NEED A PERFECT PAPER? PLACE YOUR FIRST ORDER AND SAVE 15% USING COUPON:

Research Study Evaluation – Cystic Fibrosis PLEASE READ FULL INSTRUCTIONS. NO PLAGIARISM! NO QUOTES, MUST PARAPHRASE. I WILL CHECK FOR RECYCLED WORK AND PL

Research Study Evaluation – Cystic Fibrosis PLEASE READ FULL INSTRUCTIONS. NO PLAGIARISM! NO QUOTES, MUST PARAPHRASE. I WILL CHECK FOR RECYCLED WORK AND PL

Click here to Order a Custom answer to this Question from our writers. It’s fast and plagiarism-free.

Research Study Evaluation – Cystic Fibrosis PLEASE READ FULL INSTRUCTIONS. NO PLAGIARISM! NO QUOTES, MUST PARAPHRASE. I WILL CHECK FOR RECYCLED WORK AND PLAGIARISM. THIS ASSIGNMENT IS DUE 08/16/21 AT 9PM PST. IF YOU CANT MEET THIS DEADLINE, DONT AGREE TO DO MY ASSIGNMENT. PRICE ISNT NEGOTIABLE. PLEASE READ GRADING RUBRIC. TEACHERS USE THE GRADING RUBRIC TO DETERMINE GRADE. IF DIRECTIONS ARENT BEING FOLLOWED, I WILL DISPUTE RIGHT AWAY. LETS AVOID THAT.  
YOU MUST USE TEMPLATE PROVIDED AND PLEASE READ THE ARTICLE ATTACHED. 
 
Prior to beginning work on this assignment, review the multimedia file How to Read a Scholarly Article (Links to an external site.). Using the Research Study Evaluation Template  download, you will critically evaluate the assigned research article. 
The Research Study Evaluation
 

Must include a separate title page with the following:

Title of paper
Student’s name
Course name and number
Instructor’s name
Date submitted

Must use the template provided.
Must address the article with critical thought by examining, reflecting, and evaluating the article from an objective viewpoint, using facts to support your argument in the conclusion section of the template.
Must properly cite the source article in APA style, as outlined in the Writing Center (Links to an external site.). Peak Oxygen Uptake and Mortality in Cystic Fibrosis: Systematic
Review and Meta-Analysis

Fernanda Maria Vendrusculo, João Paulo Heinzmann-Filho, Juliana Severo da Silva,
Margarita Perez Ruiz, and Márcio Vinícius Fagundes Donadio

BACKGROUND: Aerobic fitness, as measured by peak oxygen uptake (V̇O2 peak), correlates with
survival in children and adults with cystic fibrosis (CF). We sought to evaluate the effects of V̇O2
peak on mortality rates in subjects with CF. METHODS: An online search in PubMed, Embase,
LILACS, and SciELO databases was conducted, and cohort studies that assessed mortality rates
after oxygen absorption measurements during a maximal exercise test were included. Data were
extracted independently by 2 reviewers. The quality analysis of the selected articles was performed
using the Newcastle-Ottawa scale. The main outcome evaluated was the mortality of subjects with
CF. Whenever possible, and if appropriate, a random effect meta-analysis was performed. RESULTS:
Six cohort studies were included in this systematic review including 551 subjects. Five studies were
classified with high methodological quality. Two analyses were carried out to evaluate the influence
of V̇O2 peak on mortality. Total difference standardized mean between V̇O2 peak averages in the
survival or non-survival groups was �0.606 (95% CI � �0.993 to �0.219, P � .002). In addition,
subjects with a lower V̇O2 peak had a significantly higher mortality risk (relative risk 4.896,
95% CI � 1.086 to 22.072, P � .039) in an 8-y follow-up period. CONCLUSION: Low levels of peak
oxygen uptake are associated with an increase of 4.9 in the risk of mortality in subjects with CF.
This indicates that V̇O2 could be an important follow-up variable to measure, in addition to FEV1.
Key words: cystic fibrosis; oxygen consumption; exercise capacity; exercise test; mortality; survival.
[Respir Care 2019;64(1):91–98. © 2019 Daedalus Enterprises]

Introduction

Cystic fibrosis (CF) is a multisystemic genetic disease
characterized by progressive loss of lung function and con-
sequent limitation of aerobic fitness.1 Although morbidity
and mortality are still a major concern in the disease man-

agement, life expectancy is increasing each year with ad-
vancement in the diagnosis and treatment; according to
data from the Cystic Fibrosis Foundation, the expected
median survival in the year 2015 was 41.7 y.2 Thus, as
lung function is better maintained and aging of patients
increases, other comorbidities rise and there is a growing
importance of factors such as the preservation of aerobic
fitness status.3

In general, many factors have been associated with a
worse prognosis in individuals with CF, among them sex,4

decline in lung function,4-7 number of exacerbations,6,7

nutritional status,7-9 chronic colonization of the airways,10,11

and peak oxygen consumption (V̇O2 peak).
5,11,12 It is known

that the reduction of V̇O2 peak is of multifactorial origin,
given that the mechanisms that can limit aerobic fitness
include respiratory, cardiovascular, and of peripheral mus-
cles.13 Therefore, performance on the cardiopulmonary ex-
ercise test (CPET) depends on more than lung function
and thus reflects the effects of the disease on other organ
systems earlier on,14 although FEV1 has still been cited as

Drs Heinzmann-Filho, Donadio, Vendrusculo, and Ms da Silva, are af-
filiated with the Laboratory of Pediatric Physical Activity, Centro Infant,
Institute of Biomedical Research, Pontifícia Universidade Católica do
Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil. Dr Perez
Ruiz is affiliated with the School of Doctoral Studies and Research,
Universidad Europea de Madrid, Madrid, Spain.

The authors have disclosed no conflicts of interest.

Correspondence: Márcio Donadio, Laboratory of Pediatric Physical Ac-
tivity, Centro Infant, Institute of Biomedical Research, Av. Ipiranga,
6690, 2° andar, Porto Alegre, Rio Grande do Sul, CEP 90610-000, Bra-
zil. E-mail: mdonadio@pucrs.br

DOI: 10.4187/respcare.06185

RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1 91

the best predictor of mortality in children and adults with
CF.4,11,12 Thus, considering only lung function as a disease
progression marker may not identify other factors that lead
to morbidity and mortality in these subjects. Therefore,
aerobic fitness evaluation through CPET seems to be a
more comprehensive method.15

CPET is considered the gold standard for evaluating
aerobic fitness and has been used not only to follow the
evolution of the disease,16 because it evaluates the perfor-
mance and interaction of the cardiovascular, respiratory,
and metabolic systems,17 but also for the prescription of
physical exercise.18 In addition, studies have shown high
reproducibility of CPET for young19 and adult20 subjects
with CF, demonstrating a coefficient of variation of 9.3%
and 6.9%, respectively. Moreover, the recent statement on
exercise testing in CF recommends performing CPET in
individuals aged � 10 y as an important part of the annual
review process.15

Exercise intolerance due to hyperinflation and increased
respiratory work caused by airway obstruction may be
present as the disease advances,21 although it is increas-
ingly common to find some pediatric patients who do not
present dynamic hyperinflation during exercise. Aerobic
fitness correlates with survival in children12 and adults5,11

with CF. Nixon et al11 was the first to demonstrate that V̇O2
peak (� 45 mL/kg/min) could be a predictor of survival in
young individuals. A few years later, this finding was
replicated by the study of Pianosi et al,12 which showed
that subjects with V̇O2 peak � 82% of predicted had a
better rate of survival.

Thus, we hypothesized that a low V̇O2 peak was an
independent predictor of mortality in individuals with CF.
Therefore, we performed a systematic review and quanti-
tative meta-analysis of all available studies that reported
the effects of peak oxygen consumption on mortality rates
in individuals with CF.

Methods

This systematic review was performed following the
Meta-analysis of Observational Studies in Epidemiology
(MOOSE) guidelines,22 and data were described according
to the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses guidelines.23 The protocol of this re-
view was registered in the international prospective regis-
ter of systematic reviews and was accepted under the num-
ber CRD42016045759.

Search Strategy

Studies were identified from the following databases:
PubMed, Embase, LILACS, and SciELO. The terms used
were (“exercise test” or “exercise testing” or “cardiopul-
monary exercise test” or “cardiopulmonary exercise test-

ing” or “peak oxygen uptake” or “maximal oxygen con-
sumption” or “exercise tolerance” or “exercise capacity”)
and (“mortality” or “survival”) and (“cystic fibrosis”). No
filters were used. A manual search was performed on the
bibliographic references of the selected articles to search
for additional publications that were pertinent to the study
purpose. The searches were conducted in March 2017.

Study Selection

Two authors (FMV and JSdS) independently evaluated
article titles and abstracts, thereby selecting the studies to
be included in the review. Cohort studies of subjects with
CF that assessed mortality rates after oxygen uptake mea-
surements during a maximal exercise test were included.
Articles that did not use variables of the maximal exercise
test to predict mortality, articles that assessed the mortality
of individuals already on the lung transplant list (because
the inclusion of severely ill individuals would potentially
bias the analysis), review studies, case studies, experimen-
tal models, abstracts, response letters, editorials, and du-
plicate publications, as well as those that did not meet
inclusion criteria, were excluded after the analysis of the
abstract or full text. Disagreements over the inclusion cri-
teria of a particular study were discussed and resolved
through consensus. A third author (MVFD) evaluated and
resolved the discrepancies whenever disagreement or
doubts between the 2 authors remained.

Data Extraction

The following data were extracted from each of the
selected studies: title, first author’s name, year of publi-
cation, country of origin, language of publication, type of
study, age of subjects, sample size, type of equipment
used, type of protocol used, duration of follow-up, V̇O2
peak, breathing reserve, ventilatory equivalent for peak
oxygen consumption (V̇E/V̇O2), and ventilatory equivalent
for carbon dioxide production (V̇E/V̇CO2). In addition, data
from the variables of the cardiopulmonary exercise test
and other variables that could predict the mortality of CF
patients were collected. Any discrepancies were resolved
by consensus among the researchers. Moreover, whenever
appropriate, an attempt to contact authors of the included
studies was performed in order to request additional in-
formation.

Quality Analysis

The quality analysis of the selected articles was per-
formed individually by 2 authors (FMV and JPH-F) using
the Newcastle-Ottawa Scale, which assigns a maximum of
9 points to the highest quality studies according to the
3 evaluated parameters: selection (4 points), comparability

PEAK OXYGEN UPTAKE AND MORTALITY IN CF

92 RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1

(2 points), and outcome (3 points).24 The overall quality of
the study was defined as poor (score 0 –3), reasonable
(score 4 – 6), or high (score 7–9). The findings were dis-
cussed together with a third author (MVFD), and the dis-
crepancies or doubts were resolved by consensus.

Synthesis of Data and Statistical Analysis

When possible and appropriate, a randomized meta-
analysis of the studies was conducted. The standard dif-
ference of the V̇O2 peak averages between the survival and
non-survival groups was performed by extracting the av-
erage data, sample size, and P value from each study in-
cluded in that analysis. The association of high or low V̇O2
peak with mortality was calculated between the survival
and non-survival groups by extracting the relative risk and
the 95% CI and/or the number of events (death) and the
total of participants in each group, using the DerSimonian-
Laird randomized model.

Forest plots with the point size reflecting study weight
were used to graphically represent the results of meta-
analysis. The I2 and Q tests were used to quantify the
degree of heterogeneity between the studies. It was not
possible to evaluate the bias of publication with the Egg-
er’s test due to the small number of studies included in
each analysis. All analysis were performed in the compre-
hensive meta-analysis software (Biostat, Englewood, New
Jersey).

Results

A total of 8,698 articles were found (3,886 in PubMed,
4,787 in EMBASE, and 25 in LILACS). Of these,
2,786 studies were excluded because they were repeated in
the database searches, and 5,904 studies were excluded
because they did not meet the eligibility criteria of our
study. Eight studies were assessed for eligibility, and after
analysis of the full text, 2 studies were excluded for in-
cluding individuals already on a transplant list.25,26 There-
fore, 6 studies were included in this review, and 4 studies
were included in the meta-analysis. Figure 1 shows the
flow chart of the articles found and the reasons for the
exclusion of studies.

The selected articles included a total of 551 subjects,
and the sample size of each study varied between 28 and
149 subjects, with ages ranging from 10 to 30.2 y and
follow-up time between 2.8 and 8 y (Table 1). Only 2 stud-
ies presented CFTR genotype classification, although no
separate analyses were performed.9,10 All studies used the
cycle ergometer to perform CPET. However, when eval-
uating the type of protocol, 3 studies used the Godfrey
protocol,9-11 2 performed a ramp protocol,5,27 and 1 study12

used a step increment. The V̇O2 peak, breathing reserve,

V̇E/V̇O2, and V̇E/V̇CO2 data from each article are presented
in Table 2.

Regarding the overall methodological quality, 5 of the
included studies5,9,11,12,27 were classified as high quality,
and two5,11 of these received the maximum score (9 points).
On the other hand, only 1 article10 was classified as rea-
sonable quality and was assigned 6 points. Table 3 pres-
ents the parameters evaluated in the Newcastle-Ottawa
Scale.

Table 4 shows the data of significant variables to predict
mortality in CF subjects. V̇O2 peak was significant in 5 stud-
ies,5,9-12 and breathing reserve was significant in 1 study.9

In the study by Nguyen et al,27 only the arterial-alveolar
oxygen gradient was significant. With regard to other vari-
ables, FEV1 was significant in 5 studies,5,9,11,12,27 body
mass index (BMI) was significant in 2 studies,9,27 and

Records identified through
database searching

Duplicates removed
2,786

Records excluded
5,904

Studies included individuals
awaiting lung

transplantation: 2

Studies presented only data
of total sample: 2

Full-text articles
assessed for eligibility

8

Records screened
5,912

Studies included in
systematic review

6

Studies included in
meta-analysis

4

Studies included in
meta-analysis of
standard mean

difference 2

Studies included in
meta-analysis of

relative risk 2

PubMed: 3,886
Embase: 4,787
LILACS: 25
SciELO: 0

No CPET performed: 2,450
No CF individuals: 1,807
Review papers: 1,163
No access to abstract: 241
Experimental models: 206
No outcomes of interest: 37

8,698

Fig. 1. Flow chart. CPET � cardiopulmonary exercise testing;
CF � cystic fibrosis.

PEAK OXYGEN UPTAKE AND MORTALITY IN CF

RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1 93

Pseudomonas cepacia colonization was significant in
1 study.11 To determine the influence of CPET variables
on the mortality of subjects with CF, 3 studies9,11,12 used
Cox proportional hazards, whereas the other 3 studies used
log rank tests,10 multivariate logistic regression,27 and chi-
square tests.5

Meta-analysis

Two different analyses were carried out to evaluate the
influence of V̇O2 peak on mortality in subjects with CF,
and 2 studies were included in each analysis. Figure 2A
shows data from articles reporting differences between
averages of V̇O2 peak in the survival and non-survival
groups. The I2 analysis did not show heterogeneity be-
tween studies (I2 � 0%, P � .84). The total difference
standardized mean was �0.606 (CI 95% � �0.993
to �0.219, P � .002), indicating that subjects in the non-
survival group had a lower V̇O2 peak compared to survi-
vors.

Subjects with a lower V̇O2 peak (� 45 mL/kg/min or
� 82% of predicted) were associated with a signifi-
cantly higher risk for mortality (relative risk 4.896,
95% CI � 1.086 to 22.072, P � .039). There was a
small but not significant heterogeneity in the studies
(I2 � 31.56%, P � .23) included in this analysis (Fig. 2B).
It was not possible to generate funnel charts in the analysis
because of the small number of studies included.

Discussion

Low aerobic fitness has been reported in individuals
with CF and is associated with several factors, including
impairment of lung function,28 poor nutritional status,29

low muscle power,28 cardiac dysfunction,30 high level of
inflammation,10 and physical deconditioning.28 V̇O2 peak,
defined as the peak amount of oxygen that can be trans-
ferred and utilized during exercise, is the main parameter
in the evaluation of aerobic capacity.18 Our systematic
review and meta-analyses demonstrate that subjects with

Table 1. Main Methodological Characteristics of the Studies

Study Country of Origin Type of Cohort Sample Size Age, y* Follow-up, y

Hulzebos et al9 Netherlands Prospective 127 12.7 (11–14) 7.5
Van de Weert-van Leeuwen et al10 Netherlands Prospective 149 13.2 (12–13) 2.8
Nguyen et al27 France Retrospective 51 30.2 (16–67) 3
Pianosi et al12 Canada Prospective 28 10 (7–16) 8†
Moorcroft et al5 United Kingdom Retrospective 87 19.8 (15–40) 5
Nixon et al11 United States Prospective 109 17 (7–35) 8

* Mean (range).
† Approximate value.

Table 2. Main Results of Cardiopulmonary Exercise Test Variables of the Studies Included in the Systematic Review

Study Baseline V̇O2 Peak Breathing Reserve at Maximum Exercise V̇E/V̇O2 V̇E/V̇CO2

Hulzebos et al9 41.5 � 8.8 mL/kg/min 0.25 � 0.1* 37.4 � 6.8 32.3 � 5.4
93.3 � 17.9% predicted

Van de Weert-van Leeuwen et al10 41.4 � 8.8 mL/kg/min NR NR NR
96.2 � 18.2% predicted

Nguyen et al27 Died: 51.8 � 15.6% predicted 100.1 � 20.5† NR NR
Survived: 66.1 � 20.7% predicted 74.5 � 21.3†

Pianosi et al12 41.2 mL/kg/min 0.92‡ NR NR
Moorcroft et al5 Died: 53.7% predicted NR Died: 38.7 NR

Survived: 66.6% predicted Survived: 32.4
Nixon et al11 35 mL/kg/min NR NR NR

70% predicted

* 1 � (Peak minute ventilation � maximum voluntary ventilation).
† Peak minute ventilation (%) of maximum voluntary ventilation.
‡ Peak minute ventilation/maximum voluntary ventilation.
V̇O2 � oxygen uptake
NR � not reported
V̇E/V̇O2 � ventilatory equivalent for oxygen
V̇E/V̇CO2 � ventilatory equivalent for carbon dioxide

PEAK OXYGEN UPTAKE AND MORTALITY IN CF

94 RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1

lower V̇O2 peak rates (ie, values � 82% of predicted or
45 mL/kg/min) demonstrated a 4.9-fold increased risk for
a fatal outcome, indicating that measurement of aerobic
fitness could be a tool for prognosis in patients with CF.
Furthermore, the difference between means indicated that
subjects in the non-survival group had a lower V̇O2 peak
compared to the survivors. This association of oxygen
consumption with mortality has also been described for
individuals with COPD31,32 and chronic heart failure.33,34

To our knowledge, this is the first meta-analysis to eval-
uate the association of V̇O2 peak with mortality in subjects
with CF.

Nguyen et al27 was the only study included that found
no relationship between V̇O2 peak and mortality. They dem-
onstrated only that alveolar-arterial gradient for oxygen at
peak exercise was significantly associated with mortality.
On the other hand, the remaining articles demonstrated an
association between V̇O2 peak and mortality. However,
other variables, including FEV1 and BMI, were also sig-
nificant in predicting mortality. A higher BMI has been
associated with an increased likelihood of survival in sub-
jects with CF,7-9,35 corroborating the results from Nguyen
et al27 and Hulzebos et al.9 Furthermore, FEV1 has been
considered the best predictor of mortality in subjects with
CF,4,11,12 including those on lung transplant lists.36 Ac-
cording to Kerem et al4 individuals with FEV1 � 30% of
predicted should be referred for lung transplantation. Moor-
croft et al5 showed that, despite the correlation of V̇O2 peak
with survival, FEV1 is still the best indicator of prognosis.
On the other hand, Rosenthal37 described that lung func-
tion between 8 y and 12 y was a poor indicator of the risk
of dying or being transplanted. Moreover, Pianosi et al12

demonstrated that the change in V̇O2 peak over time is
more useful as a prognostic marker than the commonly
used longitudinal decline in FEV1. In addition, abnormal-
ities in aerobic fitness in early disease in stable subjects
may reflect changes that are not detected with spirometry,
given that Dodd et al38 have demonstrated that the corre-
lation between thoracic computed tomography abnormal-
ities and exercise limitation is stronger than the correlation
between spirometry and BMI with exercise limitation. Thus,
it is possible that V̇O2 peak is a better prognostic marker
early in life than FEV1, considering that CPET is depen-
dent on more than lung function and thus reflects the ef-
fects of the disease on other organ systems earlier on;
however, further studies are needed to directly address this
question.

Information obtained through CPET plays an important
role in the care and follow-up of patients with CF because
of its contribution to prognosis and functional informa-
tion.18 Thus, an annual follow-up of V̇O2 peak is relevant
to identify individuals at risk for a worsening prognosis,15

as well as those who may benefit from more intense ther-
apy,39 considering that aerobic fitness correlates with sur-Ta

bl
e

3.
N

ew
ca

st
le

-O
tt

aw
a

S
ca

le
:

M
et

ho
do

lo
gi

ca
l

Q
ua

li
ty

of
C

oh
or

t
S

tu
di

es
In

cl
ud

ed
in

th
e

S
ys

te
m

at
ic

R
ev

ie
w

S
tu

dy
R

ep
re

se
nt

at
iv

en
es

s
of

th
e

E
xp

os
ed

C
oh

or
t

S
el

ec
ti

on
of

th
e

U
ne

xp
os

ed
C

oh
or

t†

A
sc

er
ta

in
m

en
t

of
E

xp
os

ur
e‡

O
ut

co
m

e
of

In
te

re
st

N
ot

P
re

se
nt

at
S

ta
rt

of
S

tu
dy

C
on

tr
ol

fo
r

Im
po

rt
an

t
F

ac
to

r
or

A
dd

it
io

na
l

F
ac

to

A
ss

es
sm

en
t

of
O

ut
co

m
e

F
ol

lo
w

-u
p

L
on

g
E

no
ug

h
fo

r
O

ut
co

m
e

to
O

cc
ur

F
ol

lo
w

-u
p

of
C

oh
or

t
A

de
qu

at
e

T
ot

al
Q

ua
li

ty
S

co
re

H
ul

ze
bo

s
et

al
9

*
*

*
*

*
*

*
*

8
V

an
de

W
ee

rt
-v

an
L

ee
uw

en
et

al
1
0

*
*

*
*

*
*

6

N
gu

ye
n

et
al

2
7

*
*

*
*

*
*

*
7

P
ia

no
si

et
al

1
2

*
*

*
*

*
*

*
*

8
M

oo
rc

ro
ft

et
al

5
*

*
*

*
**

*
*

*
9

N
ix

on
et

al
1
1

*
*

*
*

**
*

*
*

9

A
st

ud
y

co
ul

d
be

aw
ar

de
d

a
m

ax
im

um
of

1
st

ar
(*

)
fo

r
ea

ch
it

em
ex

ce
pt

fo
r

th
e

it
em

C
on

tr
ol

fo
r

Im
po

rt
an

t
F

ac
to

r
or

A
dd

it
io

na
l

F
ac

to
r.

T
he

de
fi

ni
ti

on
/e

xp
la

na
ti

on
of

ea
ch

co
lu

m
n

of
th

e
N

ew
ca

st
le

-O
tt

aw
a

S
ca

le
is

av
ai

la
bl

e
on

li
ne

.2
4


T

he
ca

te
go

ry
do

es
no

t
ap

pl
y

to
th

e
ex

po
su

re
in

ve
st

ig
at

ed
in

th
e

sy
st

em
at

ic
re

vi
ew

.
T

hu
s,

al
l

st
ud

ie
s

w
er

e
eq

ua
ll

y
gr

ad
ed

.

D
es

cr
ip

ti
on

of
th

e
er

go
m

et
er

an
d

th
e

pr
ot

oc
ol

us
ed

.
§

A
m

ax
im

um
of

2
st

ar
s

co
ul

d
be

aw
ar

de
d

in
th

is
it

em
.

S
tu

di
es

re
ce

iv
in

g
1

st
ar

:
T

es
te

d
F

E
V

1
on

a
m

ul
ti

va
ri

at
e,

un
iv

ar
ia

te
or

m
ix

ed
m

od
el

an
al

ys
is

;
2

st
ar

s:
te

st
ed

3
of

th
e

4
va

ri
ab

le
s

(a
ge

,
bo

dy
m

as
s

in
de

x,
se

x,
an

d
ch

ro
ni

c
co

lo
ni

za
ti

on
by

P
se

u
d
o
m

o
n
a
s

a
er

u
g
in

o
sa

or
B

u
rk

h
o
ld

er
ia

ce
p
a
ci

a
)

in
th

e
m

od
el

s
de

sc
ri

be
d

pr
ev

io
us

ly
.


C

oh
or

t
st

ud
ie

s
w

it
h

a
m

ea
n/

m
ed

ia
n

fo
ll

ow
-u

p
ti

m
e


5

y
(6

0
m

on
th

s)
re

ce
iv

ed
1

st
ar

;
if

th
e

m
ea

n
fo

ll
ow

-u
p

ti
m

e
w

as
no

t
cl

ea
rl

y
in

di
ca

te
d,

th
en

th
e

st
ud

y
re

ce
iv

ed
no

st
ar

.

PEAK OXYGEN UPTAKE AND MORTALITY IN CF

RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1 95

vival in children12 and adults5,11 with CF. In addition, it is
well-established that exercise increases V̇O2 peak, indicat-
ing its importance as a therapeutic tool that could influ-
ence prognosis.40

The studies included in this systematic review and meta-
analysis showed variation in follow-up time, ranging from
2.8 y to 8 y. Considering that these are studies to evaluate
mortality, a short follow-up time may be considered as a
limitation because it could influence this outcome. In ad-
dition, it is already known that the evolution of CF is
characterized by a decline in lung function and exercise

limitation,1 highlighting the role of long-term follow-up
periods in the evaluation of mortality rates.

As for the reported variables of CPET, the included
studies showed a large variability, which prevented us
from including some articles in certain analyses and to
evaluate the influence of other variables such as ventila-
tory reserve data, V̇E/V̇O2, and V̇E/V̇CO2. A high breathing
reserve index at the lactate threshold represents a reduc-
tion of pulmonary mechanical reserve and was already
reported as a predictor of mortality in individuals with CF
waiting for lung transplantation.25 In addition, V̇E/V̇O2 mea-

Table 4. Variables Used as Mortality Predictors in Patients with Cystic Fibrosis

Study Exercise Capacity Variables Other Variables

Hulzebos et al9 V̇O2/kg (% predicted): 2.96 (1.06–8.23)* FEV1%: 17.84 (4.02–79.08)*
Breathing reserve: 3.35 (1.19–9.48)* BMI: 8.1 (2.93–22.51)*

Van de Weert-van
Leeuwen et al10

Maximum V̇O2/kg (% predicted) � 80: 96.3% mortality† NA
Maximum V̇O2/kg (% predicted) � 80: 80.0% mortality

Nguyen et al27 Peak P(A-a)O2: 0.794 (0.668–0.943, P � .009)‡ FEV1%: 1.015 (0.904–1.139, P � .80)‡
Body mass index: 1.8 (1.1–2.9, P � .03)‡

Pianosi et al12 Peak V̇O2 intercept: 0.910 (0.816–1.014, P � .09)* FEV1 intercept: 0.915 (0.868–0.964, P � .001)*
Peak V̇O2 slope: 0.048 (0.005–0.430, P � .007)* FEV1 slope: 0.008 (0.0003–0.210, P � .004)*

Moorcroft et al5 Peak V̇O2 (cut-off 56%): 64% sensitivity and
72% specificity

FEV1 (cut-off 55%): 91% sensitivity and 74% specificity

Nixon et al11 Peak V̇O2 % (� 58 vs � 82): 3.2 (1.2–8.6, P � .02)§ FEV1% (� 50 vs � 65): 1.1 (0.4–2.7, P � .83)§
Pseudomonas cepacia (present vs absent):

5.0 (2.6–9.5, P � .001)§

* Hazard ratio (95% CI).
† P � .02.
‡ Odds ratio (95% CI).
§ Relative risk (95% CI).
V̇O2 � oxygen uptake
P(A-a)O2 � alveolar-arterial oxygen difference
BMI � body mass index

Study or Subgroup

Nguyen et al27

Moorcroft et al5

Total (95% CI)

Heterogeneity: Tau2 = 0; Chi2 = 0.039, df = 1 (P = .84); I2 = 0%
Test for overall effect: Z = −3.071 (P = .002)

51.8

53.7

66.1

66.6

14

22

36

37

65

102

.041

.02

.002

37.93

62.07

100

−0.656 (−1.284 to −0.028)

−0.575 (−1.066 to −0.085)

−0.606 (−0.993 to −0.219)

0

6

6

7

41

48

16

36

52

12

71

83

.035

.02

.039

23.46

76.54

100

19.615 (1,229 to 313,077)

3.20 (1.195 to 8.567)

4.896 (1.086 to 22.072)

Study or Subgroup

Pianosi et al12

Nixon et al11

Total (95% CI)

Total events
Heterogeneity: Tau2 = 0.519; Chi2 = 1.461, df = 1 (P = .23); I2 = 31.56%
Test for overall effect: Z = 2.068 (P = .039)

Non survivorA

B

Non survivor

Means Total Means P Weight, %Total
Survivor

Survivor

IV, Random, 95% CI
Std. Mean Difference

High peak VO2
. .

Events EventsTotal P Weight, %Total
Low–moderate peak VO2

High peak VO2
. .

Low–moderate peak VO2

M-H, Random, 95% CI
Risk Relative

M-H, Random, 95% CI
Risk Relative

IV, Random, 95% CI
Std. Mean Difference

−1.00 −0.50 0.50

0.01 0.1 1 10 100

0 1.00

Fig. 2. Meta-analysis of studies that reported mean difference in V̇O2 peak between survival or non-survival groups (A) and the association
(relative risk, 95% CI) of V̇O2 peak (high vs. low–moderate) with mortality (B). Low V̇O2 peak was considered when � 45 mL/kg/min or 82% of
predicted.

PEAK OXYGEN UPTAKE AND MORTALITY IN CF

96 RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1

surement has also been shown to be important in predict-
ing mortality.5,9 Despite the relevance of the analyzed vari-
ables, it is important to recognize that CPET is not widely
available in CF centers and requires specific equipment
and expert personnel to perform and interpret the test. On
the other hand, increasing life expectancy and new thera-
peutic options are changing the clinical presentation of CF,
and markers such as lung function are better maintained
over time, highlighting the importance of other factors
such as aerobic fitness. Thus, studies designed to evaluate
the prognostic value of CPET as compared to nutritional
status, lung function, and other exercise tests are needed to
further understand the role of aerobic fitness as a disease
progression marker in CF.

Regarding the methodological quality of the studies in-
cluded, in general, a high quality was found because only
1 study10 presented a reasonable classification according
to the Newcastle-Ottawa Scale, which strengthens our sys-
tematic review and meta-analysis. In addition, the I2 test in
the analysis of the difference between means did not show
heterogeneity, and the relative risk analysis showed a low
heterogeneity among the included studies, which may con-
firm the power of the analysis presented, despite the small
number of articles.

One of the main limitations of this study is the small
number of articles included in each analysis and the vari-
ability of the parameters evaluated. Due to the different
presentations of data, only 2 articles were included in each
of the analyses. Therefore, it was not possible to perform
a funnel chart to evaluate publication bias of the studies. A
short follow-up period, especially for a …

Place your order now for a similar assignment and have exceptional work written by one of our experts, guaranteeing you an A result.

Need an Essay Written?

This sample is available to anyone. If you want a unique paper order it from one of our professional writers.

Get help with your academic paper right away

Quality & Timely Delivery

Free Editing & Plagiarism Check

Security, Privacy & Confidentiality