1. health and fitness
2. disease

Long-term Oxygen Therapy on Pulmonary
Hemodynamics in COPD Patients*
Effects of
A 6-Year
Prospective Study
Jan Zielinski, MD, FCCP; Miroslaw Tobiasz, MD; Iwona Hawrylkiewicz, MD;
Pawel Sliwinski, MD; and Grzegorz Palasiewicz, MD
Objective: To investigate effects of 6 years of domiciliary oxygen therapy on pulmonary
hemodynamics in a large group of COPD patients.
Design: Prospective longitudinal study with serial measurements.
Setting: Research institute of pulmonary diseases.
Patients: Ninety-five patients (72 men, 23 women), mean age 58±9 years, had COPD but were
free of any other serious disease. Functional characteristics at entry, mean±SD, were as follows:
FVC=2.24±0.51 L; FEV1=0.84 ±0.31 L; Pa02=55±6 mm Hg; PaC02=48±9 mm Hg; mean
pulmonary arterial pressure (PAP)=28±11 mm Hg; and pulmonary vascular resistance
(PVR)=353±172 dynes-cm-5.
Methods: Pulmonary hemodynamics were investigated using Swan-Ganz thermodilution cathe¬
ters. After initial assessment, all patients were started on a regimen of long-term oxygen therapy
(LTOT). Follow-up consisted of medical examination, spirometry, and arterial blood gas analysis
every 3 months. Pulmonary artery catheterization was repeated every 2 years.
Results: Seventy-three subjects survived 2 years of LTOT. In 39 subjects catheterized after 2
years, PAP fell from 25±8 to 23±6 mm Hg (not significant [NS]). From 31 patients who completed
4 years of LTOT, hemodynamic data were obtained in 20. In these 20 patients, PAP averaged
24±7 mm Hg at entry, and 23±5 and 26±6 mm Hg after 2 and 4 years, respectively (NS). In 12
patients who completed 6 years of LTOT, PAP was 25±7 at entry, and 21 ±4, 26±7, and 26±6 mm
Hg at 2, 4, and 6 years, respectively (p<0.01 for 2 vs 6 years). PVR was 313±159 dyne-s-cm-5 at
entry, and 268±110, 344±82, and 332±205 dynescm"5 at 2, 4, and 6 years, respectively (NS).
During 6 years of follow-up, Pa02 decreased from 61 ±3 to 46±9 mm Hg (p<0.001) and PaC02
increased from 44±13 to 49±9 mm Hg (p<0.01).
Conclusion: LTOT for 14 to 15 h/d resulted in a small reduction in pulmonary hypertension after
the first 2 years followed by a return to initial values and subsequent stabilization of PAP over 6
years. The long-term stabilization of pulmonary hypertension occurred despite progression ofthe
airflow limitation and of hypoxemia. (CHEST
1998; 113:65-70)
Keywords: COPD; long-term oxygen therapy; pulmonary hemodynamics
Abbreviations: CO=cardiac output; LTOT=long-term oxygen therapy; MRC Medical Research Council;
NOTT=Nocturnal Oxygen Therapy Trial; PAP=pulmonary arterial pressure; PH=pulmonary hypertension;
PVR=pulmonary vascular resistance
=
T) ulmonary hypertension (PH) is a common com-
¦*¦
plication of advanced COPD. It develops as a
result of chronic alveolar hypoxia leading to the
pulmonary arterial wall remodeling.12 In the past,
the PH in COPD patients was found to be an
important prognostic factor.35
*From the Department of Respiratory Medicine, Institute of
Tuberculosis and Lung Diseases, Warsaw, Poland.
Study supported by State Research Committee Grant No. 669/
S4/92.
Manuscript received April 10, 1997; accepted June 13, 1997.
Zielinski, MD, FCCP, Department of
Reprint requests to: Jan
Medicine, Institute of TB and Lung Diseases, Plocka
Respiratory
01-138
Poland
26,
Warsaw,
Therefore, the first trials with prolonged oxygen
treatment in patients with severe COPD were con¬
ducted to assess its effects on
arterial pres¬
(PAP).6 The results
pulmonary
very encouraging. A
in
the
PH
reduction
was observed after
significant
several weeks of continuous7 or 15 to 17 h/d oxygen
sure
were
treatment.89
Investigations on longer use of long-term oxygen
therapy (LTOT) also showed positive results. Stark
et al10 observed in five COPD patients a fall in a
mean PAP by 12 mm Hg after 8 months of LTOT
given for 15 h/d. Cooper et al11 found a decrease in
PAP by 2.2 mm Hg after 1 year of LTOT for 15 h/d
CHEST / 113 / 1 / JANUARY, 1998
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65
patients. All those studies, however,
were not controlled and enrolled relatively small
numbers of patients.
In two controlled studies, oxygen treatment group
vs no oxygen group (Medical Research Council
[MRC])12 or continuous oxygen vs nocturnal oxygen
(Nocturnal Oxygen Therapy Trial [NOTT])13 were
compared. In the MRC study,12 patients breathing
with oxygen for 15 h/d showed the stabilization of
PAP during almost 2 years of treatment. In patients
from the control group (no oxygen), PAP increased
Hg per year.
byIn2.8themmNOTT
trial,13 patients treated with contin¬
uous oxygen (in fact 18 h/d), demonstrated a fall in
PAP by 3 mm Hg, whereas no change in PAP was
observed in patients receiving oxygen for 12 h. The
in 40 COPD
second measurements were performed after 6
months of oxygen treatment.
Weitzenblum et al14 studied pulmonary hemody¬
namics in COPD patients before and after introduc¬
tion of LTOT. Before oxygen, PAP increased on
average by 1.5 mm Hg/yr. In the same group of
patients breathing oxygen for 16 h/d, PAP decreased
byIn2.2 mm Hg/yr.
studies mentioned above, pulmonary hemody¬
were assessed only twice, before and after
shorter or longer periods of oxygen therapy. Those
studied revealed some discrepancies in the assess¬
ment of the magnitude of a fall in PAP in short-term
studies vs long-term use of domiciliary oxygen. There
was no prospective study describing effects of LTOT
over a long period, with repeated measurements of
hemodynamics at regular intervals.
pulmonary
The aim of our study was to investigate pulmonary
hemodynamics in a large group of COPD patients
receiving LTOT. Pulmonary catheterization was re¬
peated in survivors every 2 years.
namics
Table
and Lung Function Data in
1.Anthropometric
95 COPD Patients at Entry for LTOT
Variable
Mean±SD
Age, yr
58±9
72:23
2.24±0.51
0.84±0.31
55±6
73±9
Sex ratio, M:F
FVC, L
FEVi, L
Pa02, mm Hg
Pa02/02*
48±9
PaC02, mm Hg
7.38±0.05
PH
*Pa02/02:=arterial oxygen tension breathing supplemental oxygen.
position using the
pressures
were
Swan-Ganz thermodilution catheter. The
on a polygraph (Minograph 34 or
recorded
Mingograph 81 Polygraph; Siemens-Elema; Solna, Sweden).
was measured in triplicate using a
computer (CO Computer 5000; Universal Medical Instrument
Inc; Rahway, NJ; or COM-1; Edwards Labs; Irvine, Calif). The
details of the pulmonary catheterization were described else¬
where.19
Spirometry was performed using a dry spirometer (Vitalo¬
graph; Maidenhead, UK). Normal values were those of the
Cardiac output (CO)
European Community for Coal and Steel.20 Arterial blood gases
measured using microelectrodes (Radiometer ABL; Radi¬
ometer; Copenhagen, Denmark; or Corning 248; Halstead, UK).
All patients gave written informed consent. The study protocol
was approved by the Ethics Committee of the Institute.
After initial measurements, patients were started on a regimen
of LTOT using an oxygen concentrator (Healthdyne BX-5000;
Brussels, Belgium). The regular follow-up consisted of a medical
examination, spirometry, and blood gas measurements every 3
months. Pulmonary artery catheterization was repeated at 2-year
were
intervals.
Statistical Analysis
Results are reported as mean values±SD. Baseline data were
compared with follow-up data using a paired t test or analysis of
variance. Statistical significance was assumed when p<0.05.
Results
From 95 enrolled
Materials
and
Methods
Ninety-five consecutive COPD patients, 72 male and 23
female, who were qualified for LTOT between 1986 and 1991,
The diagnosis of COPD was based on
participated in the study.
generally accepted criteria.15 Qualification criteria for LTOT
were described elsewhere.16 Briefly, to qualify, patients had to
present with stable hypoxemia (Pa02<55 mm Hg) assessed in
the steady-state period of the disease. Also patients with moder¬
ate hypoxemia (Pa02=56 to 65 mm Hg) were accepted for
LTOT if signs of chronic cor pulmonale or tissue hypoxia were
present (hematocrit>55%, ECG signs of right ventricular hyperthrophy,17 or signs of PH on the chest radiograph18).
The mean age of studied patients at entry to the study was
58±8
and their functional
characteristics (Table 1) showed
years,
severe airflow limitation with chronic respiratory failure and mild
polycythemia. Pulmonary hemodynamics at baseline (Table 2)
revealed resting PH and highly elevated pulmonary vascular
resistance
(PVR).
Pulmonary hemodynamics were studied at rest in the supine
66
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patients,
Thirty-nine subjects agreed
Table
73 survived 2 years.
catheterized again.
to be
2.Pulmonary
Hemodynamics in 95 COPD
Patients at Entry to the Study*
Variable
Mean±SD
Heart rate, beats/min
90±15
39±12
4±4
38±12
17±7
28±11
9±6
PRVS, mm Hg
PRVD, mm Hg
PPAS, mm Hg
Ppad> mm Hg
PPA, mm Hg
Pw, mm Hg
CO, L/min
PVR, dyne-s-cm~5
4.77±1.67
353±172
ventricle
ventricle
dia*Prvs=right
systolic pressure, PRVD=right
stolic pressure; PPAS=pulmonary arterial systolic pressure;
Ppad=pulmonary arterial diastolic pressure; PPA=mean pulmonary
arterial pressure; Pw=mean pulmonary wedge pressure.
Clinical
Investigations
On average, they had been using oxygen for 14.7 h/d.
Results of the initial and the second catheterization
are shown in Table 3. There were no significant
changes in the studied variables. 4
years of LTOT.
Thirty-one patientstocompleted
Twenty-one agreed have the third pulmonary
catheterization. The average oxygen use in that
group was 13.5 h/d. The results of all three catheterizations performed in those patients are shown in
Table 4. There were no statistical differences in the
ten¬
hemodynamic parameters. Only arterial oxygen
sion decreased significantly (p<0.05) after 4 years of
LTOT as compared to the initial values and the
values after 2 years.
Nineteen patients completed 6 years of LTOT.
Twelve of them were willing to contribute to the
study again. They had been using oxygen for 14.6
h/d. The results of four pulmonary catheterizations
and evolution of arterial blood gas values in those
patients are shown in Table 5.
Discussion
this is the longest prospective
knowledge,
effects
of breathing supplemental
study describing
on
oxygen pulmonary hemodynamics in patients with
severe COPD, complicated by hypoxic PH. The
results of our investigation are strengthened by
intermediate data taken at regular intervals. The
study has clearly14shown that LTOT administered for
h/d induced a small reduction of
approximately
PH during the first 2 years of LTOT. Thereafter, PH
returned to the initial
To
our
level and showed stabilization
for the
next 2
years.
Our results obtained
investigations
are
during the first 2 years of
consistent with the studies of
Table 3.Pulmonary Hemodynamics and Arterial
Blood Gases in 39 COPD Patients Before and After
2 years of LTOT*
Variable
Entry
After 2 yr
p Value
Heart rate, beats/min
88±16
86±15
NS
37±11
36±10
NS
3±3
NS3±3
37+11
34±10
NS
15±7
15±5
NS
25 ±8
23 ±6
NS
8±3
NS 7±5
4.75±1.5
5.21 ±2.0
NS
CO, L/min (34)
313±144
311±134
NS
PVR, dyne-s-cm~5 (27)
59±8
53±8
<0.05
Pa02, mm Hg
46±9
50±9
NS
PaC02, mm Hg
*For abbreviations see Table 2. Numbers in parentheses represent
the number of subjects in whom the variable was registered if not in
all. Values are means±SD. NS not significant.
PRVS, mm Hg (31)
PRVD, mm Hg (31)
PPAS, mm Hg
PPAD, mm Hg
PPA, mm Hg
Pw, mm Hg (29)
=
NOTT13 and Weitzenblum et al14 that showed sim¬
ilar reduction in PAP after 6 and 31 months of
LTOT,
respectively.
If our patients were not treated with oxygen, one
could expect the slow but steady rise in PAP. In the
MRC study,12 21 patients in the control group
showed an increase in the mean PAP by 2.8 mm
Hg/yr. Weitzenblum et al14 found in 16 COPD
patients an annual increase in PAP of 1.5 mm Hg.
It seems that the progression of PH in COPD
patients not treated with oxygen may differ from one
another. Weitzenblum et al21 were able to
subject totwo
groups of COPD patients. In the first
separate
a
group, long-term stabilization of PH was observed.
In the second, there was a rapid progression of PH.
The difference in the PAP course was related to
deterioration of the arterial blood gas values. In the
latter group, 5-year follow-up showed an increase in
PAP from 17.7 to 30.3 mm Hg. At the same time,
Pa02 decreased from 66 to 59 mm Hg. Our patients
would belong to the latter group, as there was a
definite fall in Pa02 from 61 to 49 mm Hg during 6
years. Therefore, one would expect a significant
increase in PAP during the 6 years had they not been
treated with oxygen.
finding
study
in our
An interesting
was
in the CO with oxygen treatment. This
an
increase
phenomenon
after 2 and 4 years of LTOT; however, it
did not reach the significance level. An increase in
the CO after 1 year of LTOT was also found by
Leggett et al22 and Cooper et al11
The increase in the CO may reflect the improve¬
ment in the right ventricle function after oxygen
treatment. In short-term studies, oxygen given to
COPD patients improved right ventricular func¬
tion, as measured by the right ventricular ejection
fraction.2324 However, Biernacki et al,25 using a
more accurate method of measurement of the
right ventricle function, did not find any change in
the right ventricular contractility or in the cardiac
index after short-term administration of oxygen.
The results of our study could be biased by the
fact that not all subjects who started on LTOT and
survived >2 years were investigated for the second
time. In fact, 39 of 73 survivors were recatheterized. To elucidate this problem, we compared the
initial functional and hemodynamic data of catheterized and noncatheterized patients. There was
no difference in the mean FVC, FEVX, Pa02,
PaC02, or PAP between those two groups at entry
to the study. We may assume that the investigated
patients were functionally similar to the patients
who refused the second catheterization. There¬
fore, our data seem to be representative for the
whole studied sample.
The compliance was better after 4 and 6 years of
was seen
CHEST / 113 / 1 / JANUARY, 1998
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67
Table 4.Pulmonary Hemodynamics and Arterial Blood Gases in 20 COPD Patients Before, After 2 and
After 4 Years of LTOT*
Variable
Heart rate, beats/min
PRVS, mm Hg
PRVD, mm Hg
PPAS, mm Hg
PPAD, mm Hg
PPA, mm Hg
Pw, mm Hg
CO, L/min
PVR, dyne-s-cur5
PaOs, mm Hg
PaC02, mm Hg
*For abbreviations
see
Entry
2yr
4 yr
p Value
87±18
35±8
3±3
35±8
15±6
24±7
8±4
4.42±1.5
344 + 147
62 ±5
48±9
88+14
32±7
3+2
32±7
89±16
39±7
4+4
37±8
17±6
26±6
8±3
NS
NS
NS
NS
NS
NS
NS
NS
NS
Tables 2 and 3. Values
15+5
23+5
7±4
5.58±2.3
320±137
57±6
49±8
are means
5.53±2.1
312+65
47±7U
<0.05
NS
54±8
+SD.
difference between entry and 4 years, p<0.05.
Significant
*
between 2 and 4
Significant difference
years,
p<0.05.
LTOT. The hemodynamic data were obtained in 20
of 31 subjects who completed 4 years of LTOT.
Pulmonary
hemodynamics were measured in 12 of
19 patients who completed 6 years of LTOT.
even after many
Whyof does PAP not normalize,
There
were
years breathing oxygen?
hopes based
on results of animal studies that LTOT might reverse
the PH in COPD patients. The pulmonary circula¬
tion of the rat was widely used as a model to study a
human hypoxic PH.
In rats recovering from chronic hypoxia, the re¬
gression of pulmonary vascular changes
was
arterial intima increased out of proportion to either
the changes in the media or the adventitia.
Histopathologic studies of the pulmonary arteries
of patients who died after being treated with domi¬
have shown persistent structural
ciliary oxygen were
changes. They
especially evident in the intima
of small pulmonary arteries and arterioles.2930 There
is no evidence so far (and to our knowledge) that
LTOT is able to eliminate the noncellular irrevers¬
ible intimal fibroelastosis.31
Another reason for limited effects of oxygen on
vasculature may be an insufficient num¬
pulmonary
ber of oxygen-breathing hours. The MRC and
NOTT studies showed better effects of 18 h vs 15 h
of oxygen breathing on pulmonary hemodynam¬
ob¬
served.26 However, Heath27 pointed out that a rat
poor animal model to study hypoxic PH in
man. In hypoxic rats, there is a rapid muscularization
of small pulmonary arteries and arterioles leading to
severe medial hypertrophy. In man, however,
chronic hypoxia leads to migration of vascular
smooth muscle cells into the intima and to their
proliferation there. This results inin rather moderate
PH. Wright et al28 showed that COPD patients,
was a
ics.12-13
et
Selinger
from
al32 demonstrated that removal of
oxygen
patients with COPD who had been
LTOT
caused immediate increases in PAP
receiving
and PVR.
Sliwinski et al33 showed that some COPD patients
Table 5.Pulmonary Hemodynamics and Arterial Blood Gases in 12 COPD Patients Before and After 2, 4, and
6 Years
Variable
PPA, mm Hg
Pw, mm Hg
CO, IVmin
PVR, dynes-cm-5
Pa02, mm Hg
PaCOs, mm Hg
of LTOT*
Entry
2 yr of LTOT
25±7
7±2
4.55±1.5
21±4
6±2
6.58±0.9
268 ±110
56±7
44±7
313±159
61±3
44±13
4
vr
of LTOT
6 yr of LTOT
26±7f
26±6*
6±3
5.87±0.7
344 ±82
7±3
4.43±0.5
332±205
49±7§
50±7I!
46±9§
49±9!l
*For abbreviations see Table 2. Values are meansd SD.
fTwo years vs 4 years, p<0.05.
*Two years vs 6 years, p<0.01.
^Initial vs 4 years and initial vs 6 years, p<0.001.
"initial vs 4 years and vs 6 years, p<0.01.
68
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Clinical
Investigations
breathing supplemental
oxygen, 2 L/min, may expe¬
rience significant arterial blood desaturations during
sleep. This may result in episodes of increased PAP
every night.
Apart from insufficient oxygen-breathing hours, in
some patients it is impossible to raise arterial oxygen
pressure above 60 mm Hg. Furthermore, abnormal
distribution of ventilation, leaving a certain number
of alveoli deprived of supplemental oxygen, may
contribute to the persistence of the structural
changes in the pulmonary arteries.
Long-term domiciliary oxygen prolongs life in
patients with COPD, despite inexorable progres¬
sion of airflow limitation and of hypoxemia. One of
the beneficial effects of oxygen is an elimination of
alveolar hypoxia. This prevents progression of the
PH and development of clinical signs of cor
of COPD
pulmonale. In the 1950s, a great numberfailure.34
It
were
from
heart
patients
dying
right
seems that the advent of LTOT changed this
picture. A recent multicenter study on causes and
circumstances of death in COPD patients under¬
going LTOT35 showed that only 13% died from
patients died from
right heart failure.or Most
chronic
acute or chronic
failure.
progressive
respiratory
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Clinical
Investigations