Document 1106335

Copyright ©ERS Journals ltd 1993
European Respiratory Journal
Eur Respir J, 1993, 6, 1371-1377
Ptinted in UK • all rights reserved
ISSN 0903 •
SERIES 'HIGHLIGHTS ON PULMONARY HYPERTENSION'
Edited by T. Higenbottam and R. Rodriguez-Roisin
;~' ;
~
Effect of pulmonary hypertension on gas exchange
A.G.N. Agustl*, R: Rodriguez-Roisin**
Effect of pulmonary hypertension on gas exchange. A.G.N. Agustf, R. Rodriguez-Roisin.
©ERS Journals I..Jd.
ABSJ'RACT: This paper revie~'S the effects of pulmonary anery bypertei\Sion on gas
excbant,>e by e..'J>Ioring tbree different ~ namely: 1) bow dOt!S gas exchange behave in
diseases characterized by increased vascular tone (primary pulmonary hypertension
(PPH), chronic o~1ructive pulmonary di<;ease (COPD) and interstitial pulmonary fibrosis
(IPF)) or decrea'ied vascular tone (" hepatopulmonary syndrome"); 2) bow does exercise,
as a 0()1)-pharmacological tool of increasing pulmonary blood Oow, modiiY gas e..Xl'hange in
these diseases; and 3) how do several drugs that lower (vasodil.ators) or increase
(almitrine) the active component of pulmonary hypertension interact with gas exchange.
Available data show tha.t: J) in PPH a high pulmonary vascular tone enhances gas
exchange and wb.cn it is lowered, either by oxygen or vasodilators, ventilation perfusion
(VA/0) distributions deteriorate; 2) in COPD a lowered (vasodilat.ors) or augmented
(almitrine) active vascular lone is almost invariably paralleled by a deterioration or
enhanl-ernent of ventilation-perfusion matching, respectively; 3) in IPF an adequate active
response of the pulmoJUlry vasculature is essential to maintain gas exchange, both at
rest and during exerci-;c; and 4) in patients with liver cirrhosis a low pulmonary vascular
tone induces an abnonnaJ ~A/Q distribution.
In SUI1l.DllUy, these data show that any situation and/or therapeutic intervention that lowers the active va'ICUiar tone deteriorates VA/0 relationships and vice ven;a. 1be final effect
of pulmonary vascular tone on ru1.erial oxygen tension (PaoJ is less predictable. Tbe reason for f.hi.; li1'1Certainty is that the ac:tua1 ~ value depends on the interplay of the intraand extrap.~onary factors that control gaq exchange in huiJlJlllS, and not only on l.he
degree of VA/Q mi!>nwtchlllg.
Eur Respir J., 1993. 6, 1371-1377.
Pulmonary hypertension is a common and severe complication of lung disease. It~ deleterious effects on right
ventricular mechanics and performance have been well described. However, the effects of pulmonary hypertension on
gas exchange are less well understood The purpose of this
paper is to show that gas exchange in pulmonary hypertension, as a result of high vascular tone, is much better than
in lung diseases characterized by low pulmonary vascular
tone.
It is important to differentiate structural and functional
changes of the pulmonary vasculature which cause pulmonary hypertension. Functional change is characterized by
the contractile response to hypoxia (hypoxic pulmonary
vasoconstriction), where vascular tone is increased. Its
main physiological characteristic is that of reversibility when
nonnoxia is restored. Structural change is where there is a
fixed component from anatomical derangement or loss of
pulmonary capillary surface area. Such pulmonary hypertension is caused by the lung disease itself. By definition,
this fixed form is not reversible by oxygen or drugs.
To demonstrate that a high pulmonary vascular tone
enhances and preserves a more homogeneous ventilationperfusion cV AJQ) matching, three different issues will be
explored: l) the contrasting effects on gas exchange in
those diseases where vascular tone is increased, e.g. primary pulmonary hypertension, chronic obstructive pulmonary
)
*Servicio de Neumologfa, Hospital Un.iv.
Son Dureta, Palma de Mallorca, Spain.
**Servei de Pneumologia i All~rgia
Respiratoria, Hospital Clinic, Barcelona,
Spain.
Correspondence: A.G.N. Aguslf
Servicio Neumologfa
Hospital Son Dureta
Cl Andrea Doria 55
07014 Pal.ma de Mallorca
Espana
Keywords: Exercise
gas exchange
hypoxemia
inert gases
pulmonary circulation
VAIQ distributions
Received: March 31 1993
Accepted for publication May 23 1993
disease (COPD) and cryptogenic fibrosing alveolitis, compared with diseases where pulmonary vascular tone is
decreased, e.g. hepatopulmonary syndrome [1, 2]; 2) the
way in which exercise, as a nonpharmacological mean of
increasing pulmonary blood flow, modifies gas exchange in
these diseases; and 3) the effects of drugs lowering (vasodilators), or increasing (almitrine), pulmonary vasomotor tone on
gas exchange.
The majority of studies used the multiple inert gases
elimination technique (MIGET) [3-5] to estimate the distribution of VA/Q relationships, this being the most suitable
technique to determine pulmonary gas exchange in patients
and to study it~ relationship to pulmonary vascular resistance
[6, 7]. The methods used in MIGET will not be described
in detail; we refer the reader to recent reviews on this subject [6, 7].
Gas exchange in diseases associated with high
vascular tone
Primary pulmonary hypertension (PPH)
PPH can be considered the model of diseases characterised by increased pulmonary vascular tone. DANIZXER and
1372
A.G.N. AGUSTI, R. RODRIGUEZ-ROISIN
BOWER [8] were the first to use the MIGET in a group of
patients with PPH. They showed that, at rest breathing room
air, VAIQ relationships were essentially well-preserved, with
most of the ventilation and perfusion being distributed to
alveolar units with normal VAIQ ratios; most patients also
showed a small second mode characterised by perfusion
of units with a very low VAIQ ratio (<0.1 excluding shunt),
or even with a VAIQ ratio of zero (<0.005, shunt) [8].
To study the relationship of VAIQ distribution to pulmonary hemodynamics in these patients, hypoxic pulmonary
vasoconl>triction wa~ reversed with high fractional inspired
oxygen levels. The cardiac output increased and pulmonary
vascular resistance decreased. It can be concluded that
restoration of norrnoxia reduced pulmonary vasoconstriction, so diminishing resistance to flow and enabling an
increase in cardiac output. Norrnoxia appears, therefore, to
have a beneficial effect on pulmonary haemodynamics.
However, at the same time, the physiological shunt increased
(from 2 to 7% of cardiac output) and the second mode in
the perfusion distribution described above, that is the amount
of blood flow perfusing poorly-ventilated areas, also increased significantly. Thus, despite the improved pulmonary haemodynamics with oxygen, VAIQ relationships clearly
deteriorated (8]. The investigators interpreted these findings
as evidence of the deleterious effects of releasing hypoxic
pulmonary vasoconstriction (active tone) on gas exchange in
patients with PPH. Therefore, the increased pulmonary
vascular tone of these patients under baseline conditions
(breathing room air) was, in fact, contributing to preserve gas
exchange [8].
DANTZKER and BoWER [8] also tested the effec.ts of several
vasodilator drugs on VAIQ relationships in these patients.
They observed that after infusing either isoproterenol or
nitroprusside, VAIQ relationships again deteriorated markedly, with a significant increase in both shunt and petfusion to
poorly-ventilated alveolar units with low VAIQ ratios (<0.1)
[8]. Two ye~ later, MELoT et al. [9] reported similar
results on VAIQ relationships in patients with PPH after
nifedipine, a calcium channel blocker.
In summary, studies in patients with PPH have shown that
a high pulmonary vascular tone enhances gas exchange,
and that when it is lowered, either by oxygen or with
vasodilators, VAIQ distributions deteriorate.
Chronic obstructive pulmonary disease (COPD)
Abnormal pulmonary gas exchange with hypoxaemia
and hypercapnia is characteristic of COPD. These patients
often develop pulmonary hypertension. Both structural and
functional factors contribute to the development of pulmonary hypertension in COPD. The structural changes
are associated with a loss of capillary surface area, particularly in patients with pulmonary emphysema. There is
also increased pulmonary vascular tone, because of the
presence of poorly-ventilated lung units, due to hypoxic
pulmonary vasoconstriction. It is not clear how these two
components of pulmonary hypertension interact with gas
exchange, and more specifically VAIQ relationships.
In 1990, Aousn et al. [10] investigated the effect~ of
exercise and the vasodilator nifedipine on VAIQ relationships
in a group of patients with advanced, but otherwise clinically
stable, COPD with mild to moderate pulmonary hypertension. The rationale behind their study wa~ that exercise
is a non-pharmacological method of increasing pulmonary
blood flow, whilst nifedipine increases pulmonary blood
flow by relaxing vascular smooth muscle. At the same
time, nifedipine "reverses" the hypoxic pulmonary vasoconstriction component of pulmonary hypertension [10].
The authors choose to include patients with only moderate
pulmonary hypertension on the assumption that these patient~
would probably have both increased active tone and anatomical derangement of the pulmonary vasculature, whilst
patients with more advanced COPD and severe pulmonary
hypertension may have a greater anatomical destruction of
the capillary bed, and hence be less responsive to manipulations of the vascular tone [10]. This assumption has
recently been stressed by other authors on the basis of physiological deterrninations [11], morphometric studies [12,
13] and, very recently, in vitro investigations of the functionality of the pulmonary endothelial cells of patients with
COPD submitted to lung transplant [14, 15].
Figure 1 shows the haemodynamic profile (at rest and during exercise, with and without nifedipine) of the patients
studied by AauSTI et al. (10]. Without nifedipine (continuous line), submaximal exercise (at 60% maximal 0 2 consumption) induced a marked increase both in cardiac output
and mean pulmonary artery pressure. After nifedipine, at
rest, mean pulmonary artery pressure did not change, but cardiac output increased. When these patients exercised after
nifedipine (dashed line), cardiac output also increased (with
respect to resting conditions with nifedipine). In absolute
terms, cardiac output was higher than that measured during
exercise without the drug. However, despite this higher cardiac output, pulmonary hypertension during exercise was
lower with than without nifedipine. Overall, these data
were interpreted as evidence of the vasodilator effect of
nifedipine upon the pulmonary circulation.
Figure 2 shows tl1e VAIQ ratio distributions obtained in
a representative patient of the series JIOJ. At rest, before
nifedipine, U1ere is a clearly abnonual VAIQ distribution, with
50
40
Cl
~ 30
E
[ 20
10...
10
0 +---------r--------.---------,
10
15
0
5
1
Or l·minFig. I. - Plot of cardiac output (Qr) ven.us mean pulmona!y arte1y pressure
(Ppa) obtained at rest and during submaximal exercise (60% of 'V<¥nax) in
a group of patient~ with advanced COPD, before (continuous line) and after
(dashed tine) the administration of nifedipine. Results are presented as
mean:tso. V¥l3X: maximal 0 1 coosumplion: COPO: chronic OOitm:tive pliIOOilal)' disease. F<r ti.utD!r explanalion. see leXl (From (10] reprOOuced with
permission of Ch£~1).
PULMONARY HYPERTENSION AND GAS EXCHANGE
Before N
1.0
Rest
Exercise
c
0
·oo
";"
c
·e
...:.
0.5
0.5
0
0
Q)
a.
0
en
c::
2i
-o
c
«!
c::
;
0
Cl
100
After N
1.0
~~
1.0
:::l
't::
.2
.g"'
a)
1.2
1.0
0
....J
100
1373
0.6
0.6
0.4
1.0
0.2
~
E
~
0.5
0.5
0
200 400
600
600 1000
Oxygen uptake ml-min- 1
0
0.1 1 10 100
0 0.1 1 10 100
Ventilation-perfusion ratio
Fig. 2. - Ventilation-perfusion distribution obtained in a representative
COPD patient studied at rest and during exelcise, before and after lhe ad.ministnuion of nifedipine (N). COPD: chronic obstructive pulmonary disease;
0 - : ventilation: - .--- : perfusiort For furtOOr expl!lrlalion. see text
(From [I0l reproduced wih pcnnission of Chest).
perfusion distributed to low VAIQ units (<0.1 excluding
shw1t). and also ventilation to units with high VtJQ ratios
(I 0 excluding de-dd space). Tlus type of VAIQ distribution
is characteristic of COPD [6, 7]. Exercise (before nifedipine) induced a marked improvement in gas exchange, as
shown by the narrowing of bolh the ventilation and blood
flow dislributions. 1his improvement paralleled the marlced
increase in the pulmonary artery pressure (fig. l). By contrast, at rest nifedipine induced both pulmonary vasodilation
(fig. I) and a significant deterioration of VAIQ relationships (fig. 2). lt should be noted lhar aller nifedipine (at
rest) there is more blood flow distributed to alveolar units
with a low VtJQ ratio. Therefore, !he effects of nifedipine
at rest upon pulmonary gas exchange in patients with COPD
were very similar to those previously described for patients
with PPH. That is, by lowering the active component of
pulmonary hypertension. the mechanisms that tend to preserve VAIQ relationships became less effective. However,
the study by Aousn et at. [10] extended previous observations to exercLc;e conditions. The lower right panel of figure
2 shows that despite this deleterious effect of nifedipine
on VAIQ distributions. exercise had an intense influence
on gao; exchange, and was still capable of improving VAIQ
matching in these patients. Observe that with respect to resting conditions after nifcdipine, VAIQ distributions obtained
dwing exercise with nifedipine were narrower and less heterogeneous (fig. 2). Nevertheless. the effects or nifedipine
(i.e. the effects or interfering with the active component
of pulmonary hypertension) were sti.U apparent during exercire, as shown by the broader VAIQ distributions shown during exercise with than without nifedipine.
Figure 3 summarizes all this infonnation by presenting a
plot of oxygen uptake (Vo2, ml·min-•). i.e., intensity of
exercise, versus: a) Log50 perfusion (a variable that informs
b)
60
<?1-
~ 50
>
0
200
400 600
600 1000
Oxygen uptake ml-min-1
Fig. 3. - Summacy plot of the effects of exercise and nifedipine on pulmonary gas exchange in patients with COPD. Results are presented as
mean:±so. a) shows a plot of oxygen uptake {VoJ (i.e. intensity of exercise)
vem4S 1<>&-u perfusion (uxlicating dispasioo of blood flow dislribution). b) rresents the relationship betwen Vo, and the deadspace to tidal volume ratio
(Vo!VT). Shaded areas represent expected nomtal values aJ rest - - :
before nifcdipine; - - : nfler nifcdipine. COPD: chronic obstructive pulmonary disease. For further explan:u.ion, see texL • : represents signficance
(From LJO). reproduced with permission Chest).
or
of the dispersion (so) on a log scale (log) of the blood
flow distribution) [3, 7]; and b) the dead space to tidal volume ratio (VoNT). The shaded areas represent the expected normal values for both variables at rest. The VoNT
response to both nifedipine and exercise will not be discussed here, for the sake of brevity. For that analysis,
we refer the interested reader to the original reference [lO].
With respect to log50 perfusion, note that before nifedipine
(fig. 3, continuous line), exercise decreased the dispersion of
pulmonary perfusion i.e. exercise improved gas exchange.
The administration of nifedipine, however, increased the
dispersion of blood flow. This indicates that, by lowering
the pulmonary vascular tone (fig. I), nifedipine interfered
with the mechanisms that try to preserve the matching
between alveolar ventilation and capillary perfusion. However, even in the presence of this interference, exercise
was still able to decrease (i.e. improve) the dispersion of pulmonary perfusion again (fig. 3, upper panel, continuous
line). Finally, the comparison of both exercise points, with
1374
A.G.N. AGUSTI, R. RODRIGUEZ-ROISIN
and without nifedipine, reveals that there is more VAIQ mismatch following administration of the drug (fig. 3). This
exemplifies the net effect of a lower pulmonary vascular tone
on gas exchange during exercise in COPD patients. Taken
together, these data in patients with COPD show again (as
in the case of patients with PPH) that a high pulmonary vascular tone enhances and preserves gas exchange, both at rest
and during exercise.
There are also data available exploring what happens to
gas exchange if pulmonary vascular tone is phannacologically augmented e.g., by giving almitrine bismesylate, a
drug originally designed as a ventilatory stimulant, which has
been shown to enhance hypoxic pulmonary vasoconstriction
[16- 18]. It has been clearly documented that, by increasing the active pulmonary vascular tone, almitrine improves
ventilation-perfusion matching and, thereby, arterial oxygenation. However, this is at the expense of a slight, but
significant, increase in pulmonary artery pressure, and some
clinically significant neurological side-effects [16]. Therefore,
at the present time, its clinical indication in patients with
COPD is questioned Nevertheless, for the pwpose of this
review, almitrine constitutes an excellent pharmacological
example of how any increase in pulmonary vascular tone
improves gas exchange.
In summary, it is clear that in patients with OOPD, as well
as PPH, a lowered (vasodilators) or augmented (almitrine)
active pulmonary vascular tone is almost invariably paralleled by a deterioration or enhancement of VAIQ matching,
c)
2.0 .....---------,---.
0.5
0.5
1.0
·ec:
0
c:
c:
0.01
0
Q)
c..
1.0
•
0 ,_o,...,,~oo..--....,.----,---,---,---,.....J
0
::::1
"t::
JSS
•
•
c:
t"O
JSS
~unt
~
-o
Patients with JPF characteristically have restrictive ventilatory impairment, decreased diffusing capacity of the lungs
for carbon monoxide (OLeo), and mild arterial hypoxaemia,
that generally, but not always, worsens during exercise
[21]. The histopathological picture reveals a slructuralloss
of alveolar-capillary units. It is not surprising, therefore, that
in advanced stages of the disease, patients with IPF develop pulmonary hypertension [22]. It has been attributed
largely to the physical loss of capillary surface area. However, hypoxic pulmonary vasoconstriction may also play a
role in the development of pulmonary hypertension in these
patients [22]. Again, the relationship between the active
component of pulmonary vascular disease and gas exchange
in IPF is not clear.
To clarify this question VAIQ distributions were obtained
in a group of patients with IPF studied at rest breathing
room air (baseline conditions), at rest breathing 100% 0 2 (to
release hypoxic pulmonary vasoconstriction), and during
exercise whilst breathing room air (again as a nonpharmacological tool to increase pulmonary blood flow) [23].
Figure 4 presents the VAIQ ratio distributions obtained in
b)
1.0 ,.--- -- -----,
";"
·u;
Idioparhic pulmonary fibrosis (IPF)
a)
1.0 . -- - - - - - - - ,
JSS
0
respectively. Whether or not this statement will be altered by
the use of new drugs, such as urapidil or nitric oxide [15, 19,
20], which may have a highly selective effect on the pulmonary vasculature, is still a matter of current research.
100
0
0.01
0
0
0
100
4.0
MRG
0.01
100
0.01
100
MRG
0
~
3.0
f
E
"
~
0.5
•
0
0
0
~
0.01
2.0
0.5 •
--
100
1.0
•
0
L,or-""'"..--...,--.--.---,...---,.....J
0
0.01
100
0
0
0
Ventilation/perfusion ratio
Fig. 4. - Venlilalioo-pctfuOOII distribution obrained in two represenllllive patients (JSS and MGR) with idiopalhic pulmonaly fibrosis: a) at rest brealhing room
air; b) at rest breathing 100% 0 2; and c) during exercise (brealhing room air). -o-: venlilalion;~ :perlusion. fU further explanalion, see texl (From
[23), reproduced with permission of Am Rev Respir Dis).
1375
PULMONARY HYPERTENSION AND GAS EXCHANGE
two of these patients. Note that, at rest breathing room air,
both patients showed relatively well-preserved VAIQ distributions, with a very small amount of shunt and/or blood
flow perfusing units with low VAIQ ratios. Instead, these
patients had most of their perfusion and ventilation going
to alveolar units with essential normal VAIQ ratios. Despite this similarity at baseline, the two patients displayed
different patterns of response, both to the administration
of oxygen and to exercise. The VAIQ ratio distributions of
the patient depicted in the upper panels of figure 4 (JSS)
showed no noticeable change with high fractional inspiratory 0 2 (FtoJ or during exercise. By contrast, both oxygen and exercise had pronounced effects upon VAIQ distributions in the patient depicted in the lower panels (MRG).
It can be observed that, compared to baseline, the inha1ation
of 0 2 by this patient induced a marked increase in the
amount of blood flow perfusing poorly ventilated areas
(shown in the figure as a second mode in the perfusion distribution) and shunt. However, when this patient exercised,
VAIQ mismatching was significantly improved with respect
to baseline. These data indicate that some patients with IPF
may have a pulmonary vasculature that is responsive to
0 2 (MRG), whilst others are insensitive to it (JSS), thereby
suggesting a more fixed (anatomical) vascular derangement.
Interestingly, the former group improved VAIQ relationships during exercise, while the latter showed no such
response.
To test the hypothesis that the preservation of an active
pulmonary vascular tone was desirable in terms of gas
exchange (particularly during exercise), the authors tried to
quantitate the degree of pulmonary vascular responsiveness
to 0 2 • As an "index" of pulmonary vascular reactivity, they
calculated the increase in perfusion of poorly-ventilated
lung units whilst breathing pure 0 2, which probably represents release of hypoxic pulmonary vasoconstriction [7, 10,
23]. This variable, i.e. percentage change from baseline in
the dispersion of the perfusion distribution whilst breathing
100% oxygen (.::llog, Q), seems to be more sensitive to
small changes in the pulmonary vascular tone than the
standard haemodynamic measurements (pressure and flow)
[7, 10, 23). Figure 5 shows this index of pulmonary vascular reactivity plotted against the values (all of them during
exercise) of: a) mean pulmonary artery pressure; b) an
index of the overall degree of VAIQ homogeneity, (DISP RE*); and c) P~. Ftgure 5a shows a significant relationship
between "vascular reactivity" and pulmonary hypertension
during exercise. Those patients having no or minimal vascular response to 0 2 (at rest) suffered severe degrees of
pulmonary hypertension during exercise, whilst those exhibiting evidence of release of hypoxic vasoconstriction at rest
did not develop pulmonary hypertension during exercise.
These latter patients probably had a more distensible and/or
recruitable pulmonary circulation than the former ones.
Ftgure 5b shows an excellent relationship between vascular
reactivity and overall degree of VA!Q mismatch during
exercise. Those patients with more active tone at rest (i.e.
those having more release of hypoxic vasoconstriction) had
less VAIQ mismatch during exercise. Finally, figure 5c
shows that those patients with a high pulmonary vascular
active tone at rest were those who did not present arterial
desaluration during exercise, whilst those having no or min-
80
a)
..
Cl
:X:
E
E
r=-0.67
p<0.05
•
60
Cl>
<J)
·~
Q)
><
Q)
40
••
Cl
•
c
·;::
::::J
'"0
....
20
al
CL
, a_
0
0
40
80
120
160
L\log800100% 0 2, %baseline
14
Q)
<J)
12
><
Q)
10
·eCl>
01
c
·;::
b)
•
r=-0.72
p<0.0025
••
8
::::J
'"0
Lu
d:
a..
(f)
0
6
•
4
•
2
•
0
0
40
80
120
160
L\log800 100% 0 2 , %baseline
120
c)
..
Cl
~
100
•
E
80
40
r=0.64
p<0.01
20
0
'--.---.~----.~---.-~--,
0
40
80
120
160
.6.1og800 100% 0 2 , %baseline
Fig. 5. - On lhe abscissa. change in dispersion of lhe perlusion dislribution
while breathing 100% 0 2 (%change from baseline conditions) (~<>&oQ).
This variable is an expres<;ion of lhe degree of release of hypoxic pulmonaxy
vasoconstiction. It is plotted against a) mean pulmonaxy artery pres<;ure
(i>pa); b) a variable that indicates the overall degree of VAIQ mismatching
(DIPSP R·E*); and c) ~· For further explanation, see text (Prom [23),
reproduced with permission of Am Rev Respir Dis).
imal pulmonary vascular response to 0 2 (at rest) presented
significant arterial hypoxaemia during exercise [23].
In summary, these data indicate that IPF patients with
more fixed changes of the pulmonary vasculature (probably
because they also have a more advanced clinical disease)
showed no evidence of hypoxic vasoconstriction being relieved by 0 2 at rest and, at the same time, showed more
severe pulmonary hypertension, more VAIQ mismatch and
1376
A.G.N. AGUSTI, R. RODRIGUEZ-ROISIN
lower P~ during exercise (fig 5). Taken together, these
data indicate that. an adequate active response of the pulmonary vasculature is also essential in patients with IPF to
preserve gas exchange, both at rest and during exercise.
Gas exchange in diseases associated with
low vascular tone
The hepatopulmcnary syndrome
The term "hepatopulmonary syndrome" was coined to
describe the abnormalities of pulmonary gas exchange
and lung circulation that may occur in patient~ with cirrhosis of ~e liver, in the absence of any intrinsic lung or
heart disease [241. The possibility that some patients with
cirrhosis may associate cyanosis, clubbing and dyspnoea
has been known since 1884 [25]. However, we have only
recently begun to understand the pathophysiological basis
for this clinical observation [ 1, 2, 26-29). The hepatopulmonary syndrome is now thought to be a condition characterized by pulmonary vasodilation and abnormal gas
exchange [1, 2, 26-29], with blunted or decreased pulmonary vascular response to hypoxia [30, 31]. It therefore seems
appropriate for the purposes of this review to analyse in
detail how this low active vascular tone affects pulmonary
gas exchange.
The ftrst study to use the MIGEf in cirrhosis was published in 1987, by R ODRIOUEZ-R OJSIN et a[ [32). All of the
patients studied were in stable clinical condition (without
ascites or fluid retention), had normal spirometry, and no evidence of.cardiac disease [32]. At rest breathing room air,
these pattent'i showed the characteristic hyperdynamic cardiocirculatory state of cinhosis, characterised by high cardiac
output and low pulmonary vascular resistance [32]. When
they were given 12% 0 2 to breathe (to investigate hypoxic
pulmonary vasoreactivity), pulmonary vascular resistance
increased only marginally, particularly in those patients
with cutaneous spider naevi [32J. Subsequent studies during
exercise confirmed this observation (blunted and/or absent
hypoxic vasoconstriction) and demonstrated that patients
with cinhosis usualy have an abnonnally dilated pulmonary
circulation [33].
Despite the absence of airflow limitation and/or fluid retention, and the presence of normal cardiac function, patients
with cirrhosis showed substantial VAIQ mismatch [32, 33].
"!hls. was characterized by the presence of perfusion to low
VAIQ units and, in some patients, a moderate degree of
shunt [32, 33]. These abnormalities of gas exchange were
more pronounced in patients with cutaneous spider naevi
(those who also depicted the more severe haemodynamic
abnormalities) [32]. Studies by other groups extended these
observations to patients with more severe degrees of arterial hypoxaemia, in whom pure shunt seems to acquire more
physiological relevance [34-37], as well as some level of
diffusion disequilibrium to oxygen transfer [35-36]. Both
abnormalities of the pulmonary circulation and of gas
exchange seem to be more pronounced in those patients with
a severe degree of liver failure [1, 2, 31]. Also of interest
is the fact that most of these gas exchange and haemodynamic abnormalities appear to resolve following normal-
ization of liver function after transplant [2, 24]. Therefore,
it is now generally accepted that the "hepatopulmonary
syndrome" is characterized by an abnormally low pulmo~ vascular ton~, ~ eviden~ by a blunted or absent hypoXIc vasoconstnct.ton, that mterferes with an appropriate
matching of alveolar ventilation and capillary perfusion and
that usually runs in parallel to liver function. Very recently,
several diagnostic criteria for this syndrome have been proposed [2].
In summary, for the purpose of this review, the studies
alluded to in patients with liver cirrhosis, stressed again
the important interrelationships between the pulmonary vascular tone and gas exchange, by demonstrating that, in this
case, a low pulmonary vascular tone interferes with the
homogeneous distribution of VA!Q ratios.
Summary and conclusions
We have reviewed the interaction of pulmonary vascular
tone and gas exchange in primary pulmonary hypertension,
COPD, IPF and liver cirrhosis. We have shown that any
situation and/or therapeutic intervention that lowers the
active vascular tone deteriorates VA!Q relationships, and
vice versa. Therefore, this paper has presented evidence to
support the fact that, in terms of g~ e~change, a high pul~onary vasc~lar tone enhances V AIQ matching in lung
dtsease and IS, therefore, desirable. However, the final
e~ect of pulmonary vascular tone on arterial P~ is less predictable. The reason for this uncertainty is that the actual
Pa01 valu~ depends on the interplay of the intrapulmonary
factors (V
relationships, intrapulmonary shunt and diffusion limitation to oxygen) and extrapulmonary factors
(cardiac output, overall ventilation and oxygen consumption)
that contro!s 8l!S exchange in humans, and not only on the
degree of VAIQ mismatching [7]. A deep analysis of these
interactions is beyond the scope of this paper. The interested reader is referred to other papers that discuss this point in
more depth [6, 7, 33, 38, 39]. Finally, we have not discwsed the well-known deleterious effects of pulmonary hypertension on right ventricular mechanics and performance.
Nonetheless, these latter effects should always be borne in
mind when facing any given clinical decision.
AIQ
Ackoowkdgermnts: 'The aul.hors acknowledge the
secretarial help of I Chaves, and MJ. Labot
Refe.rences
I. Agustf AGN, Roca J, Bosch J, Rodriguez-Roisfn. - The
lung in patienl~ with cirrllosis. J Hepatol1990; lO: 251-257
2. Rodriguez-Roisin R. Agusti' AGN, Roca J. - The hepatopulmonary syndrome: new name, old complexities. Tlwrax 1992;
47: 897-902.
3. Wagner PD, Naumann PF, Laravuso RB. - Simultaneous
measurement of eight foreign gases in blood by gas chromatography. J Appl Physiol 1974; 36: 6()0...<)()5
4. West m. Wagner PD. Pulmonary gas exchange. - In:
West m, ed. Bioengineering aspecL~ of the lung. New York,
Marcel Dekker, 1977, pp 361-364.
PULMONARY HYPERTENSION AND GAS EXCHANGE
5.
Rodrigucz-Roisin R, Roca J, Guitan R, Agusti AGN, Torres
A. Wagner PD. - Measurements of distributions of ventilationperfusion ratios: multiple inert gases elimination technique. Rev esp
Fisiol 1986; 42: 465-482.
6.
Dantzker DR. - VentiJation-perfusion inequality in lung disChest 1987; 91: 749-754
7. Rodriguez-Roisin R, Wagncr PD. - Clinical relevance of
ventilation-pelfusion inequality detennined by inert gas elimination.
Eur Respir J 1989; 3: 469-482.
8. Dantzkcr DR, Bower JS. - Pulmonary vascular tone
improves VAIQ matching in oblitcrative pulmonary hypertension. J
Appl Physiol: Respirat Environ Exercise Physsio/ 1981; 51:
607-{)13.
9. Melot C, Naeije R, Mols P, Vandcnbossche JL, Denolin H. Effects of nifedipine on ventilation/pert'usion matching in primary
pulmonary hypertension. Chest 1983; 83: 203-207.
10. Agusti AGN, Barbera JA, Roca J, Wagner PO, Guitart R,
Rodriguez-Roisin R. - Hypoxic pulmonary vasoconstriction and
gas exchange during exen:ise in chronic obstructive pulmonary dis~- Chest 1990; 97: 268-275.
11. Saadjian A. Philip-Joet F. Levy S, Arnaud A. - Vascular
and cardiac reactivity in pulmonary hypertension due to chronic
obstructive lung disease: assessment with various oxygen concenttations. Eur Respir J 1992; 5: 525-530.
12. Barbera JA, Roca J, Rarnirez J, Wagner PO, Ussetti P,
Rodriguez-Roisin R. - Gas exchange during exercise in mild
chronic obstructive pulmonary disease. Am Rev Respir Dis 1991;
144: 520-525.
13. Barbera JA, Riverola A, Ram.irez J, et al. - Effects of pulmonary vascular abnormalities on hypoxic pulmonary vasoconstriction in mild chronic obstructive pulmonary disease (Absttact).
Am Rev Respir Dis 1991; 143: AI78(A).
14. Dinh-Xuan AT, Higenbottarn TW, Clelland CA, et al. Impairment of cndotheliurn-<iependent pulmonary artery relaxation
in chronic obstructive lung disease. N Engl J Med 1991; 324:
1539-1547.
15. Dinh-Xuan AT. - Endothelial modulation of pulmonary
vascular tone. Eur Respir J 1994; 5: 757-762.
16. Voisin C, Howard P, Ansquer JC. - Alrnitrine bismesy1ate:
a long-term, placebo-controlled, double-blind study in COAD.
Vectarion International Multicentre Study Group. Bull Eur
Physiopathol Respir 1987; 23 (suppl. 11): 169-182.
17. Mclot C. Naeije R, Rothschild T. Mertens P, Mols P,
Hallemans R. - Improvement in ventilation-pert'usion matching
by alrnitrine in COPD. Chest 1983; 83: 528-533.
18. Romaldini H, Rodriguez-Roisin R, Wagner PD, West JB. Enhancement of hypoxic pulmonary vasoconstriction by alrnitrine
in the dog. Am Rev Respir Dis 1983; 128: 288-293.
19. Adnot S, Radermacher P, Andrivet P. Dubois-Rande JL,
Dypeyrat A. Lernaire F. - Effects of sodium-nitroprusside and
urapidil on gas exchange and ventilation-pert'usion relationships in
patients with congestive heart failure. Eur Respir J 1991; 4:
69-75.
20. Rossaint R, Falke KJ, Lopez F. Slarna K. Pison U, Zapol
WM. - Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1992; 340: 399-405.
21. Agusti AGN, Roca J, Rodriguez-Roisin R, Xaubet A, AgustiVidal A. - Different patterns of gas exchange response to exercise in asbestosis and idiopathic pulmonary fibrosis. Eur Respir J
1988; 1: 510-516.
~-
1377
22. Jackson LK, Fu1mer JD. - Structural-functional features of the
interstitial lung diseases. In: Fishrnan AP, ed. Pulmonary Diseases
and Disorders. Vol l. New York, McGraw-Hill 1988; pp. 739-754
23. Agust£ AGN, Roca J, Gea J, Wagner PD, Xaubet A,
Rodrfguez- Roisin R. - Mechanisms of gas-exchange impairment
in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1991; 143:
219-225.
24. Eriksson LS, Si:iderman C, Wahren J, Ericzon BF, Eleborg L,
Hedenstierna G. - ls hypoxaemia of cirrhotic patients due to a
functional "hepato-pulrnonal" syndrome? (Abstract). J Hepatol
1988; 7: S29.
25. Fliickinger M. - Vorkommen von trommelschlagelforrnigen
Fingerend phalangen ohne chronische Veranderungen an der
Lungen oder am Herzen. Wien Med Wschnschr 1884; 34:
1457-1458.
26. Krowka MJ, Cortese DA. - Pulmonary aspect~ of chronic
liver disease and liver transplantation. Mayo C/in Proc 1985; 60:
407-418.
27. Rodriguez-Roisfn R, Agustf AGN, Roca J. - Pulmonary
function and liver disease. Curr Opin in Gastroemerol 1988; 4:
609-614.
28. Krowka MJ, Cortese DA. - Pulmonary aspects of liver dis~and liver transplantation. Clin Chest Med 1989; 10: 593-<i16.
29. Krowka MJ, Cortese DA. - Hepa!Opulmonary syndrome: an
evolving perspective in the era of liver transplantation. Heparology
1990; 11: 138-142.
30. Daoud FS, Reeves IT, Schaeffer JW. - Failure of hypoxic
pulmonary vasoconstriction in patients with liver cirrllosis. J C/in
Invest 1972; 51: 1076-1080.
31. Naeije R, Hallemans R, Mols P, Melot C. - Hypoxic pulmonary vasoconstriction in liver cirrllosis. Chest 1981; 80: 570574.
32. Roclrfguez-Roisin R, Roca J, Agustf AGN, Ma<;tai R, Wagner
PD. Bosch J. - Ga~ exchange and pulmonary vascular reaCtivity in patients with liver cinilosis. Am Rev Re~pir Dis 1987; 135:
1085-1092.
33. Agusti AGN, Roca J, Rodrfguez-Roisin R, Mastai R, Wagrx!r
PD. Bosch J. - Pulmonary haemodynamics and gas exchange
during exercise in liver cirrhosis. Am Rev Respir Dis 1989; 139:
485-491.
34. Melot C, Naeije R, Decharnps P, Hallernans R, Lejeune P. Pulmonary and extrapulrnonary contributors to hypoxaemia in
liver cirrhosis. Am Rev Respir Dis 1989; 139: 632-Q40.
35. Edell ES, Cortese DA, Krowka JM, Rehder K. - Severe
hypoxaemia and liver dis~. Am Rev Respir Dis 1989: 140:
1631-1635.
36. Castaing Y, Manier G. Haemodynamic disturbances and
VAIQ matching in hypoxemic cirrhotic patients. Chest 1989; 96:
1064-1069.
37. Agusti AGN, Roca J, Bosch J, Garcfa-Pagan JC, Wagner PD,
Rodriguez-Roisin R. - Effects of propranolol on arterial oxygenation and 0, ttansport to tissues in patients with cirrhosis. Am
Rev Respir Dis 1990; 142: 306-310.
38. Torres A. Reyes A. Roca J, Wagner PD, Rodriguez-Roisin R.
- Ventilation-pert'usion mismatching in chronic obstructive pulmonary disease during ventilator weaning. Am Rev Respir Dis
1989; 140: 1246-1250.
39. Dantzker OR, Lynch JP, Wegg JG. - Depression of cardiac
output is a mechanism of shunt reduction in the therapy of acute
respiratory failure. Chest 1980; 77: 636-Q42.