in patients with severe obstructive Simonsen,

269
in patients with severe obstructive
disease: a negative report
H.A. Christensen, K. Simonsen, P. Lange, P. Clementsen,
J.P. Kampmann, K. Viskum, J. Heideby, U. Koch
;11 poJ{ort:r with severe obsrruclive pulmoi1Llry disease: a negaJive
1. Chli.Jttn.:rt:n, K. Simon.ren, P. Lange, P. Clementsen, 1 .P. KampiTiilnn,
Hti<hby, U. Koch.
Poslllve pressure during expiration by race masks applied
bllS gained wide acceptance In the treatment or chronic
the crncacy Is s till unproven. T he effect or 6 months or
PEEP·masks (posltJve end-expiratory pressure) was
In 47 patJents with severe lrrevers:lble obstructive pulmo(rorced expiratory volume In one second (FEV1} about
hypersecretion. Patients were doublt·bllndly randomlzed
adn dolly treatment wltb PEEP·masks with either 10 or 0 cm
Mter 6 months of trea tment, no s tatistical dlfTerence was
the !WO g roups In change or median va.lues (month 6 •
, lurced vltaJ capacity (J!'VC), arterial oxygen tens ion
1
or sputum or dysp noea. Median vrdues or arterial carbon
(P11c o1) decreased s lgnlncantly (0.03 kPa} In the placebo
Intensity and dys pnoea during waJklng- on staJrcases
:.t.... Jn.... nrl In the placebo group. No dlfTerence among groups
or days bedridden, hospitalized, number or exace r·
le consumption. We conclude, that the use or PEEP·
patients Is without clinical documentation and cannot be
obslructive pulmonary disease (COPD)
bronchodilators and glucocorticoids is a
with few effective treatments availgroup of patients with hypoxia, oxygen
prolonged life expectancy [1] and physical
exercise tolerance [2, 3], while no
clinical benefits have been proven by using
muscle training [2, 4], chest physiotherapy
reconditioning [5- 8). Treatment with
steroids, be~az-agonists, melhylxanthines and
bromide is commonly used, in spite of irre·
pulmonary function tests, and results from
trials have been confiicting [2, 9-ll] .
pressure improves the distribution
by re-expanding collapsed lung tissue,
by collateral reinflation [12) and thereby
residual capacity in states of acute
). This principle has been extensively used
of adult respiratory distress syndrome
respiratory distress syndrome (NRDS),
. a~d treatment of post-operative atelecC)'S!Jc ftbrosis. While the efficacy of positive
has been convincingly demonstrated in
of ARDS and NRDS [14-161. its value in
Dept P of Pulmonary Medicine and the Chest·Ciinic,
Bispebjerg Hospital, Copenhagen, Denmarlc.
Correspondence: H.R. CbrisiCDsen, Frogthegnet 78,
2830, Virum, DeMtark.
Keyworda: Chronic bronchitis; chron ic obstructive
pulmooary disease; end-expiratory pressure.
Received: May, 1989; accepted after revision
October 6, 1989.
The PEEP-masks were kindly donated by AMBU• and
Simonsen and Weel, Denmarlc.
the treatment of atelectasis and cystic fibrosis seems less
clear [13, 17-221.
Positive airway pressure in COPD has been investigated thoroughly in two large studies [1, 23}. In the
IPPB-trial (intermittent positive pressure breathing) [23),
treatment wi th n.ebulized beta1-agonists alone was
compared with the effect of nebulizcd bc!az·agonists combined with intermittent positive pressure breathing in
1,000 patients with variable degrees of reversible airway
obstruction. During a three year foUow·up, no significant
differences were observed between the two groups with
respect to morbidity, mortality, lung function and quality
of life.
In the study of KU!IN et al. [1]. lPPB was compared
with oxygen therapy in 44 hypoxaemic patients with
severe irreversible COPD. After fou r years of treatment
the survival rate in the oxygen group was twice that
observed in the IPPB group (p:::0.06).
Positive airway pressure durmg expiralipn with now
independent resistance (PEEP: positive end-expiratory
pressure), has gained wide acceptance in the treatment of
patients with COPD and chronic copious and viscid
sputum. No controlled trials have, however, been performed in these ptllicnts. We therefore undertook the
268
H.R. CHRISTENSEN ET AL.
present randomized study to evaluate a possible effect of
PEEP-masks (fig. 1) compared with placebo masks in
patients wilh severe irreversible COPD and chronic mucus
hypersecretion during a period or 6 months.
Fig. l. - A PEEP-mask (positive end-expiratory pressure).
Methods
Subjects
The study population was recruited from patients
attending tbe outpatient chest-clinic of Bispebjerg
Hospital, Copenhagen. All patients suffered from severe
COPD with rorced expiratory volume in the ftrst second
(FEY 1) less than 40% of predicted values and PEY JFYC
(forced vital capacity) less lhan 0.7. TI1e increase in FEY 1
and FVC after inhalation of 200 J.lg albuterol and 40 J..l&
ipratropium bromide and after one week of oral treatment with 30 mg prednisolone daily wac; less lhan 20%
of pretreatment values.
Patients receiving concomitant medication were considered valid, if consumption remained unchanged
throughout the study. AU patients complied with the
definition of chronic bronchitis given by the British
Medical Research Council [24].
Subjects with pulmonary malignancy, pulmonary
fibrosis, heart failure, arterial hypertension, chest
malformations. arteria! insufficiency in the lower extremities and other disabling diseases affecting the musculoskeletal system were excluded. No patient received
beta-blocking agents
Design of the study
The patients were randomized double-blindly to 6
months of treatment with face masks with an expiratory
resistance of either I 0 cm or 0 cm water pressure
(placebo-masks). Even though the valves were adjusted
to these resistances, lhe addition or the
resulted in an increa-;e of 1.5 cm water
masks [25]. The resistances were
manometer before and after the trial and no
observed. A resistance of I 0 cm water
chosen because of an anticipated optimal
the increase in anerial oxygenation and "~~rca:!laill
output (26]. Another reason was the i
p<ltients to cope with a resisLanee greater than
water for more than a few minutes. AU mas)(s
identical, with no possibility of change in the
during the study.
ln the beginning of the trial, all patients
by trained chest-physiotherapists in the usage
and were told to apply it for at least l5
a day. At two later visits these i .. srror~· ·-.ft ...
repeated and !he .patient"s technique was
acceptable and consistent throughout
Compliance was checked by thorough
visit.
Before randomization and at monthly
following parameters were evaluated: I) PBV
before and after bronchodilator inhalation
albutcrol and 40 ~tg ipratropium bromide;
nnires assessing smoking habits, degree of
ness, cough and sputum production, number
exacerbations and antibiotic and other medical
3) number of days bedridden and hospil!llit>~
tion, visual analogue scales (V AS) asscs.cting
cough, amount and viscosity of sputum and
capacity were completed by the paticnc.s at
Blood gas tensions of oxygen and carbon
measured before and after 3 and 6 monLIIS of
At the final visit, the patients were aqked tO
global effect of the treatment.
All the patients were evaluated by the same
and chest-physiotherapist throughout the study.
was performed according to the Helsinki 11
and approved by the Ethical Committee of
Data analyses
The data were evaluated by lhe Mann· .
Fisher's exact test and the Chi-squared test SUlCC
distribution of all values could not be
p level of 0.05 was considered as significant.
Results
Sixty patients were randomized to the stud)',
each group. Forty seven of the patients
study, 25 patients in the PEEP-mask group.
placebo-mask group. Thirteen patients withclr~W
study due to causes not related to the tnal.
characteristics at the Lime of inclusion are
table 1. There was no statistically ·
between the two groups in terms of lhe
indicating that the randomization was succeS!>IU':.
five (96%) patients had smoked tobacco
PEEP-MASKS IN CHRONIC BRONCHITIS
40 yrs. Thirty one (66%) were still smoking
of inclusion. The number of smokers and
was equal in the two groups.
had severe airway obslruction with
me of FEV1 of about 1 I (range 0.50had severe arterial hypoxaemia (median
range 7.39-11.69 k.Pa, (table 1).
269
was significantly different from that in the placebo group,
as Paco2 increased by 0.05 kPa in the active group
compared with a decline of 0.03 kPa in the placebo group.
The results of VAS are shown in table 3. Only with
respect to dyspnoea while walking on a staircase, and to
the degree of cough, was a statistically significant
difference found between the two groups. The greatest
Table 1. - Base-line characteristics of 47 patients studied (values
given as medians, ranges in parentheses)
PEEP-masks (10 cm water)
No. of patients
Male/Female
Age yrs
FEV1 I
FYC I
Pao 2 kPa
Paco2 kpa
25
14/11
62 (43-71)
1.03 (0.50-1.45)
1.95 (1.35-3.85)
9.10 (7 .65-11.00)
5.66 (4.34-8.62)
Placebo-masks
22
7/15
65 (54-75)
0.90 (0.55-1.35)
1.80 (0.80-3.90)
9.10 (7 .39-11.69)
5.65 (4.14-7.02)
No significant difference between the two groups by Mann-Whitncy and
(male/female) Fishe.r's exact test. FEV 1: forced expiratory volume in one
second; FVC; forced vital capacity; Pao1 ; arterial oxygen tension; Paco2 ;
arterial carbon dioxide tension; PEEP: positjve end-expiratory pressure.
study, one of the current smokers in the
and two in the placebo-mask group
t11e pulmonary function tests and blood
are shown in table 2. When comparing the
(he investigated parameters between the last
visit, no statistically significant differences
to FEY1 , FVC and Pao2 were found between
changes were observed within each of the
after 6 months of treatment compared with
The change of Paco2 in the active group
improvement was seen in the placebo-group. Amount
and viscosity of sputum were unchanged. On the VAS
scales (function scale) the patients could indicate the
maximal level of physical activity limited by dyspnoea.
This scale also showed no difference between groups.
No significant difference (Chi-squared) was found from
the questionnaire assessing cough, dyspnoea and mucus
hypersecretion graded as being unchanged, worse or
better. Consumption of medicine was unchanged during
the 6 months tria}. period. In number of days bedridden,
hospitalized, number of exacerbations and antibiotic
Table 2. - Changes (month 6 - month 0) in FEY1 FVC and arterial gas
tensions between PEEP and placebo groups (values given as medians,
ranges in parentheses)
----~-----------------------------------
PEEP-masks
FEVI I
FYC I
Pao2 kPa
Paco2 kPa
0.00
0.05
0.12
0.05
(-0.50-0.35)
(-0.80-0.60)
(-2.55-1.64)
(-0.40-3.30)
Placebo-masks
Sign
0.00 (-0.35-0.35)
0.00 (-0.48-0.55)
-0.05 (-1.59- 2.01)
-0.03 (-2.02-0.62)
NS
NS
NS
•
*: 0.0l<p<0.02 (Mann-Whitney). For abbreviations see legend to table 1.
Table 3. - Changes (month 6 - month 0) in visual analogue scales (mm)
(values given as medians, ranges in parentheses). Negative values in this
table indicates an improvement
PEEP-masks
Dyspnoea walking on staircase
Dyspnoea walking on ground level
Cough
Amount of sputurn
Viscosity of sputum
20 cm runction scale
-1 (-69-53)
3 (-56-53)
-11(-69-75)
-8 (-51-49)
-1 (-80-70)
4 (-88-115)
Placebo-masks
-6 (-63-50)
-3 (-63-60)
-21 (-46-35)
1 (47-57)
-7 (-67-79)
-1 (-88-83)
Sign
•
NS
••
NS
NS
NS
*: O.OI<p<0.02; .,..: p<0.01 (Mann-Whimey test). PEEP: positive end-expiratory
pressure.
270
H.R. CHRISTENSEN ET Al.
consumption no differences between the two groups were
observed.
The final assessment of the global effect of whether
the treatment influenced the condition to the better, to
the worse or was without change at all is shown in table
4. No signific~t difference was found between the
groups.
Table 4. - Global self-assessment of 6 months
treatment with PEEP or placebo-masks
Better
Placebo
n=21•
Active
n=22•
Worse
Unchanged
10
5
6
NS
14
1
7
NS
Chi-square = 3.39, nonsignificant; •: Data are missin& from 1 and-3 patients, respectively; PEEP:
piJ~il.i.ve
end-expiratory pressure.
Only two complained about the usage of the mask.
Although both had difficulties in b~thing through the
system, they completed rhe study. One had a placebomask and one an active. BC$ides this, no adverse events
wete recorded.
Although we had data from the monthly visits, we
decided to· make the statistical analysis between rhe first
and last visit in order to avoid repeated s.tatistical testing.
To illustrate changes during time for the measured
variables, a series of plots like the one seen in figure 2
we.re made. The changes in FEV 1 are representative for
all our variables. From these plots no indication of major
diffen:n<;:es were found between the groups at any time
during rhe trial.
FEV1 (median and range)
Litres
0 Placebo
• Active
2.2
1.8
1.4
1.0
0.6
0.2
!l
0
ff f
2
f!
3
l f I!
4
5
6
Months
Fig. 2. - Forced expiratory volume in one second (FEV,) in both
PEEP and placebo-mask groups during the 6 months treatment.
Values give:n aa medians and ranges. PEEP: positive end·expiratory
pressure.
No correlation was found between the initial FEV1 or
FVC and the change in FEV 1 or FVC during the study
(Spearmarms correlation R about 0.2).
Discussion
In l)aticnts with chronic airflow
elastic recoil, the equal pressure point is
the alveoli increasing the areas of airways
dynamic compression during expiration. This
counteracted by breathing at large lung vol
ing airway conductance and prcvCllting
The usual habil of "pursed lips" by thcso
move the equal pressure point more
prevent premature closing of smaller airways.
During the last ten years positive exn•''r"'''-···
imitating "pursed lips", has been
many forms of respiratory diseases such as
cystic fibrosis and COPD. The clinical bcnc(it
has, however, never been documented in
ducted clinical trials. The present Stully Of 6
treatment with PEEP-masks in patients with
severe COPD with mucus hypersecretion
placebo-masks, did not show any effects on
or Paor Paco1 decreased s ignificantly but
unimportant in the placebo-group (0.03 kPa).
investigators impression that the reason for
results was bad compliance, as the patients
at each visit about the usage of the mask
technique was controlled several times.
VAS scales have been extensively used in
tive clinical evaluation of pain [27, 28}, scdn
[29] and as a part in the assessment of quality
positive correlation has been found betwee)l
naires and VAS concerning dyspnoea [29].
cal evaluation, however, is difficult due to thegeneral accepted unit of measurement and a
inter- and intra-individual variation in
different sensorial modalities. The
interpreting VAS, the lack of "a golden
it difficult to correlate these complaints of the
objective physiological measurements.
With this in mind, we found a minor mnm'lllllll
both groups compared with pretreatment va.tues
all measured variables on the VAS scales, th,o
improvement being in the placebo-group, but
groups it only reached significance for
walking on a staircase and the degree
cally important parameters such as
exacerbations, days of being bedridden,
episodes and days of antibiotic treatment d
between the groups during the study.
.
The statistical analysis is based on the data
frrst and the last clinical visit, since we felt that
of this disease should show an efficacy on a
basis and this p(ocedure also prevented
cal testing. From the plots illustrating
time, we round no indication that n1ajor
·~··-..
A • .,.,..
at any time-point during the trial. Theref?~e, t.IJO
a statistical analysis of data from other vtstts
,
given a different result is minimal.
Our results are in agreement with other trials
ing various forms of positive pressure
patients with COPD [1, 23] . Our study. 1"'"Ltenoo•
first using the simple device of a PEEP·m~sk for
PEEP- MASKS IN CHRONIC BRONCHITIS
COPD and mucus hypersecretion, for
t}ictapcuti c possibilities are limited.
the generally used PEP-mask (positive
10
we.ssu re.1, our masks secured by the way of a
1 on the left) a continuous flowres is~ance [30], thereby ensuring a
constant effect on the respiratory tract.
of 10 cm water was chosen in the
increasing pressure up to this value
oxygenation at a given inspired oxygen
pressures above 10 cm might decrease
and thereby decrease the net tissue
(26]. An additive effect of positive
.nressu1rv might be an opening of the collateral
:IWtne•t:., recruiting nonventilated collapsed
Furthermore, 10 cm water pressure seemed
the maximal resistance tolerated by our
a further increase might have decreased
considerably.
(iaussinn distribution statistics, based on the
and FVC, the magnitude of a type 2 error
to 5% for a risk of overlooking a differm! or more, I % of overlooking a difference
more, values hardly clinically relevant
is, therefore, that the widely indiscrimiPEEP-masks is without a ny c linical
and therefore cannot be recommended
with irreversible COPD and mucus
1
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272
H.R. CHRISTENSEN BT AL.
Les ~rWSques d PEEP chez les patients avec maladie pulmanaire obstructive severe. Une etude nigative. H .R. Chrisrensen,
K. Simonsen, P. Lange, P. Clementsen, J.P. Kampmaflfl,
K. Viskum, J. Heideby, U. Koch.
RESUME: La pression positive appliqu~e au cours de
!'expiration par des masques faciaux a ~t.e largement utilis~e
dans le traitement de la bronchite chronique, mais son
efficacit~ n'est toujours pas d~ontru. Les effets de trait.emcnts de six mois au moyen de masses l PEEP (positive c:nd
expiratory pressure) ont ete etudies chez 47 patients aneints
d'une maladie pulmonaire obstructive irrevemble sev~re (VEMS
d'environ 1 litre) et d'hypers6cretion de mucus. Les patients onl
~le randomises en double aveugle vers un traitement quotidien
d'au moins 45 minutes au moyen de masques PEEP avec soit
10, soil 0 cm depression d'eau. Apres six mois de traitc:ment.
l'on n'a trouve aucune difference stntisliquemc
m
.
entre Ic.s d cux groupcs en cc qu1 conceme le$
du VEMS (mois 6 - mois 0), de la capacit6
Paco1, de la quantit6 d'expectoration, ou de la
valcurs mewancs de Pao1 ont diminue de r~
(0.03 kPa) dans le groupe placebo. L'intensit6 do
dyspnu au a>urs d'une marche sur escalicrs, 0 111
signiricativcment dans le groupe placebo. L'on n'a
diffmnce entre lc:s groupes en ce qui eoncerno le
jours d'alitcmcnt ou d'hospitalisation, ou le
eucctbactions, ou encore la quantil~
Nout coneluons que !'utilisation de masques
patients n'est pas usez docume.nt.ee cliniquement
ette recommand6c.
Eur Respir J., 1990, 3, 267-272.