 2005), which could have related to selection of
NIV during exercise training on functional exercise capacity is also participants with less severe COPD (Bianchi 2002) or the provi-
unclear, as this outcome was measured in only one study (Bianchi sion of lower levels of ventilatory support (Bianchi 2002; Reuveny
2002) by the 6MWT. Changes in six-minute walk distance are an 2005) compared with other studies (Hawkins 2002; van ’t Hul
important prognostic indicator for people with COPD and have 2006). Consequently, the findings of the present review may not
been shown to relate to mortality (Polkey 2013) and risk of hospi- be applicable to all people with moderate to very severe COPD.
talisation (Spruit 2012). Similarly, the effect of NIV during upper Although the studies included in the present review were reason-
limb exercise training is unknown, as none of the included studies ably homogeneous and representative of current clinical practice
used upper limb exercise as a training modality. Upper limb train- with respect to the exercise training programmes, substantial di-
ing is recommended as part of a comprehensive pulmonary reha- versity was reported regarding the delivery of NIV. Three differ-
bilitation programme (Spruit 2013), and some evidence suggests ent NIV modes were used (bilevel, PAV and IPS), and ventila-
that NIV during unsupported arm exercise improves endurance tory support ranged from a low to a moderate level. None of the
exercise capacity during a single exercise session (Menadue 2009a). included studies assessed high-level pressure support, which has
Consequently, HRQL, functional exercise capacity and upper limb shown promising results during ground walking in people with
training should be considered as outcomes for future studies. very severe COPD (Dreher 2007). During pressure preset venti-
Among the combined total of 63 participants who trained with lation, the amount of tidal volume assistance delivered will vary,
NIV, no adverse events were reported. However, as the total num- depending on factors such as respiratory system compliance, air-
ber of participants who trained with NIV was relatively small, the ways resistance and inspiratory time (Mehta 2001). As a result,
effect of NIV during exercise training on adverse events is unclear a given level of pressure support can have a different effect on
in people with moderate to very severe COPD. tidal volume between participants and even within an individual,
for example, if dynamic hyperinflation occurs during exercise and
respiratory system compliance is reduced. However, as subgroup
Overall completeness and applicability of analyses could not be performed, the influence of these factors on
evidence the treatment effects associated with NIV during exercise training
is unclear. As yet, the optimal mode and settings for NIV dur-
The studies included in the current review recruited participants
ing exercise training are unknown. FInally, although NIV during
with severe to very severe COPD (GOLD 2013), with the ex-
exercise training could potentially benefit select individuals with
ception of one study (Bianchi 2002), which recruited participants
COPD, implementation of this technique does have resource im-
with moderate to severe COPD. The impact of disease severity on
plications and would require experienced staff and access to appro-
the efficacy of training with NIV could not be formally assessed
priate equipment and may involve extra costs, which could limit
in the present review. However, based on outcomes from the in-
the feasibility of this technique in some settings.
dividual included studies, it appears that disease severity could be
an important factor in patient selection for this technique, with
greater benefit reported in studies in which individuals with severe
to very severe COPD were recruited, compared with those with
Quality of the evidence
moderate disease (Bianchi 2002). In addition to selecting people Six studies with a combined total of 126 participants who com-
with severe COPD, two studies (Reuveny 2005; van ’t Hul 2006) pleted the study protocols (63 with NIV during exercise train-
selected participants who demonstrated a very limited ventilatory ing; 63 with exercise training alone or exercise training with sham
reserve at peak unassisted exercise, suggesting a ventilatory lim- NIV) were included in the current review. Limitations in the liter-
itation to exercise. In the latter study (van ’t Hul 2006), partic- ature were noted in terms of the small number of studies included
ipants were included only if they were tolerant of NIV, indicat- in the analyses, the small numbers of participants within the in-
ing that participants were highly selected. It is unclear whether cluded studies and issues related to methodological quality such
a trial of NIV was undertaken to test acceptability before enrol- as lack of blinding or inadequate reporting of allocation conceal-
ment in the other included studies. Three of the included stud- ment. These limitations are reflected in assessments of the quality
ies (Reuveny 2005; Toledo 2007; van ’t Hul 2006) also did not of the evidence, which ranged from low for exercise capacity out-
comes to moderate for HRQL, training intensity and post training small number of meta-analyses could be performed, often with
isoload blood lactate levels (see Summary of findings for the main results from only two to four studies combined, occasionally with
comparison). data from as few as 37 participants. Statistical power also was prob-
The key methodological limitation of the studies was lack of blind- ably compromised in individual studies. Two studies (Reuveny
ing. Only one study blinded participants, three used blinded asses- 2005; Toledo 2007) failed to present post-training results for be-
sors and none of the included studies blinded trainers, which may tween-group comparisons of expected outcomes such as exercise
have introduced performance or detection bias. Consequently, im- capacity, despite conducting parallel RCTs to assess the effects of
portant outcomes such as exercise capacity and HRQL could be training with NIV versus exercise training alone. This reporting
influenced by bias, as all analyses included data from unblinded bias may have occurred because significantly different results be-
studies. Unblinded studies have been shown to overestimate treat- tween groups were not detected. Another study (Hawkins 2002)
ment effect size by 9% compared with blinded studies (Pildal was powered to assess post-training isoload blood lactate. How-
2007). Blinding an intervention such as NIV is difficult but may ever, the combination of dropouts and difficulty gaining vascular
be achieved with the use of sham NIV. However, if an inappro- access in some participants reduced the power of the study to de-
priate sham NIV is used, the treatment effect size could be altered tect differences between groups. When isoload blood lactate data
by sham NIV either impeding exercise performance or assisting from this study were combined with data from Toledo 2007 in the
exercise performance compared with what would have occurred present review, statistical power was improved, and a difference
during unassisted exercise. Therefore a sham NIV would have to between interventions was found to favour training with NIV. A
be shown to be appropriate for a given patient population before larger number of RCTs with greater numbers of participants are
commencement of a training study. For example, the sham NIV needed to achieve sufficient statistical power to confidently assess
used by one study (van ’t Hul 2006) was previously demonstrated the effects of NIV during exercise training on key outcomes.
to have an equivalent effect on exercise performance as unassisted Significant heterogeneity across studies was detected in only three
exercise (van’t Hul 2004). Sensitivity analyses were performed to analyses: HRQL (activity subsection of the SGRQ); peak exercise
determine whether lack of blinding exaggerated effect sizes in the blood lactate; and training intensity. The most likely reason for
present review. Because of the small number of included studies, heterogeneity for the activity subsection of the SGRQ was a dif-
this could be performed only for isotime exercise VE and train- ference in disease severity between the two studies. The condition
ing intensity. No substantial changes in effect size were observed, of participants from one study (van ’t Hul 2006) was more severe
suggesting that these results are robust. (based on FEV1 and ventilatory reserve at peak exercise) than that
Allocation concealment was adequately performed and reported in of participants recruited by the second study (Bianchi 2002), and
most of the trials. However, two studies (Johnson 2002; Reuveny a trend was found to favour NIV during training improving this
2005) did not provide an adequate description of allocation con- outcome. In contrast, the second study (Bianchi 2002) reported
cealment in the paper, and the study authors could not be con- a trend for improvement in this outcome in favour of the control
tacted to provide additional information. In addition, although group. It is unlikely that the treatment effect was overestimated by
allocation concealment was adequately described in another study the first study (van ’t Hul 2006), as allocation concealment was ad-
(Hawkins 2002), it may have been compromised for a small num- equate and both participants and assessors were blinded. However
ber of participants as the result of block randomisation. If the subgroup and sensitivity analyses could not be performed to inves-
size of the blocks used during block randomisation is fixed and tigate the cause of heterogeneity, as only two studies reported this
known, it may be possible to predict future group allocation for outcome. Three studies were included in the analysis of peak exer-
some participants in an unblinded trial (Berger 2005). Inclusion cise blood lactate. The training programme in one study (Toledo
of studies without adequate allocation concealment has been re- 2007) was substantially longer (12 weeks) than the programmes in
ported to overestimate effect size by 18% to 37% (Moher 1998, the other two studies (six to eight weeks) (Hawkins 2002; Reuveny
Pildal 2007). In the present review, only a limited number of sen- 2005). Greater training effects can be achieved with a training
sitivity analyses could be conducted to assess the impact of includ- programme duration of 12 weeks or longer in comparison with
ing trials without adequate description of allocation concealment. programmes with a duration of six to eight weeks (Ries 2007).
The change in effect size was small to negligible for peak work rate This factor appeared to account for the difference in effect sizes
(watts), training intensity, peak exercise blood lactate and peak between studies, as demonstrated in a sensitivity analysis for which
exercise VE, indicating that these results were also robust. data from the study with the longer programme duration (Toledo
Another factor that may have impacted the results of the current 2007) were removed, with the summary effect size reduced and I2
review is lack of statistical power. Only six studies were eligible for decreased to zero. Finally, differences in disease severity appeared
inclusion in the review, and within each study, sample sizes were to explain heterogeneity across studies in the analysis of training
generally small, with dropout rates in five of the studies ranging intensity. Two studies (Hawkins 2002; van ’t Hul 2006) recruited
from 21% to 42%. In addition, a variety of measurement tools participants with severe to very severe COPD and reported an
were used to assess outcomes of interest. Consequently, only a increase in training intensity with NIV during exercise training
compared with control, whereas another study (Bianchi 2002) re- with COPD compared with control (exercise without NIV). The
cruited a ’milder’ group of participants and found no difference in present review also found some evidence that endurance exercise
training intensity between those who trained with NIV and the capacity may be improved with NIV during exercise, although,
control group, suggesting that individuals with less severe disease in contrast to van’t Hul 2002, for which included studies tested
may not derive benefit from NIV during exercise. A sensitivity endurance exercise capacity while participants breathed on NIV,
analysis that excluded data from Bianchi 2002 increased the sum- studies included in the present review tested exercise capacity post
mary effect size and reduced I2 to zero. training and without NIV. Also, the present review did not find a
reduction in dyspnoea associated with NIV during training. How-
ever, as dyspnoea was measured after training and without NIV
Potential biases in the review process during exercise in the studies included in the present review, the
difference in results may simply reflect the fact that the reduction
Strengths of the review process include adherence to a predefined in dyspnoea is a temporary phenomenon related to respiratory
protocol (Menadue 2009b), with the exception of several small muscle unloading (Maltais 1995) as a direct result of the applica-
alterations (see Differences between protocol and review), and the tion of NIV.
performance of a comprehensive literature search (including non- To date, three literature reviews have specifically addressed the role
English trials and grey literature). A potential weakness of the re- of NIV during exercise training as part of a pulmonary rehabilita-
view process was the inability to assess for the likelihood of pub- tion programme (Araujo 2005; Corner 2010; De Backer 2010).
lication bias because of the small number of included trials. To Meta-analyses were not performed in any of the reviews. Araujo
reduce the risk of publication bias, a number of clinical trial regis- 2005 did not discuss any of the studies included in the present
ters were searched, conference abstracts were reviewed and inter- review, and Corner 2010 included five RCTs from the current
national experts in the field of NIV were asked to identify further review (Bianchi 2002; Hawkins 2002; Johnson 2002; Reuveny
published or unpublished trials. However, no additional potential 2005; van ’t Hul 2006) and one quasi-randomised study (Costes
studies were found. Not all of the studies included in the present 2003) that was excluded from the present review, and excluded one
review reported results in favour of NIV during exercise training. RCT (Toledo 2007) that was included in the present review. De
Nevertheless, publication bias cannot be excluded. Finally, not all Backer 2010 included all six RCTs from the present review, as well
of the authors of included studies could be contacted to provide as one quasi-randomised study (Costes 2003) and one randomised
additional information regarding study design or data. This may cross-over study (Barakat 2007), all of which were excluded from
have affected the judgement of some categories of risk of bias and the present review. Conclusions were similar between the three
limited the data included in meta-analyses for some outcomes. reviews, namely, that NIV may permit patients with moderate to
very severe COPD to train at a higher intensity and gain greater
improvement in exercise capacity compared with exercise training
Agreements and disagreements with other alone. The current review largely supports these findings. How-
studies or reviews ever, it is unclear whether the observed improvement in exercise
capacity is clinically worthwhile.
Two non-Cochrane systematic reviews and meta-analyses have pre-
Several pulmonary rehabilitation practice guidelines have included
viously investigated the effects of NIV during exercise. Ricci 2013
recommendations regarding the role of NIV as an adjunct to exer-
evaluated the physiological effects of NIV during exercise train-
cise training during pulmonary rehabilitation. Most recently, the
ing in people with stable COPD compared with control (exercise
American Thoracic Society/European Respiratory Society State-
training alone or exercise training with sham NIV or supplemental
ment ’Key Concepts and Advances in Pulmonary Rehabilitation’
oxygen). In addition to the six RCTs included in the present review,
(Spruit 2013) referred to the findings of the literature review by
Ricci 2013 included one quasi-randomised study (Costes 2003)
Corner 2010, which concluded that NIV appears to enhance the
and one study that compared supplemental oxygen during exercise
effects of exercise training, with greatest benefit observed in in-
training with NIV during exercise training (Borghi-Silva 2010).
dividuals with severe disease. It was also stated that as NIV is a
In contrast to the present review, Ricci 2013 found no difference
difficult and labour-intensive intervention, its use may be feasi-
between NIV during exercise training and control with respect to
ble only in centres with significant expertise with NIV, and for
lactate. Also no difference between NIV during exercise training
individuals with demonstrated benefit from using NIV during
and control was found for heart rate, oxygen consumption (VO2 )
exercise (Spruit 2013). Also in 2013, the British Thoracic So-
and workload. However, very limited data were provided, as the
ciety Guideline on Pulmonary Rehabilitation in Adults (Bolton
study authors did not state which studies were included in each
2013) stated that NIV should not be used routinely during pul-
meta-analysis and did not report the summary effect for outcomes
monary rehabilitation in patients with chronic hypercapnic res-
other than VO2 . The second systematic review (van’t Hul 2002)
piratory failure who do not already receive domiciliary NIV, and
reported significant benefit for exercise endurance time and dysp-
that patients with chronic hypercapnic respiratory failure who use
noea during a single application of NIV during exercise in people
domiciliary NIV should be offered the opportunity to exercise Implications for practice
with NIV during pulmonary rehabilitation, provided that this is
This review provides evidence that NIV during exercise training
tolerable and accepted by the patient. In 2007, The Joint Ameri-
may allow people with COPD to exercise at a higher training in-
can College of Chest Physicians/American Association of Cardio-
tensity and to achieve a greater physiological training effect com-
vascular and Pulmonary Rehabilitation Evidence-Based Clinical
pared with exercise training alone or exercise training with sham
Practice Guidelines stated that NIV during exercise training may
NIV. Although some evidence suggests that NIV during exercise
be of benefit for select patients with severe COPD and may per-
training improves the percentage change in peak and endurance
mit modest improvements in exercise performance above that of
exercise capacity, these findings are not consistent across other
exercise training alone (Ries 2007). The current review provides
measures of peak and endurance exercise capacity. The results for
evidence to support some of these recommendations, for example
quality of life were uncertain and our analysis did not exclude there
that NIV during exercise may lead to improvement in endurance
being an effect with NIV during exercise. It is currently unknown
exercise capacity above that of exercise training alone. However,
whether the demonstrated benefit of NIV during exercise training
regarding patient selection for this technique, although the results
is clinically worthwhile or cost-effective.
of individual studies suggest that individuals with severe to very
severe COPD may respond better to NIV during exercise training
Implications for research
than those with milder disease, an insufficient number of included
studies in the present review precluded the performance of sub- To conclusively determine the effects of NIV during exercise
group analyses to determine the effect of disease severity on out- training, additional RCTs with larger numbers of participants are
comes. The present review does not provide evidence for the use needed. It is essential that studies have a strong methodological
of NIV during exercise training in people with chronic hypercap- design to minimise the risk of bias, as well as high-quality report-
nic respiratory failure secondary to COPD, as none of the studies ing to enable accurate assessment of the risk of bias. In particu-
included in the present review recruited participants with chronic lar, blinding of participants, trainers and assessors is required, al-
hypercapnia. However, as benefit for exercise capacity and dysp- though arguably difficult, with an intervention such as NIV. Im-
noea has been observed in this population during an acute appli- portant outcomes that should be evaluated include endurance ex-
cation of NIV during exercise (Bianchi 1998), investigation of the ercise capacity, HRQL and physical activity. Assessment of exer-
role of NIV during exercise training is warranted. Some guidelines cise capacity using tests for which the MID is known may help to
(Spruit 2013) recommend selecting individuals for NIV during clarify whether clinically relevant improvements in exercise capac-
training who have previously demonstrated an acute benefit from ity can be obtained. Longer-term follow-up of study participants
exercise with NIV. However, currently no evidence is available to (e.g. 12 months) should also be performed. In addition, future
suggest that selecting individuals on these grounds will result in studies need to quantify the extra time and costs associated with
greater training effects with NIV, as the predictive validity of the NIV during exercise training, so that this potential barrier can be
acute response is low (van ’t Hul 2006). weighed against any potential benefits.
Although a number of pulmonary rehabilitation review articles The optimal mode and settings for NIV during exercise training
(Spruit 2013; Troosters 2005; Troosters 2010) allude to NIV dur- are not well defined and may directly alter the efficacy of NIV
ing exercise training as a difficult, costly and time-consuming in- during exercise training. However, a larger number of studies are
tervention, none of the studies included in the present review re- required before subgroup analyses can be performed to determine
ported the additional costs associated with using NIV during ex- the effects of ventilator mode and settings on important outcomes.
ercise training when compared with exercise training alone. One Studies included in the present review used only low to moderate
of the included studies (Bianchi 2002) did report that staff spent levels of ventilatory support during exercise training. Assessment
an average of 11 ± 3 minutes setting up the ventilator. However, of high-level ventilatory support during exercise training is war-
it is unclear whether this time was spent during the initial ses- ranted. Evaluation of NIV during exercise training in subgroups,
sion or during each session of the rehabilitation programme, or such as those with or without a limited ventilatory reserve at peak
how this compared with the amount of time spent with the group (unassisted) exercise and individuals with or without significant
who performed exercise training without NIV. The issue of cost, dynamic hyperinflation during exercise, may help to better define
in terms of staff time and additional resources, requires further a target population for this intervention. People with chronic hy-
investigation before conclusions can be drawn as to whether NIV percapnic respiratory failure who are considered appropriate can-
could or could not be a cost-effective adjunct to exercise training didates for nocturnal NIV could potentially benefit from NIV
for people with COPD. during exercise training and should be assessed in future studies.
AUTHORS’ CONCLUSIONS ACKNOWLEDGEMENTS
Thank you to Elizabeth Stovold and Susan Hansen for assis-
tance with the search strategy and for conducting searches of the
Cochrane Airways Group Register of Trials, and to Dr Emma
Welsh, Toby Lasserson and Emma Jackson for support provided
throughout the review process. Also, thank you to Professor Jen-
nifer Alison for advice and comments on the review.
Phillippa Poole was the Editor for this review and commented
critically on the review.
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Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Bianchi 2002
Methods Study design: parallel randomised controlled trial

Inclusion criteria: male participants with COPD diagnosed by American Thoracic
Society criteria; referred to outpatient pulmonary rehabilitation; stable clinical condition
Exclusion criteria: chronic respiratory failure; other organ failure; cancer; inability to
co-operate; arterial exercise-induced hypertension (systolic blood pressure > 200 mmHg
or diastolic blood pressure > 130 mmHg)
Statistical analysis: between groups: repeated measures analysis of variance; differences
between dropouts and programme completers: Fisher’s exact test; P value < 0.05 signifi-
cance
Participants Participants recruited from: referred to outpatient multi-disciplinary pulmonary reha-

bilitation programme
Number screened: 83
Sample size: 9 NIV group; 10 control group
Age mean (range), years: 64 (61 to 67) NIV group; 65 (61 to 69) control group
Gender: 0 female participants NIV group; 0 female participants control group
FEV1 mean (SD) % predicted: 48 (19) NIV group; 40 (12) control group
FVC mean (SD) % predicted: 77 (15) NIV group; 74 (19) control group
RV mean (SD) % predicted: 161 (69) NIV group; 181 (49) control group
PaO2 mean (SD) kPa: 10.0 (1.1) NIV group; 10.0 (1.1) control group
PaCO2 mean (SD) kPa: 5.2 (0.6) NIV group; 5.2 (0.5) control group
PImax mean (SD) cmH2 O: 82.9 (25.8) NIV group; 72.4 (23.4) control group
PEmax mean (SD) cmH2 O: 147.9 (26.8) NIV group, 139.2 (25.1) control group
Domiciliary NIV: nil
Long-term oxygen therapy: nil
Interventions NIV: proportional assist ventilation: flow assist 3.5 (1.6) cmH2 O/L/s, volume assist 6.
6 (2.2) cmH2 O/L with EPAP 2 cmH2 O during exercise training
Control: unassisted exercise training
Supplemental oxygen during exercise training: no
Type of exercise training: cycle ergometry
Intensity of training: 50% to 70% of peak work capacity
Number of sessions per week: 3
Duration of each session: 30 minutes, supervised
Total duration of training: 6 weeks
Number of training sessions attended (/18): NIV group 17.4 ± 1.3 sessions; control
group 17.0 ± 1.8 sessions
Programme setting: outpatient, hospital-based
Outcomes Maximal cycle ergometry: unassisted, load increased 10 watts/min; six-minute walk test;
dyspnoea; leg discomfort; St George’s Respiratory Questionnaire
Evaluation: assessment performed at baseline and immediately following the training
programme
Bianchi 2002 (Continued)
Dropouts A total of 33 participants were recruited. Of the 18 randomly assigned to NIV, 9 com-
pleted the protocol (50% dropout rate). Reasons for dropout: intolerance of NIV (N =
5); acute exacerbation of COPD (N = 2); exercise-induced hypertension (N = 1); and
unexpected coronary disease (N = 1). Of the 15 randomly assigned to the control group,
10 completed the protocol (33% dropout rate). Reasons for dropout: acute exacerbation
of COPD (N = 2); exercise-induced hypertension (N = 2); unexpected coronary disease
(N = 1)
Funding No information provided
Notes Country: Italy

Study author contacted: full response
Risk of bias Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Low risk Quote (from correspondence): “The se-
bias) quence of allocation was computer gener-
ated”
Allocation concealment (selection bias) Low risk Quote (from correspondence): “...con-
cealed envelopes”
Blinding of participants and personnel High risk Quote (from report): “Patients and inves-
(performance bias) tigators were unblinded during the study”
All outcomes
Blinding of outcome assessment (detection High risk Quote (from report): “Patients and inves-
bias) tigators were unblinded during the study.”
All outcomes
Incomplete outcome data (attrition bias) Low risk Comment: Total number of participants
All outcomes recruited, number of dropouts from each
group and reasons for dropping out are
reported. Dropout rate was higher in the
group that trained with NIV (44%) com-
pared with the group that trained without
NIV (33%). Five of the eight dropouts in
the NIV group were due to NIV intoler-
ance. Both intention-to-treat analyses and
per-protocol analyses were performed for
key outcomes
Selective reporting (reporting bias) Low risk Comment: Published report contains all
expected outcomes, including those that
were prespecified
Bianchi 2002 (Continued)
Other bias Low risk None evident
Hawkins 2002

Inclusion criteria: severe COPD; current smoker or had a history of smoking
Exclusion criteria: orthopaedic or cardiovascular contraindications to exercise
Statistical analysis: within groups: paired t-tests; between groups: unpaired t-tests;
strength of relationship between physiological variables: Pearson’s correlation coefficient;
P value < 0.05 significance
Participants Participants recruited from: respiratory medicine clinic

Number screened: 34
Age mean (SD), years: 66 (7) NIV group; 68 (9) control group
Gender: 0 female participants NIV group; 2 female participants control group
RV/TLC mean (SD) %: 62 (9) NIV group; 59 (15) control group
PaO2 mean (SD) kPa: 8.6 (0.9) NIV group; 8.1 (1.2) control group
PaCO2 mean (SD) kPa: 5.6 (0.7) NIV group; 5.8 (0.9) control group
Domiciliary NIV: no information provided
Long-term oxygen therapy: no information provided
Interventions NIV: proportional assist ventilation: flow assist 3.6 (0.7) cmH2 O/L/s, volume assist 12.
7 (1.5) cmH2 O/L during exercise training
Supplemental oxygen during exercise training: yes (two participants with unassisted
training; one participant with non-invasive ventilation during exercise training)
Intensity of training: initially 70% of peak work capacity, then increased progressively
by 5 watts when able to maintain the existing work rate for cycle of 30 minutes
Number of training sessions attended (/18): not reported
Programme setting: outpatient, hospital-based
Outcomes Isoload arterialised venous blood lactate concentration; maximal cycle ergometry: unas-
sisted, workload increased 5 to 10 watts/min; constant power cycle ergometry: unas-
sisted, at 70% of baseline peak work capacity
Evaluation: Baseline testing was performed on two occasions before the training pro-
gramme was begun, and on two occasions within one week of completion of the training
programme
pleted the protocol (29% dropout rate). Of the 15 randomly assigned to the control
group, 9 completed the protocol (40% dropout rate). Reasons for dropout: acute exac-
erbation of COPD (N = 4); non-compliance with the exercise programme (N = 4); non-
Hawkins 2002 (Continued)
pulmonary hospitalisation (N = 2)
Funding Peter Hawkins was funded by grant (F97/1) from the British Lung Foundation. Dimitra
Nikoletou was funded by Respironics Inc, which also provided the ventilators used in
the study
Notes Country: United Kingdom

Random sequence generation (selection Low risk Quote (from correspondence): “The en-
bias) velopes were shuffled and then numbered
in sequence”
Allocation concealment (selection bias) Low risk Quote (from report): “Patients were ran-
domised using sealed envelopes”
Quote (from correspondence): “The en-
velopes were opaque”
Quote (from correspondence): “Subjects
were randomised in groups of 6”
Comment: It may have been possible to
predict group allocation for 4/29 partic-
ipants because the randomisation blocks
were of a fixed size at a single centre and in-
vestigators were not blinded to group allo-
cation. However, as the proportion of par-
ticipants potentially affected was very low,
the overall judgement of risk of bias was
low
Blinding of participants and personnel High risk Comment: Participants and trainers would
(performance bias) not have been blinded, as sham non-inva-
All outcomes sive ventilation was not used
Blinding of outcome assessment (detection High risk Quote (from correspondence): “The inves-
bias) tigators performing the post exercise test
All outcomes were aware which group the subject was in”
group and reasons for dropping out are re-
ported. Numbers of dropouts were reason-
ably balanced between groups. Per-proto-
col analyses were performed and data re-
ported for key outcomes. An intention-to-
treat analysis was not reported
Hawkins 2002 (Continued)
were prespecified
Johnson 2002

Inclusion criteria: diagnosis of COPD; FEV1 < 50% predicted; ability to walk on a
treadmill; referred to outpatient pulmonary rehabilitation
Exclusion criteria: exertional angina; congestive cardiac failure; valvular heart disease;
uncontrolled cardiac dysrhythmias; other conditions limiting ability to exercise or use a
nasal mask
Statistical analysis: within groups: paired t-tests; between groups: unpaired t-tests; P
value < 0.05 significance
Participants Participants recruited from: referred to outpatient pulmonary rehabilitation pro-

gramme
Number screened: 39
Sample size: 11 NIV group; 11 control group; 10 heliox group
Age mean (SD), years: 69 (9) NIV group; 67 (8) control group; 72 (9) heliox group
Gender: 3 female participants NIV group; 4 female participants control group; 6 female
participants heliox group
FEV1 mean (SD) % predicted: 32 (9) NIV group; 31 (11) control group; 34 (13) heliox
group
FVC mean (SD) % predicted: 57 (15) NIV group; 53 (10) control group; 57 (16)
heliox group
RV mean (SD) % predicted: 203 (63) NIV group; 199 (73) control group; 191 (66)
heliox group
PaO2 mean (SD) mmHg: 72 (10) NIV group; 69.2 (9) control group; 70.3 (6.0) heliox
group
PaCO2 mean (SD) mmHg: 42.4 (4.3) NIV group; 43.3 (4.5) control group; 43.5 (3.
7) heliox group
Interventions NIV: bilevel support: IPAP 8 to 12 cmH2 O, EPAP 2 cmH2 O during exercise training
Control: humidified air at 10 L/min via a non-rebreather mask during exercise training
Heliox: 10 L/min of humidified heliox (79% helium, 21% oxygen) via a non-rebreather
mask during exercise training
Supplemental oxygen during exercise training: yes. Oxygen was titrated to maintain
oxygen saturation of at least 90% throughout the entire testing and training periods.
Maximum oxygen delivery flow rate during unassisted training: 2.7 ± 1.6 L/min; during
training with NIV: 2.6 ± 1.8 L/min. Information was not provided regarding the number
of participants in each group who used supplemental oxygen
Type of exercise training: treadmill
Intensity of training: 50% to 60% of maximum METS based on initial incremental
Johnson 2002 (Continued)
treadmill test, then increased (speed and grade) once 20 minutes of continuous exercise
was achieved at this level
Number of training sessions attended (/12): Quote: “Nearly all of the patients were
present for 10 sessions”
Programme setting: outpatient, centre-based
Outcomes Incremental maximal treadmill test: unassisted, workload increased 0.5 mph every 4
minutes, when predetermined maximum speed achieved, incline was increased at 3%
every 4 minutes
Evaluation: Testing was performed the week before and within the week following
completion of training
Dropouts A total of 39 participants were recruited. Of the 15 randomly assigned to NIV, 11

completed the protocol (27% dropout rate). Of the 13 randomly assigned to the control
group, 11 completed the protocol (15% dropout rate). Of the 11 randomly assigned to
Heliox, 10 completed the protocol (9% dropout rate). Reasons for dropout: exertional
angina (N = 1); congestive heart failure (N = 1); flare of chronic liver disease (N = 1);
acute exacerbation of COPD (N = 1); tibial fracture (N = 1); scheduling conflict (N =
1); non-compliance (N = 1)
Funding Funded through Brooke Army Medical Center local research funds
Notes Country: United States of America

Study author contacted: no response
Random sequence generation (selection Unclear risk Comment: No information provided

bias)
Allocation concealment (selection bias) Unclear risk Comment: No information provided
Blinding of participants and personnel High risk Quote (from report): “No attempt was
(performance bias) made to blind the Heliox group and unas-
All outcomes sisted exercise training group patients to
their training modality”
Comment: It would not have been possible
to blind participants or trainers in the NIV
training group either
Blinding of outcome assessment (detection Unclear risk No information provided regarding blind-
bias) ing of outcome assessors. This probably was
All outcomes not done
Johnson 2002 (Continued)
ably well balanced between groups. Per-
protocol analyses (not intention-to-treat
analyses) were performed for key outcomes
were prespecified
Other bias High risk Quote (from report): “Review of the pa-
tient’s exercise logs showed that they uni-
formly exercised more than the supervised
sessions, with an average total of approx-
imately four times per week. Hence, our
comparison of training modalities repre-
sented only a portion of the patients exer-
cise sessions since the others were done at
home”
Comment: Participants performed two su-
pervised sessions per week according to
group allocation (unassisted, with heliox
or with non-invasive ventilation). The un-
supervised, unassisted training at home
(without non-invasive ventilation or with-
out Heliox) may have confounded the re-
sults (contamination)
Comment: baseline difference between
groups for key outcomes (non-invasive ven-
tilation group significantly lower compared
with unassisted group for unassisted exer-
cise time and unassisted maximum work-
load)
Reuveny 2005

Inclusion criteria: diagnosis of severe COPD based on smoking history, clinical find-
ings and pulmonary function testing; FEV1 < 40% predicted and < 12% reversibility;
ventilatory limitation to exercise, defined as exercise breathing reserve < 5 L/min
Exclusion criteria: cardiovascular, orthopaedic or neuromuscular disease that could limit
exercise capacity
Statistical analysis: within groups: paired t-tests; between groups: ANOVA; linear re-
gression for differences in breathing pattern; P value < 0.05 significance
Participants Participants recruited from: no information provided

Number screened: no information provided
Gender: 1 female participant; 18 male participants
FEV1 /FVC mean (SD) %: 59 (16) NIV group; 58 (16) control group
RV/TLC mean (SD) % predicted: 164 (19) NIV group; 165 (17) control group
Long-term oxygen therapy: nocturnal oxygen used in four participants from the NIV
group and two participants from the control group
Interventions NIV: bilevel support: IPAP 7 to 10 cmH2 O, EPAP 2 cmH2 O during exercise training
Supplemental oxygen during exercise training: yes. Supplemental oxygen was provided
to 8/10 participants in the control group and 9/9 participants in the NIV group to
maintain oxygen saturation of at least 92% during training
Intensity of training: initially started at > 2 km/h based on what the participant could
maintain for 15 minutes. Speed increased at 0.2 km/h each week after participants could
maintain the target intensity for 45 minutes, with the aim of achieving 65% to 70% of
the initial maximum walking speed. Zero slope
Duration of each session: 45 minutes
Outcomes Maximal cycle ergometry: unassisted, load increased 15 watts/min

Evaluation: Testing was performed within one week before and at the end of the pro-
gramme
pleted the protocol (25% dropout rate). Reasons for dropout: failed to adjust to the mask
(N = 3). Of the 12 randomly assigned to the control group, 10 completed the protocol
(17% dropout rate). Reasons for dropout: lung transplant (N = 1); back pain (N = 1)
Funding Supported in part by a grant from the Israel Lung Association, Tel Aviv
Reuveny 2005 (Continued)
Notes Country: Israel

Study author contacted: no response
Random sequence generation (selection Unclear risk Comment: no information provided

bias)
Allocation concealment (selection bias) Unclear risk Quote (from report): “sealed envelope.”
Unsure if opaque etc
Blinding of participants and personnel High risk Quote (from report): “Although it was not
(performance bias) feasible to blind the patients or the trainers
All outcomes to the condition of their exercise training”
Blinding of outcome assessment (detection Low risk Quote (from report): “...the investigators
bias) conducting exercise testing and interpret-
All outcomes ing the exercise data did so without know-
ing to which group the patients were as-
signed”
Incomplete outcome data (attrition bias) High risk Quote (from report): “Of the 24 patients
All outcomes 5 did not complete the study: 3 from the
BiPAP group, who failed to adjust to the
mask, and 2 from the control group-one
due to lung transplant and one because of
back pain”
Comment: Total number of participants
recruited, number of dropouts from each
ably well balanced between groups. How-
ever, all dropouts in the non-invasive venti-
lation group were due to mask intolerance,
which may have introduced bias, as only
participants who could tolerate non-inva-
sive ventilation were included in the analy-
sis, as opposed to those who were allocated.
An intention-to-treat analysis was not re-
ported
Selective reporting (reporting bias) High risk Comment: Study report fails to include re-
sults for a key outcome that would be ex-
pected to have been reported for such a
study
Between-group results were not reported
Reuveny 2005 (Continued)
for post-training exercise capacity or for

most physiological outcomes. Primary
study outcome(s) were not stated. Instead,
the study authors report that certain signif-
icant changes (when compared with base-
line) were detected in the group that trained
with NIV only (not the control group)
. The only between-groups comparisons
reported were for training intensity and
change in peak exercise tidal volume
Other bias Unclear risk Quote (from report): “...no improvement

was found in the control group. This may
have been due to the relatively short twice-
weekly training, while effective protocols
reported in the literature utilized between
three and five training sessions per week”
Comment: As the control group did not
improve with pulmonary rehabilitation,
the efficacy of the rehabilitation pro-
gramme appears questionable. The group
that trained with non-invasive ventilation
did improve. However, as both trainers and
participants were not blinded to the inter-
vention, bias cannot be ruled out, although
the progression of training intensity was
standardised; this should have helped to en-
sure that participants were exposed to the
same type of training programme
Toledo 2007

Inclusion criteria: clinical and spirometric diagnosis of COPD; FEV1 < 60% predicted
and FEV1 /FVC < 70%; clinically stable for a minimum of six months
Exclusion criteria: no associated cardiovascular, orthopaedic or neuromuscular disor-
ders or reactive hypertension related to effort that would impede involvement in the
programme
Statistical analysis: within groups: Wilcoxon test; between-group comparisons: Mann-
Whitney U-test; P value < 0.05 significance
Participants Participants recruited from: referred to respiratory physical therapy service at a univer-
sity hospital
Number screened: no information provided
Gender: numbers not stated
Toledo 2007 (Continued)

Interventions NIV: bilevel support: IPAP 10 to 15 cmH2 O, EPAP 4 to 6 cmH2 O during exercise
training
Intensity of training: 70% of maximum baseline speed
Duration of each session: 30 minutes
Outcomes Incremental treadmill test, increasing 0.5 km/h every 2 minutes; blood lactate; respiratory
muscle strength
Evaluation: no information provided
Dropouts A total of 18 participants completed the protocol (NIV group N = 9, control group N
= 9). No information was given regarding dropouts
Funding No information provided
Notes Country: Brazil

Study author contacted: partial response
Random sequence generation (selection Unclear risk Comment: no information provided

bias)
Allocation concealment (selection bias) Low risk Quote (from correspondence): “...ran-
domised into 2 groups by opaque and
sealed envelopes”
Blinding of participants and personnel High risk Comment: It would not have been possible
(performance bias) to blind participants or trainers, as sham
All outcomes non-invasive ventilation was not used
Blinding of outcome assessment (detection Low risk Quote (from correspondence): “Tests were
bias) made with 3 assessors and they did not
All outcomes know the group allocation”
Incomplete outcome data (attrition bias) Unclear risk Comment: Number of dropouts from each
All outcomes group (if any) and reasons for dropping out
Toledo 2007 (Continued)
are not reported. Total number of partici-

pants recruited was stated (N = 18), and all
of the 18 participants were included in the
analysis
Selective reporting (reporting bias) High risk Comment: Study report fails to include re-
sults for a key outcome that would be ex-
pected to have been reported for such a
study
Between-group results were not reported
for post-training exercise capacity or for
most of the physiological outcomes. Pri-
mary study outcome(s) were not stated. It
is not clear whether the study was pow-
ered to detect a change between groups. In-
stead, the study authors report that certain
significant changes (when compared with
baseline) were detected in the group that
trained with non-invasive ventilation only
(not the control group). The only between-
group comparison reported was isoload lac-
tate
van ’t Hul 2006

Inclusion criteria: diagnosis of COPD based on GOLD criteria; FEV1 < 60% predicted;
breathing reserve at maximal exercise < 20% of maximum voluntary ventilation; peak
minute ventilation < 50 L/min; resting PaO2 > 60 mmHg; SpO2 at maximal exercise >
85%; 40 to 75 years of age
Statistical analysis: within groups: paired t-tests or Wilcoxon test; between groups:
independent samples t-tests or Mann-Whitney U-test; strength of associations: Pearson’s
correlation coefficient; P < 0.05 significance
Participants Participants recruited from: information not available from trial report
Number screened: information not available from trial report
Gender: 4 female participants NIV group; 1 female participant control group
FEV1 /FVC mean (SD) %: 34 (6) NIV group; 36 (8) control group
PImax cmH2 O: 58 (20) NIV group; 59 (21) control group
PEmax cmH2 O: 100 (44) NIV group; 111 (28) control group
Domiciliary NIV: nil
van ’t Hul 2006 (Continued)
Interventions NIV: inspiratory pressure support 10 cmH2 O during exercise training

Control: sham IPS 5 cmH2 O during exercise training
Intensity of training: initially 65% of peak work capacity, then increased progressively
by 5% of peak work rate when able to cycle for > 15 minutes
Number of training sessions attended (/24): Participants were allowed to miss up to
4 training sessions, provided that the training period was extended (from 8 weeks to a
maximum of 9 to 10 weeks) to ensure that each participant completed all 24 training
sessions
Program setting: outpatient, centre-based
Outcomes Incremental shuttle walk test; constant work rate cycle endurance time (75% of baseline
peak work rate); St. George’s Resiratory Questionnaire
Evaluation: baseline measurements performed within 2 weeks before the start of the
training period. Post-training measurements took place within 2 weeks following the
final training session
Dropouts A total of 37 participants were recruited. Of the 19 randomly assigned to NIV, 15

completed the protocol (21% dropout rate). Reasons for dropout: acute exacerbation
of COPD (N = 3); worsening general fatigue (N = 1). Of the 18 randomly assigned to
the control group, 14 completed the protocol (22% dropout rate). Reasons for dropout:
exacerbation of COPD (N = 3); cerebrovascular accident (N = 1)
Funding The study was supported by a grant from the Dutch Lung Foundation
Notes Country: The Netherlands

Random sequence generation (selection Low risk Quote (from correspondence): “...con-
bias) cealed envelopes and block randomisa-
tion. Each block (envelope) contained four
cards. Two cards with ’experimental con-
dition’ and two cards with ’control condi-
tion’ written on it. When a patient got to be
randomised an independent observer drew
one of the cards out of this envelope. Af-
ter four procedures the envelope was empty
and the next envelope was used, and so on”
van ’t Hul 2006 (Continued)
Allocation concealment (selection bias) Low risk Quote (from report): “Patients were ran-
domly allocated (concealed envelopes)”
Blinding of participants and personnel Low risk Quote (from report): “...not possible to
(performance bias) blind the three physiotherapists to the in-
All outcomes spiratory pressure support (IPS) intensity
patients were training with, but patients
were kept naive with respect to randomisa-
tion outcome”
Blinding of outcome assessment (detection Low risk Quote (from report): “All measurements
bias) were performed by one independent inves-
All outcomes tigator (A. van’t Hul), who was not involved
in the training and who was kept blinded
to randomisation outcome”
group and reasons for dropping out are
reported. Both intention-to-treat analyses
and per-protocol analyses were performed
for key outcomes
were prespecified
ANOVA: analysis of variance; COPD: chronic obstructive pulmonary disease; EPAP: expiratory positive airway pressure; FEV1 : forced
expiratory volume in one second; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease; IPAP:
inspiratory positive airway pressure; METS: metabolic equivalents; NIV: non-invasive ventilation; PaO2 : arterial partial pressure of
oxygen; PaCO2 : arterial partial pressure of carbon dioxide; PEmax : maximal expiratory pressure; PImax : maximal inspiratory pressure;
RCT: randomised controlled trial; RV: residual volume; SD: standard deviation; SpO2 : oxygen saturation; TLC: total lung capacity
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Allan 2009 Not exercise training
Amann 2010 Not exercise training
Ambrosino 2000 Not an RCT
(Continued)
Anonymous 2007 Not an RCT
Arad 1992 Not an RCT
Araujo 2005 Not an RCT
Bach 1992 Not an RCT
Bach 1993 Not an RCT
Baer 1989 Not an RCT
Barakat 2007 Not an RCT
Bianchi 1998 Not exercise training
Borghi-Silva 2005 Not exercise training
Borghi-Silva 2010 Wrong comparison
Boye 1994 Not NIV during exercise
Bullemer 1999 Not an RCT
Carrascossa 2010 Not exercise training
Chaturvedi 2011 Not exercise training
Chen 2012 Not COPD
Chiang 2006a Not COPD
Chiang 2006b Not exercise training
Corner 2010 Not an RCT
Costa 2006 Not an RCT
(Continued)
Costes 2003 Not an RCT
De Backer 2010 Not an RCT
den Hartog 2003 Not an RCT
Dieperink 2006 Not an RCT
Dolmage 1997 Not exercise training
Dreher 2007 Not exercise training
Dreher 2008 Not an RCT
Dreher 2009 Not exercise training
Dreher 2010 Not COPD
Duiverman 2008 Not NIV during exercise
Duiverman 2011 Not NIV during exercise
Dyer 2011 Not stable COPD
Gallagher 1989 Not COPD
Garrod 2000 Not NIV during exercise
Hernandes 2012 Not an RCT
Hernandez 2001 Not exercise training
Highcock 2003 Not exercise training
Hussain 2011 Not exercise training
Jackson 1991 Not an RCT
Keilty 1994 Not exercise training
Kleinsasser 2004 Not COPD
Kohnlein 2009 Not NIV during exercise
Kyroussis 2000 Not exercise training
Maltais 1995 Not exercise training
(Continued)
Martin 2005 Not an RCT
Medvedev 2007 Not COPD
Menadue 2009a Not exercise training
Moga 2012 Not an RCT
Monteiro 2012 Not an RCT
Nicolini 2013 Not exercise training
O’Donnell 1988a Not exercise training
O’Donnell 1988b Not exercise training
Oliveira 2010 Not exercise training
Padkao 2010 Not exercise training
Pepin 2010 Not an RCT
Pessoa 2012 Not exercise training
Petrof 1990 Not exercise training
Pires Di Lorenzo 2003 Wrong comparison
Poggi 2006 Not exercise training
Polkey 1996 Not exercise training
Polkey 2000 Not exercise training
Poon 1987 Not an RCT
Porszasz 2013 Not exercise training
Puhan 2004 Not an RCT
Revill 2000 Not exercise training
Ricci 2013 Not an RCT
Rochester 2013 Not an RCT
Rodrigues 2013 Not exercise training
(Continued)
Schmidt 1999 Not an RCT
Schonhofer 2003 Not an RCT
Schonhofer 2008 Not an RCT
Skobel 2011 Not an RCT
Soo Hoo 2003 Not an RCT
Spruit 2007 Not an RCT
van’t Hul 2002 Not an RCT
van’t Hul 2004 Not exercise training
Vitacca 2006 Not exercise training
Walterspacher 2013 Not exercise training
Wibmer 2013 Not NIV during exercise
Wijkstra 2011 Not an RCT
ZuWallack 2008 Not an RCT
DATA AND ANALYSES
Comparison 1. Non-invasive ventilation during exercise training versus exercise training alone or exercise training
with sham non-invasive ventilation
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Exercise capacity: peak cycle 3 57 Mean Difference (IV, Fixed, 95% CI) 6.34 [-1.66, 14.34]
work rate (watts)
2 Exercise capacity: peak VO2 2 37 Mean Difference (IV, Fixed, 95% CI) 0.12 [-0.08, 0.31]
(L/min)
3 Exercise capacity: percentage 4 Mean Difference (IV, Fixed, 95% CI) Subtotals only
change
3.1 Percentage change peak 3 60 Mean Difference (IV, Fixed, 95% CI) 17.01 [6.83, 27.19]
work rate
3.2 Percentage change 2 48 Mean Difference (IV, Fixed, 95% CI) 58.66 [3.72, 113.60]
constant work rate endurance
time
4 Exercise capacity: constant work 2 48 Mean Difference (IV, Fixed, 95% CI) 3.62 [-0.17, 7.41]
rate cycle endurance time
(minutes)
5 Health-related quality of 2 Mean Difference (Random, 95% CI) Subtotals only
life: St George’s Respiratory
Questionnaire
5.1 SGRQ: total score (points) 2 48 Mean Difference (Random, 95% CI) 2.45 [-2.30, 7.20]
5.2 SGRQ: symptoms 2 48 Mean Difference (Random, 95% CI) 0.87 [-10.19, 11.93]
(points)
5.3 SGRQ: activity (points) 2 48 Mean Difference (Random, 95% CI) 0.05 [-14.92, 15.02]
5.4 SGRQ: impacts (points) 2 48 Mean Difference (Random, 95% CI) 0.11 [-6.82, 7.05]
6 Training intensity: final training 3 67 Mean Difference (IV, Random, 95% CI) 13.31 [0.05, 26.57]
session (% baseline peak work
capacity)
7 Physiological outcomes: isoload 2 37 Mean Difference (IV, Fixed, 95% CI) -0.97 [-1.58, -0.36]
lactate (mmol/L)
8 Physiological outcomes: peak 3 56 Mean Difference (IV, Random, 95% CI) -0.35 [-1.10, 0.41]
exercise lactate (mmol/L)
9 Physiological outcomes: isotime 3 53 Mean Difference (Fixed, 95% CI) -0.08 [-2.82, 2.67]
exercise minute ventilation
(L/min)
10 Physiological outcomes: peak 3 47 Mean Difference (Fixed, 95% CI) 2.68 [-2.02, 7.37]
exercise minute ventilation
(L/min)
11 Physiological outcomes: change 2 38 Mean Difference (Fixed, 95% CI) 0.08 [-0.09, 0.24]
in VO2 at anaerobic threshold
(L/min)
12 Dyspnoea: isotime exercise 3 56 Mean Difference (Fixed, 95% CI) -0.18 [-1.09, 0.72]
dyspnoea (Borg scale)
13 Dropouts 5 151 Odds Ratio (M-H, Fixed, 95% CI) 1.26 [0.61, 2.59]
Analysis 1.1. Comparison 1 Non-invasive ventilation during exercise training versus exercise training alone
or exercise training with sham non-invasive ventilation, Outcome 1 Exercise capacity: peak cycle work rate
(watts).
Review: Non-invasive ventilation during exercise training for people with chronic obstructive pulmonary disease
Comparison: 1 Non-invasive ventilation during exercise training versus exercise training alone or exercise training with sham non-invasive ventilation
Outcome: 1 Exercise capacity: peak cycle work rate (watts)
Mean Mean
Study or subgroup NIV Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Bianchi 2002 9 107.8 (36) 10 101.3 (25.6) 8.0 % 6.50 [ -21.87, 34.87 ]
Hawkins 2002 10 57 (13.2) 9 51.7 (10.3) 57.1 % 5.30 [ -5.29, 15.89 ]
Reuveny 2005 9 67 (13) 10 59 (17) 35.0 % 8.00 [ -5.53, 21.53 ]
Total (95% CI) 28 29 100.0 % 6.34 [ -1.66, 14.34 ]

Heterogeneity: Chi2 = 0.09, df = 2 (P = 0.95); I2 =0.0%
Test for overall effect: Z = 1.55 (P = 0.12)
Test for subgroup differences: Not applicable
-50 -25 0 25 50
Higher with control Higher with NIV
or exercise training with sham non-invasive ventilation, Outcome 2 Exercise capacity: peak VO2 (L/min).
Outcome: 2 Exercise capacity: peak VO2 (L/min)
Mean Mean
Reuveny 2005 9 1.011 (0.284) 10 0.93 (0.223) 73.1 % 0.08 [ -0.15, 0.32 ]
Toledo 2007 9 1.3 (0.3) 9 1.1 (0.5) 26.9 % 0.20 [ -0.18, 0.58 ]
Total (95% CI) 18 19 100.0 % 0.12 [ -0.08, 0.31 ]

-2 -1 0 1 2
or exercise training with sham non-invasive ventilation, Outcome 3 Exercise capacity: percentage change.
Outcome: 3 Exercise capacity: percentage change
Mean Mean
1 Percentage change peak work rate

Hawkins 2002 10 32.9 (17.4) 9 14.5 (10.1) 64.8 % 18.40 [ 5.76, 31.04 ]
Johnson 2002 11 50 (35.4) 11 38 (35) 12.0 % 12.00 [ -17.42, 41.42 ]
Reuveny 2005 9 24.5 (20.7) 10 8.8 (26.2) 23.2 % 15.70 [ -5.43, 36.83 ]
Subtotal (95% CI) 30 30 100.0 % 17.01 [ 6.83, 27.19 ]

2 Percentage change constant work rate endurance time
Hawkins 2002 10 123 (97.2) 9 74 (50.1) 64.2 % 49.00 [ -19.56, 117.56 ]
van ’t Hul 2006 15 164 (124) 14 88 (128) 35.8 % 76.00 [ -15.83, 167.83 ]
Subtotal (95% CI) 25 23 100.0 % 58.66 [ 3.72, 113.60 ]

-200 -100 0 100 200

or exercise training with sham non-invasive ventilation, Outcome 4 Exercise capacity: constant work rate cycle
endurance time (minutes).
Outcome: 4 Exercise capacity: constant work rate cycle endurance time (minutes)
Mean Mean
Hawkins 2002 10 17.2 (9.4) 9 13 (10.8) 17.2 % 4.20 [ -4.95, 13.35 ]
van ’t Hul 2006 15 7.4 (5.4) 14 3.9 (6) 82.8 % 3.50 [ -0.66, 7.66 ]
Total (95% CI) 25 23 100.0 % 3.62 [ -0.17, 7.41 ]

-20 -10 0 10 20
or exercise training with sham non-invasive ventilation, Outcome 5 Health-related quality of life: St George’s
Respiratory Questionnaire.
Outcome: 5 Health-related quality of life: St George’s Respiratory Questionnaire
Mean Mean
Study or subgroup NIV Control Mean Difference (SE) Difference Weight Difference
N N IV,Random,95% CI IV,Random,95% CI
1 SGRQ: total score (points)

Bianchi 2002 9 10 2.8 (2.7) 80.6 % 2.80 [ -2.49, 8.09 ]
van ’t Hul 2006 15 14 1 (5.5) 19.4 % 1.00 [ -9.78, 11.78 ]
Subtotal (95% CI) 24 24 100.0 % 2.45 [ -2.30, 7.20 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.09, df = 1 (P = 0.77); I2 =0.0%
2 SGRQ: symptoms (points)
Bianchi 2002 9 10 3.45 (7.78) 52.6 % 3.45 [ -11.80, 18.70 ]
van ’t Hul 2006 15 14 -2 (8.2) 47.4 % -2.00 [ -18.07, 14.07 ]
Subtotal (95% CI) 24 24 100.0 % 0.87 [ -10.19, 11.93 ]

3 SGRQ: activity (points)
Bianchi 2002 9 10 7.3 (4.5) 52.6 % 7.30 [ -1.52, 16.12 ]
van ’t Hul 2006 15 14 -8 (5.7) 47.4 % -8.00 [ -19.17, 3.17 ]
Subtotal (95% CI) 24 24 100.0 % 0.05 [ -14.92, 15.02 ]

Heterogeneity: Tau2 = 90.67; Chi2 = 4.44, df = 1 (P = 0.04); I2 =77%
4 SGRQ: impacts (points)
Bianchi 2002 9 10 0.15 (4.1) 74.5 % 0.15 [ -7.89, 8.19 ]
van ’t Hul 2006 15 14 0 (7) 25.5 % 0.0 [ -13.72, 13.72 ]
Subtotal (95% CI) 24 24 100.0 % 0.11 [ -6.82, 7.05 ]

-50 -25 0 25 50
Favours NIV Favours control
or exercise training with sham non-invasive ventilation, Outcome 6 Training intensity: final training session (%
baseline peak work capacity).
Outcome: 6 Training intensity: final training session (% baseline peak work capacity)
Mean Mean
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
Bianchi 2002 9 88.8 (14) 10 88.8 (12.3) 33.8 % 0.0 [ -11.91, 11.91 ]
Hawkins 2002 10 111.7 (14) 9 92.9 (6) 37.5 % 18.80 [ 9.28, 28.32 ]
van ’t Hul 2006 15 97 (26.5) 14 75.2 (13.9) 28.8 % 21.80 [ 6.54, 37.06 ]
Total (95% CI) 34 33 100.0 % 13.31 [ 0.05, 26.57 ]

-100 -50 0 50 100

or exercise training with sham non-invasive ventilation, Outcome 7 Physiological outcomes: isoload lactate
(mmol/L).
Outcome: 7 Physiological outcomes: isoload lactate (mmol/L)
Mean Mean
Hawkins 2002 10 2.09 (0.38) 9 2.61 (1.56) 33.6 % -0.52 [ -1.57, 0.53 ]
Toledo 2007 9 1.3 (0.7) 9 2.5 (0.9) 66.4 % -1.20 [ -1.94, -0.46 ]
Total (95% CI) 19 18 100.0 % -0.97 [ -1.58, -0.36 ]

Heterogeneity: Chi2 = 1.08, df = 1 (P = 0.30); I2 =7%
-4 -2 0 2 4
Lower with NIV Lower with control
or exercise training with sham non-invasive ventilation, Outcome 8 Physiological outcomes: peak exercise
lactate (mmol/L).
Outcome: 8 Physiological outcomes: peak exercise lactate (mmol/L)
Mean Mean
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
Hawkins 2002 10 2.9 (0.83) 9 3 (1.06) 32.3 % -0.10 [ -0.96, 0.76 ]
Reuveny 2005 9 3.5 (0.92) 10 3.35 (0.84) 34.5 % 0.15 [ -0.65, 0.95 ]
Toledo 2007 9 1.8 (0.8) 9 2.9 (1) 33.2 % -1.10 [ -1.94, -0.26 ]
Total (95% CI) 28 28 100.0 % -0.35 [ -1.10, 0.41 ]

-4 -2 0 2 4
or exercise training with sham non-invasive ventilation, Outcome 9 Physiological outcomes: isotime exercise
minute ventilation (L/min).
Outcome: 9 Physiological outcomes: isotime exercise minute ventilation (L/min)
Mean Mean
N N IV,Fixed,95% CI IV,Fixed,95% CI
Bianchi 2002 9 10 0.375 (1.85) 57.4 % 0.38 [ -3.25, 4.00 ]
Hawkins 2002 10 9 0.13 (2.73) 26.3 % 0.13 [ -5.22, 5.48 ]
van ’t Hul 2006 15 0 -2 (3.47) 16.3 % -2.00 [ -8.80, 4.80 ]
Total (95% CI) 34 19 100.0 % -0.08 [ -2.82, 2.67 ]

-20 -10 0 10 20
or exercise training with sham non-invasive ventilation, Outcome 10 Physiological outcomes: peak exercise
minute ventilation (L/min).
Outcome: 10 Physiological outcomes: peak exercise minute ventilation (L/min)
Mean Mean
Bianchi 2002 9 10 3.35 (7.6) 10.0 % 3.35 [ -11.55, 18.25 ]
Hawkins 2002 10 9 2.4 (3.1) 59.8 % 2.40 [ -3.68, 8.48 ]
Reuveny 2005 9 0 3 (4.36) 30.2 % 3.00 [ -5.55, 11.55 ]
Total (95% CI) 28 19 100.0 % 2.68 [ -2.02, 7.37 ]

-20 -10 0 10 20
or exercise training with sham non-invasive ventilation, Outcome 11 Physiological outcomes: change in VO2 at
anaerobic threshold (L/min).
Outcome: 11 Physiological outcomes: change in VO2 at anaerobic threshold (L/min)
Mean Mean
Bianchi 2002 9 10 0.22 (0.18) 21.2 % 0.22 [ -0.13, 0.57 ]
Reuveny 2005 9 10 0.036 (0.09348) 78.8 % 0.04 [ -0.15, 0.22 ]
Total (95% CI) 18 20 100.0 % 0.08 [ -0.09, 0.24 ]

-0.5 -0.25 0 0.25 0.5

or exercise training with sham non-invasive ventilation, Outcome 12 Dyspnoea: isotime exercise dyspnoea
(Borg scale).
Outcome: 12 Dyspnoea: isotime exercise dyspnoea (Borg scale)
Mean Mean
Bianchi 2002 9 10 -0.25 (1) 21.2 % -0.25 [ -2.21, 1.71 ]
Hawkins 2002 10 9 -0.4 (0.71) 42.1 % -0.40 [ -1.79, 0.99 ]
Toledo 2007 9 9 0.1 (0.76) 36.7 % 0.10 [ -1.39, 1.59 ]
Total (95% CI) 28 28 100.0 % -0.18 [ -1.09, 0.72 ]

-4 -2 0 2 4
or exercise training with sham non-invasive ventilation, Outcome 13 Dropouts.
Outcome: 13 Dropouts
Study or subgroup NIV Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Bianchi 2002 9/18 5/15 20.7 % 2.00 [ 0.49, 8.24 ]
Hawkins 2002 4/14 6/15 31.4 % 0.60 [ 0.13, 2.84 ]
Johnson 2002 4/15 2/13 11.9 % 2.00 [ 0.30, 13.26 ]
Reuveny 2005 3/12 2/12 11.4 % 1.67 [ 0.22, 12.35 ]
van ’t Hul 2006 4/19 4/18 24.6 % 0.93 [ 0.20, 4.47 ]
Total (95% CI) 78 73 100.0 % 1.26 [ 0.61, 2.59 ]

Total events: 24 (NIV), 19 (Control)
0.02 0.1 1 10 50
ADDITIONAL TABLES
Table 1. Results for individual studies
Outcome or subgroup Study Participants Effect estimate

(mean difference (95% confidence interval))
Exercise capacity Exercise capacit
Peak work rate (metabolic Johnson 2002 22 0.2 (-0.8 to 1.2)

equivalents (METS))
Peak treadmill walking speed Toledo 2007 18 0 (-0.9 to 0.9)

(km/h)
Peak oxygen consumption (% Reuveny 2005 19 21 (5 to 37)

change)
Incremental shuttle walk test van ’t Hul 2006 29 17.0 (-2.4 to 36.4)
(m)
Table 1. Results for individual studies (Continued)
Incremental shuttle walk test van ’t Hul 2006 29 13 (2 to 24)

(% change)
Six-minute walk test (m) Bianchi 2002 19 4.3 (-64.1 to 72.7)
Incremental treadmill test dis- Toledo 2007 18 30.9 (-250.6 to 312.4)

tance (m)
Training intensity Training intensi
Peak cycle training intensity Hawkins 2002 19 5.0 (-4.0 to 14.0)

(W)
Peak treadmill training speed Reuveny 2005 19 0 (-0.5 to 0.5)

(km/h)
Physiological outcomes Physiological ou
Peak exercise minute ventila- Reuveny 2005 19 10.7 (-4.0 to 25.5)

tion (L/min)
Peak exercise aerobic threshold Reuveny 2005 19 6 (-8 to 21)

(% change)
Peak exercise oxygen pulse (mL/ Reuveny 2005 19 1.0 (-0.8 to 2.8)
beat)
Table 2. Sensitivity analysis
Outcome Initial analysis Sensitivity analysis
Effect estimate Study Reason for removal Included Effect estimate

removed studies
Exercise capacity Exercise capacit
Peak cycle work rate 6.34 (-1.66 to 14. a Disease severity b,d 6.33 (-2.02 to 14.67)
(watts) 34)
Peak cycle work rate 6.34 (-1.66 to 14. d Allocation conceal- a,b 5.45 (-4.48 to 15.37)
(watts) 34) ment
c b,d
Peak work rate (% 17 (7 to 27) Baseline differences 18 (7 to 29)
change)
Training intensity Training intensi
Table 2. Sensitivity analysis (Continued)
a b,f
Training intensity 13 (1 to 27) Disease severity 20 (12 to 28)
(% change)
Training intensity 13 (1 to 27) f Blinding a,b 10 (-9 to 28)

(% change)
Physiological outcomes Physiological ou
Isotime exercise VE -0.08 (-2.82 to 2. a Disease severity b,f -0.68 (-4.89 to 3.52)
(L/min) 67)
Peak exercise VE (L/ 2.68 (-2.02 to 7.37) a Disease severity b,d 2.60 (-2.35 to 7.55)
min)
Isotime exercise VE -0.08 (-2.82 to 2. f Blinding a,b 0.30 (-2.70 to 3.30)

(L/min) 67)
Peak exercise La -0.35 (-1.10 to 0. d Allocation conceal- b,e -0.61 (-1.59 to 0.37)
(mmol/L) 41) ment
d a,b
Peak exercise VE (L/ 2.68 (-2.02 to 7.37) Allocation conceal- 2.54 (-3.09 to 8.16)
min) ment
Peak exercise La -0.35 (-1.10 to 0. e Programme b,d 0.04 (-0.55 to 0.62)

(mmol/L) 41) duration
Dyspnoea Dyspnoea
a b,e
Isotime dyspnoea -0.33 (-0.83 to 0. Disease severity -0.34 (-0.86 to 0.17)
(Borg) 16)
Isotime dyspnoea -0.33 (-0.83 to 0. e Programme a,b -0.39 (-0.92 to 0.14)

(Borg) 16) duration
Dropouts Dropouts
a b,c,d,f
Dropouts OR 1.26 (0.61 to 2. Disease severity OR 1.07 (0.46 to 2.
59) 48)
Effect estimate is presented as mean difference (95% confidence interval) unless otherwise indicated;a Bianchi 2002; b Hawkins 2002;
c Johnson 2002; d Reuveny 2005; e Toledo 2007; f van ’t Hul 2006.
La: lactate; OR: odds ratio; VE: minute ventilation.
APPENDICES
Appendix 1. Search strategies

A randomised controlled trial (RCT) filter was applied to all database searches except for CENTRAL and PEDro, as these databases
contain only controlled trials and systematic reviews. The filter was developed by grouping database-specific terms for ‘RCT’ using
‘or.’ Then, database-specific search terms for ‘NIV’ were grouped using ‘or,’ database-specific search terms for ‘Exercise’ were grouped
using ‘or’ and database-specific search terms for ‘COPD’ were grouped using ‘or.’ Afterwards, the following four search strategies
were used for each database: (I) ‘RCT’ and ‘COPD’ and ‘NIV’ and ‘Exercise’; (ii) ‘RCT’ and ‘COPD’ and ‘NIV’; (iii) ‘RCT’ and
‘COPD’ and ‘Exercise’; and (iv) ‘NIV’ and ‘Exercise.’ We searched the following databases via Ovid: EMBASE; MEDLINE; Allied and
Complementary Medicine Database (AMED); Cumulative Index to Nursing and Allied Health Literature (CINAHL); PsycINFO. See
below for detailed search strategies for each database.
Allied and Complementary Medicine Database (AMED)
RCT NIV Exercise COPD
Search #1 Randomized controlled #11 Respiration, Artificial/ #15 Exercise/ or Exercise #24 Pulmonary Disease,
terms trial.pt. or Positive-Pressure Respi- Therapy/ or Exercise Test/ Chronic Obstructive/
#2 Controlled clinical trial. ration/ or Exercise Tolerance/ #25 Lung diseases obstruc-
pt. #12 Intermittent Positive- #16 “Physical Education tive/
#3 Randomized.ab. Pressure and Training”/ #26 #24 or #25
#4 Placebo.ab. Ventilation/ #17 Rehabilitation/
#5 Randomly.ab. #13 Ventilators mechani- #18 Physical Fitness/ or
#6 Trial.ab. cal/ Physical
#7 Groups.ab. #14 #11 or #12 or #13 Endurance/
#8 #1 or #2 or #3 or #4 or #19 Ergometry/
#5 or #6 or #7 #20 Walking/
#9 (animals not (humans #21 Bicycling/
and animals)).sh. #22 Upper Extremity/
#10 #8 not #9 #23 #15 or #16 or #17 or #
18 or #19 or #20 or #21 or
#22
The following combinations of groups of search terms using ‘and’ was performed: RCT (#10) and COPD (#26) and NIV (#14) and
Exercise (#23); RCT (#10) and COPD (#26) and NIV (#14); RCT (#10) and COPD (#26) and Exercise (#23); NIV (#14) and
Exercise (#23).
Cochrane Central Register of Controlled Trials (CENTRAL)
This search was performed in addition to the search conducted by the Cochrane Airways Group Trials Search Co-ordinator. CENTRAL
is a database of randomised trials and systematic reviews; therefore a randomised controlled trial filter was not required.
NIV Exercise COPD
Search #1 Non-invasive ventilation #8 Exercise #9 COPD

terms #2 NIV
#3 Proportional assist ventilation
#4 PAV
#5 Inspiratory pressure support
#6 IPS
#7 #1 or #2 or #3 or #4 or #5 or #6
The following combinations of groups of search terms using ‘and’ was performed: COPD (#9) and NIV (#7) and Exercise (#8); COPD
(#9) and NIV (#7); COPD (#9) and Exercise (#8); NIV (#7) and Exercise (#8).
Cumulative Index to Nursing and Allied Health Literature (CINAHL)
Search #1 Clinical trials or placebo #2 Positive pressure venti- #5 Exercise #18 Lung diseases, obstruc-
terms lation #6 Physical endurance tive
#3 Ventilators, mechanical #7 Endurance
#4 #2 or #3 #8 Rehabilitation
#9 Rehabilitation exercise
#10 Conditioning
#11 Cardiopulmonary
#12 Ergometry
#13 Treadmills
#14 Exercise test
#15 Upper extremity
#16 Upper extremity exer-
cises
#17 #5 or #6 or #7 or #8 or
#9 or #10 or #11 or #12 or
#13 or #14 or #15 or #16
Exercise (#17); RCT (#1) and COPD (#18) and NIV (#4); RCT (#1) and COPD (#18) and Exercise (#17); NIV (#4) and Exercise
(#17).
EMBASE
Search #1 Random$ #17 Artificial ventilation #22 Exercise #33 Chronic obstructive
terms #2 Factorial$ #18 Assisted ventilation #23 Arm exercise pulmonary disease
#3 Crossover$ #19 Intermittent positive #24 Exercise test
#4 Cross over$ pressure ventilation #25 Exercise tolerance
#5 Cross-over$ #20 Pressure support venti- #26 Treadmill exercise
#6 Placebo$ lation #27 Leg exercise
#7 Doubl$ adj blind$ #21 #17 or #18 or #19 or #28 Pulmonary rehabilita-
#8 Singl$ adj blind$ #20 tion
#9 Assign$ #29 Rehabilitation
#10 Allocate$ #30 Training
#11 Volunteer$ #31 Ergometry
#12 Crossover-procedure #32 #22 or #23 or #24 or #
#13 Double-blind proce- 25 or #26 or #27 or #28 or
dure #29 or #30 or #31
#14 Single-blind proce-
dure
#15 Randomized
controlled trial
#16 #1 or #2 or #3 or #4 or
(Continued)
#5 or #6 or #7 or #8 or #9
or #10 or #11 or #12 or #
13 or #14 or #15
Exercise (#32).
Latin American and Caribbean Health Science Information Database (LILACS)
Search #1 Random$ #5 Respiration, artificial #6 Exercise$ #15 COPD

terms #2 Placebo$ #7 Physical$ #16 COAD
#3 Trial$ #8 Train$ #17 DPOC
#4 #1 or #2 or #3 #9 Rehabilitat$ #18 Emphysema$
#10 Conditioning #19 Bronchit
#11 Ergometry #20 #15 or #16 or #17 or #
#12 Treadmill 18 or #19
#13 Endurance
#14 #6 or #7 or #8 or #9 or
#10 or #11 or #12 or #13
(#14).
MEDLINE
terms trial.pt. or Positive-Pressure Respi- Therapy/or Exercise Test/ Chronic Obstructive
#2 Controlled clinical trial. ration or Exercise Tolerance
pt. #12 Intermittent Positive- #15 “Physical Education
#3 Randomized.ab. Pressure Ventilation and Training”
#4 Placebo.ab. #13 #11 or #12 #16 Rehabilitation
#5 Randomly.ab. #17 Physical Fitness/or
#6 Trial.ab. Physical Endurance
#7 Groups.ab. #18 Ergometry
#8 #1 or #2 or #3 or #4 or #19 Walking
#5 or #6 or #7 #20 Bicycling
#9 (animals not (humans #21 Upper Extremity
and animals)).sh. #22 #14 or #15 or #16 or #
#10 #8 not #9 17 or #18 or #19 or #20 or
#21
Exercise (#22).
PEDro
PEDro is a database of randomised trials and systematic reviews; therefore a randomised controlled trial filter was not required. PEDro
was searched with the following terms: COPD and NIV or pressure support or ventilation and exercise or training; COPD and NIV
or pressure support or ventilation; NIV or pressure support or ventilation and exercise or training; NIV and exercise.
PsycINFO
terms trial.pt. or Positive-Pressure Respi- Therapy/ or Exercise Test/ Chronic Obstructive
#2 Controlled clinical trial. ration or Exercise Tolerance #26 Lung diseases obstruc-
pt. #12 Intermittent Positive- #17 “Physical Education tive
#3 Randomized.ab. Pressure Ventilation and Training” #27 Exp Lung Disorders
#4 Placebo.ab. #13 Ventilators mechanical #18 Rehabilitation #28 #25 or #26 or #27
#5 Randomly.ab. #14 Exp Artificial Respira- #19 Physical Fitness/ or
#6 Trial.ab. tion Physical Endurance
#7 Groups.ab. #15 #11 or #12 or #13 or #20 Ergometry
#8 #1 or #2 or #3 or #4 or #14 #21 Walking
#5 or #6 or #7 #22 Bicycling
#9 (animals not (humans #23 Upper Extremity
and animals)).sh. #24 #16 or #17 or #18 or #
#10 #8 not #9 19 or #20 or #21 or #22 or
#23
Exercise (#24).
PubMed
Search #1 Randomized controlled #9 Respiration, artificial #13 Exercise #26 Pulmonary disease,
terms trial #10 Positive pressure respi- #14 Exercise test chronic obstructive
#2 Controlled clinical trial ration #15 Exercise therapy
#3 Randomized #11 Intermittent positive- #16 Exercise tolerance
#4 Placebo pressure ventilation #17 Physical education and
#5 Randomly #12 #9 or #10 or #11 training
#6 Trial #18 Rehabilitation
#7 Groups #19 Physical endurance
#8 #1 or #2 or #3 or #4 or #20 Physical fitness
#5 or #6 or #7 #21 Ergometry
#22 Walking
#23 Bicycling
#24 Upper extremity
(Continued)
#25 #13 or #14 or #15 or #

16 or #17 or #18 or #19 or
#20 or #21 or #22 or #23
or #24
(#25).
Appendix 2. Summary of characteristics of included studies
Bianchi 2002 Hawkins 2002 Johnson 2002 Reuveny 2005 Toledo 2007 van ’t Hul 2006
Sample size 19 19 22 19 18 29
Disease severity Moderate to se- Very severe Severe to very se- Severe to very se- Severe to very se- Severe
vere vere vere vere
Setting Outpatient, hos- Outpatient, hos- Outpatient, cen- Outpatient, cen- Outpatient, cen- Outpatient, cen-
pital-based pital-based tre-based tre-based tre-based tre-based
Programme 6 weeks 6 weeks 6 weeks 8 weeks 12 weeks 8 weeks

length
Supervised ses- 3 3 2 2 3 3
sions/wk
Session 30 minutes 30 minutes 20 minutes 45 minutes 30 minutes 45 minutes

duration
Type of exercise Cycling Cycling Treadmill Treadmill Treadmill Cycling
Training inten- 50% to 70% 70% peak work 50% to 65% to 70% 70% baseline 65% peak work
sity peak work capac- capacity 60% maximum initial maximum walk speed capacity
ity METs walking speed
Comparison Unassisted ver- Unassisted ver- Unassisted ver- Unassisted ver- Unassisted ver- Sham NIV ver-
sus NIV sus NIV sus NIV sus NIV sus NIV sus NIV
NIV mode PAV PAV Bilevel Bilevel Bilevel IPS
NIV settings FA: 3.5 (1.6) FA: 3.6 (0.7) IPAP: 8 to 12 IPAP: 7 to 10 IPAP: 10 to 15 IPS: 5 versus
cmH2 O/L/s cmH2 O/L/s cmH2 O cmH2 O cmH2 O IPS: 10 cmH2 O
VA: 6.6 (2.2) VA: 12.7 (1.5) EPAP: 2 EPAP: 2 EPAP: 4 to 6 EPAP: 0
cmH2 O/L cmH2 O/L cmH2 O cmH2 O cmH2 O cmH2 O
CPAP: 2 CPAP: 0
cmH2 O
CPAP: continuous positive airway pressure; EPAP: expiratory positive airway pressure; FA: flow assist; IPAP: inspiratory positive airway
pressure; IPS: inspiratory pressure support; METs: metabolic equivalents; NIV: non-invasive ventilation; PAV: proportional assist
ventilation; VA: volume assist.
CONTRIBUTIONS OF AUTHORS
Collette Menadue: initiation and writing of protocol and manuscript, data extraction and analysis.
Amanda Piper: protocol development, data extraction, manuscript review.
Alex van’t Hul: protocol development, manuscript review.
Keith Wong: protocol development, data extraction, manuscript review.
DECLARATIONS OF INTEREST
Amanda Piper has received honoraria for educational presentations conducted on behalf of Respironics, Australia; ResMed, Australia; and
Weinmann, Germany. She has also received a grant from the ResMed Foundation. The sleep laboratory of Collette Menadue, Amanda
Piper and Keith Wong has previously received industry-sponsored project grants from ResMed, Australia, and positive airway pressure
equipment for other research projects from Philips Respironics, Australia; Air Liquide, Australia; and MayoHealthcare, Australia. Alex
van’t Hul is an author of one of the studies included in the present review.
SOURCES OF SUPPORT
Internal sources
• Royal Prince Alfred Hospital, Australia.
External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The following changes were made to the published protocol (Menadue 2009b) during the review process: an addition was made to the
criteria for the types of interventions that were eligible for inclusion in the review whereby studies that involved the use of nocturnal NIV
were included only if both the actively treated group and the control group received nocturnal NIV; rather than data extraction being
performed by one review author and verified by another review author, data from the included studies were extracted independently
by two review authors; post training outcome data were only extracted if study participants were evaluated off NIV (e.g. unassisted
test of exercise capacity); when dichotomous data were combined, the treatment effect was defined as the OR with 95% CI; if ITT
analyses were not reported, data from the per-protocol analyses were extracted for use in the meta-analysis; a fixed effect model was
used for analyses with I2 less than 30%, otherwise a random effects model was used; ventilator settings (including level of ventilatory
assistance and mode of ventilation) were added as a factor to be considered for subgroup analyses; sensitivity analyses were performed
for outcomes that included data from studies for which baseline differences between groups were accounted for by using change from
baseline data rather than post intervention data. In addition, a summary of findings table was presented. Both the summary of findings
table and the outcomes presented in the table were not planned a priori.
INDEX TERMS
Medical Subject Headings (MeSH)

∗ Noninvasive Ventilation; Exercise Tolerance [∗ physiology]; Forced Expiratory Volume [physiology]; Physical Conditioning, Human
[∗ methods; physiology]; Pulmonary Disease, Chronic Obstructive [physiopathology; ∗ rehabilitation]; Randomized Controlled Trials
as Topic
MeSH check words

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Non-invasive ventilation during exercise training for people

Menadue C, Piper AJ, van ’t Hul AJ, Wong KK

Menadue C, Piper AJ, van ’t Hul AJ, Wong KK.

Non-invasive ventilation during exercise training for people

Collette Menadue1 , Amanda J Piper1,2 , Alex J van ’t Hul3 , Keith K Wong1,2

Editorial group: Cochrane Airways Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Patient or population: people with chronic obstructive pulm onary disease

Assumed risk Corresponding risk

Exercise training alone Non- invasive ventila-

Physiolog- Physiolog- M ean physiolog- -0.97 m m ol/ L (-1.58 to 37 ⊕⊕⊕

GRADE Working Group grades of evidence.

could have indirectly af f ected this outcom e.

Description of the intervention

Studies with multiple treatment groups

Two review authors (CM and AJP) independently selected studies

Three studies (Bianchi 2002; Hawkins 2002; van ’t Hul 2006)

Several sensitivity analyses were conducted (Table 2). First, anal-

AUTHORS’ CONCLUSIONS ACKNOWLEDGEMENTS

Characteristics of included studies [ordered by study ID]

Methods Study design: parallel randomised controlled trial

Participants Participants recruited from: referred to outpatient multi-disciplinary pulmonary reha-

Funding No information provided

Notes Country: Italy

Risk of bias Risk of bias

Bias Authors’ judgement Support for judgement

Other bias Low risk None evident

Methods Study design: parallel randomised controlled trial

Participants Participants recruited from: respiratory medicine clinic

Notes Country: United Kingdom

Risk of bias Risk of bias

Bias Authors’ judgement Support for judgement

Other bias Low risk None evident

Methods Study design: parallel randomised controlled trial

Participants Participants recruited from: referred to outpatient pulmonary rehabilitation pro-

Dropouts A total of 39 participants were recruited. Of the 15 randomly assigned to NIV, 11

Notes Country: United States of America

Risk of bias Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Comment: No information provided

Allocation concealment (selection bias) Unclear risk Comment: No information provided

Methods Study design: parallel randomised controlled trial

Participants Participants recruited from: no information provided

Outcomes Maximal cycle ergometry: unassisted, load increased 15 watts/min

Notes Country: Israel

Risk of bias Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Comment: no information provided

for post-training exercise capacity or for

Other bias Unclear risk Quote (from report): “...no improvement

Methods Study design: parallel randomised controlled trial

Domiciliary NIV: no information provided

Funding No information provided

Notes Country: Brazil

Risk of bias Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Comment: no information provided

are not reported. Total number of partici-

Other bias Low risk None evident

van ’t Hul 2006

Methods Study design: parallel randomised controlled trial