Intermittent Positive-Pressure Hyperventilation with High
Inflation Pressures Produces Pulmonary Microvascular
Injury in Rats 1- 3
DIDIER DREYFUSS, GUY BASSET, PAUL SOLER, and GEORGES SAUMON
Introduction
Intermittent positive pressure ventilation
(IPPY) with peak inspiratory pressure as
high as 30 to 45 cmHzO (HIPPV) results
in pulmonary interstitial (peribron-
chovascular) and, ultimately, alveolar
edema. Webb and Tierney (1) postulated
that interstitial edema might be explained
by pulmonary interdependence (2-5) and
alveolar edema by an increase in surface
forces because of depletion or inactiva-
tion of surfactant (6-9). Both mecha-
nisms should be responsible for an in-
creased ultrafiltration rate, but the pos-
sibility of endothelial and/or epithelial
lesions consecutive to HIPPV has not
been excluded.
An increase in epithelial permeability
to proteins was demonstrated during seg-
mental static hyperinflation in rabbits
(10), and HIPPV was shown to increase
microvascular permeability in isolated
dog lungs (11). We hypothesized that
HIPPV in intact animals would produce
similar alterations.
We studied the effects of HIPPV on
lung protein and water accumulation in
rats and the related ultrastructural le-
sions. We focused on the occurrence of
edema and its spreading with HIPPV du-
ration and thus only considered the peak
airway pressure level that always pro-
duced alveolar edema (1). Pulmonary
edema consecutive to HIPPV was charac-
terized by increases in dry lung weight
and lung albumin uptake. The ultrastruc-
tural changes of endothelial and epithe-
lial arrangements were comparable to
those observed during many types of pul-
monary microvascular injury.
Methods
We compared the changes related to HIPPV
of increasing duration in rats with those in
IPPV control animals with the same overall
duration of mechanical ventilation.
Experiments were performed on male
Wistar rats (Iffa Credo, Oncins, France)
weighing 322.6 ± 15.8 (SD) g. Anesthesia was
880
SUMMARY The mechanisms by which Intermittent positive-pressure ventilation with high Infla-
tion pressure (HIPPY) Induces pulmonary edema remain uncertain. In this study wa Investigated
the physiologic and anatomic changes related to HIPPY at 45 cmH,O peak Inspiratory pressure In
rats. Edema was quantified by the extravascular lung water obtained from postmortem weighing
and by "Na distribution space. Pulmonary microvascular parmeablllty was assessed by dry lung
weight and fractional albumin uptake. After only 5 min of HIPPY, there was a significant increase
In Na space, dry lung walght, and fractional albumin uptake when compared with that In control
rats mechanically ventilated at 7 cmH,O peak inspiratory pressure. These changes suggest that
edema may be due at least In part to alterations in mlcrovescular permeability. Moderate peribron-
chovescular edema was present. At the ultrastructural level, some endothelial cells were found
detached from their basement membrane. This lesion has been previously described In other types
of pulmonary mlcrovescular injury. The above findings remained almost unchanged after 10 min
of HIPPY. After 20 min of HIPPY, wa observed the outpouring of a high protein content alveolar
flooding accompanied by a further significant Increase in fractional albumin uptake and dry lung
weight. Additional anatomic damage appeared Including epithelial lesions and hyaline membranes.
Thus, HIPPY edema presents all the features of high permeability edema. These results may he
of concern In the ventilatory management of patients with acute respiratory failure In order to avoid
additional damages induced by local overinflation. AM REV RESPIR DIS 1985; 132:880-884
Group III. These animals were ventilated
achieved with intraperitoneal administration
of sodium pentobarbital, 45 mg/kg body for 10 min with HIPPV after a 2O-min period
weight. A tracheostomy was performed, the of normal IPPV.
animals were heparinized (500 U), and a cath- Group IV. These animals were ventilated
eter was inserted into a carotid artery for sub- for 20 min with HIPPV after a lO-min period
sequent blood sampling and ultimate bleed- of normal IPPV.
ing. The animals were paralyzed with succinyl-
choline, 5 mg/kg body weight just before Physiologic Studies
IPPV. A normal IPPV at 40 cpm with a peak Each group consisted of 8 rats. Just before
inspiratory pressure of 7 cmH10 preceded the IPPV was initiated, approximately 2 /lCi of
period of 45 cmH10 HIPPV. The IPPV was 1l5I-labeled albumin and 0.2 /lCi of 22Na
performed using a volume mechanical pump (CEA, Saclay, France) were injected in 0.1 ml
(Braun, Melsungen, FRG) with an inspiratory- of saline via the dorsal penis vein. At the end
expiratory ratio of 1. Airway pressure was of the IPPV period the animals were bled to
measured through a side port in the death. The lungs were removed, dissected
tracheostomy tube using a MP45 ± 50 from the hilar structures, and weighed. The
cmH10 transducer (Validyne, Northridge, amount of extravascular water and the weight
CA) and was continuously registered. The of the blood-free dry lungs were determined
overall duration of the mechanical ventila- according to Pearce and coworkers (12), with
tion was 30 min. The HIPPV was achieved the assumption that the blood hematocrit in
by an increase in tidal volume up to the preset
peak inspiratory pressure, and the respiratory
(Received in original form December 3, 1984 and
rate was reduced to 25 cpm to avoid excessive
hypocapnia. in revised form May 21, 1985)
Four groups of animals were studied:
t From INSERM U82 and Departement de Phys-
Group I. These animals were mechanically
iologie, Faculte Xavier Bichat, Paris, France.
ventilated for 30 min at 7 cmH10 peak in- 2 Presented in part at the Annual Meeting of the
spiratory pressure (normal IPPV) and were American Thoracic Society, Anaheim, California,
used as controls. May 14, 1985.
Group II. These animals were ventilated for 3 Requests for reprints should be addressed to
5 min with HIPPV after a 25-min period of G. Saumon, INSERM U82, Faculte Xavier Bichat,
normal IPPV. 75018 Paris, France.
HYPERVENTILATION AND MICROVASCULAR INJURY 881

J,
..
~ 60
B

,.I,
sections were stained with azur II blue and
methylene blue, and ultrathin sections were
the control level after only 5 min of
HIPPV. Dry lung weight also differed sig-
j contrasted with uranyl acetate and lead ci- nificantly from that in control animals
,=,=,.I trate and examined in a Elmiskop 101 at 80
,=,..r.,.J: ..,] 4C
kV (Siemens, Berlin, FRG). Standard proce-
in all HIPPV protocols. These variations

..·· !!.
i. 20
. . ·· dures were followed for light microscopy.
in dry lung weight and fractional albu-
min uptake paralleled the indexes of pul-
monary edema. There were significant
o z 0
I II III IV I II III IV
Results correlations between Na space and dry
c D
No animal died before the end ofthe ex- lung weight (r = 0.71, P < 0.001) or frac-
.8
periment. Edema fluid (20 to 300 ,u) was tional albumin uptake (r = 0.86, p <
,..:r:: .
.8 r= Z found in the trachea of 6 of 8 animals 0.001). Similar correlations were found
.4 ~ 4 in Group IV during lung removal. Mac- between Qwl and dry lung weight (r =
0.89, p < 0.001) or fractional albumin up-
2 . • ·• "
i
!!.
:::>
2
roscopic aspect of lungs was normal in
Groups I to III; in Group IV, the lungs take (r = 0.84, p < 0.001). These latter
~ 0,-,---1.-'--'---'--' were enlarged and showed congestive relationships are shown in figures 2A
I II III IV
areas, especially in the costophrenic and B.
Fig. 1 A. Extravascular lung water (Owl) under cDntrol sinuses. The 125I-Iabeled albumin activity of the
conditions (I) and after HIPPV of 5 min duration (II), 10
min duration (III), and 20 min duration (IV). B. Na space.
tracheal fluid found in 6 animals in
C. Dry lung weight. O. Fractional albumin uptake per
Physiologic Data Group IV was 86 ± 5.4070 of plasma ac-
unit Na space (FAU) in the same animals (mean ± SO). The mean and SD values of Qwl, Na tivity (min, 67%; max, 98%).
Analysis of variance: significance of the difference be· space, dry lung weight, and fractional al-
tween HIPPV and control animals (. = p < 0.05, •• = bumin uptake both under control and Anatomic Data
P < 0.Q1, ••• = P < 0.001). Group IV differed from all
the other groups at least at p < 0.Q1. There was no sig·
HIPPV conditions together with the Histologicjindings. In Group I rats, a
nificant difference between Group II and Group III. results of the analysis of variance are slight perivascular edema was noted, as
shown in figure 1. usually observed with the intratracheal
The indexes of pulmonary edema method of fixation.
lungs was the same as that in systemic blood. (Qwl, Na space) increased with the du- Microscopically, the overall lung tis-
Extravascular lung water (QwI) and dry lung ration of HIPPV. But there was no differ- sue structure of Group II and III rats was
weight were expressed as ml and mg per kg ence between Group II and Group III, normal, with uniform distribution of al-
body weight, respectively. The activity of 1251 in contrast to the larger values found in veoli. There were no signs of emphysema-
albumin and "Na in lungs was obtained by Group IV. The Na space and Qwl were like changes such as distended or dis-
gamma counting (CG4000; Intertechnique, significantly correlated (r = 0.90, p < rupted alveolar walls. There was some
Plaisir, France), corrected for the overlap of
12Na into the 1251 channel. Albumin and Na
0.001). The calculation of cellular water interstitial edema surrounding broncho-
uptakes were obtained from the lung activity using Qwl and Na space showed that this vascular axes, mainly located around
of each tracer, the calculated blood remain- pulmonary edema was almost exclusively large vessels, but no alveolar edema. In
ing within these lungs, and the tracer activity extracellular (1.38 ± 0.117, 1.45 ± 0.116, Group IV rats, alveolar edema was dif-
in systemic blood and plasma. The results were 1.47 ± 0.137, and 1.44 ± 0.118g/kgbody fuse, with marked patches, particularly
expressed for Na as distribution space per unit weight in Group I, II, III, and IV, respec- in alveoli surrounding bronchovascular
volume of blood-free lung and for albumin tively; no significant difference by anal- spaces and in subpleural areas. Although
as the percentage of injected quantity per unit ysis of variance). The extracellular water some red blood cells were present in al-
volume of Na distribution space (fractional was 2.8 times that of the control value veolar spaces, no signs of gross hemor-
albumin uptake). for the longest duration of HIPPV. rhage was evident.
In some rats in Group IV, edema fluid was
recovered by aspiration from the trachea. The
There was an increase in transvascu- Ultrastructural jindings. At the ul-
activity of 12s1 albumin was also measured in lar protein flux when considering frac- trastructurallevel, changes affecting the
this fluid. tional albumin uptake, which was twice blood-air barrier were found in all but
Statistical comparisons of the 4 groups were
made using analysis of variance. The corre- B
lations between data were obtained using the
least squares method.
•
Anatomic Studies
Two other rats from each group were used
for conventional, semithin and ultrathin ex-
aminations. After the removal of the trachea
and lungs, the lungs were fIxed intratracheally
with cacodylate-buffered (360 mOs; pH 7.4)
1.71170 glutaraldehyde at 20 cmH,O positive
pressure and immersed for 2 h. 1\venty small
specimens were sampled from left superior
lobe for electron microscopy and placed in
fresh fixative for 15 min; the other lobes were 6
kept for light microscopy. After rinsing in cac- FAU ('lIIper unit N. apec;e)

odylate buffer, the tissues for electron micros- Fig. 2. Correlations between extravascular lung water (Owl) and (A) dry lung weight, (B) fractional albumin uptake
copy were post fIxed in osmium oxide, de- per unit Na space (FAU) in control and HIPPV animals. Open circles: control conditions, closed circles: 5·min
hydrated, and embedded in EponQII. Semithin HIPPV, closed squares: 10·min HIPPV, and closed triangles: 20-min HIPPV animals.
882
Fig. 3. Alteration of the blood·air barrier in a 5·min HIPPV rat. The thin part of the endothelial cell (En) is separated
from the basement membrane and protrudes into the capillary lumen, forming an endothelial bleb (.) filled with
plasmalike material. Arrows point to the basement membrane, which remains attached to the epithelial lining
(Ep) (AS = alveolar space; In = interstitium with collagen fibers and a septal cell (Se).
control animals. In Group II animals,
some endothelial cells were found
detached from their basement mem-
brane. It resulted in intracapillary blebs,
which were filled with a material show-
ing the same electron density as plasma
(figure 3). No other alteration was found
at this stage, either on the endothelial or
on the epithelial side. These alterations
remained essentially the same in the
animals in Group III, without any fur-
ther lesion of the endothelial or epithe-
lial cells such as cell swelling or disrup-
tion. Numerous abnormalities were ob-
served in Group IV animals in addition
to those previously described. Type I cells
were damaged, often completely de-
stroyed over long distances, denuding the
epithelial basement membrane. In some
alveoli, these injuries associated with in-
terstitial and alveolar edema led to hya-
line membranes consisting of cell debris
mixed with fibrinous deposits (figure 4).
Discussion
Our results confirm the findings of Webb
and Tierney (1), who have shown that
HIPPV with peak inspiratory pressure
of 45 cmH 2 0 leads to pulmonary inter-
stitial and alveolar edema in 13 to 35 min
in rats, the latter being prevented by posi-
tive end-expiratory pressure (PEEP). Be-
cause our objective was to define the
mechanisms and development of alveo-
lar edema with HIPPV duration, we did
not consider in this study the effects of
PEEP. We found that HIPPV resulted
in a dramatic increase in pulmonary
microvascular permeability associated
with parenchymal ultrastructural lesions.
Recent reviews of experimental pulmo-
nary edema did not make mention ofthis
particular method (13, 14). To our knowl-
edge, since the first description of HIPPV
edema, no attempt was made to clarify
the mechanisms responsible for this
edema in vivo. The explanations pro-
posed by Webb and Tierney (1) were
based on 2 different phenomena: an ex-
travasation from nonalveolar vessels be-
cause of an increase in transmural pres-
sure during inflation, accounting for in-
terstitial edema, and a depletion or
inactivation of surfactant, accounting for
alveolar edema.
Most of the experiments on fluid filtra-
tion and positive pressure inflation were
performed in isolated lungs or in the
opened chest, and even under these very
controlled conditions it remains unpre-
dictable whether increased transpulmo-
nary pressure would favor or counter-
balance edema formation (5). The effects
of an increase in alveolar pressure on the
rate of fluid accumulation in the lungs
depend on the related variations in lung
volume (15), but with different conse-
quences on alveolar or extra-alveolar ves-
sels, depending on the vascular pressure
(16). Hyperinflation was shown to en-
DREYFUSS, BASSET, SOLER, AND SAUMON
hance fluid accumulation during ex-
perimental hydrostatic edema (17).
The use of large tidal volumes with a
low resting volume was shown to increase
the surface tension of the alveolar lining
layer (6-9), which may favor the forma-
tion of hydrostatic pulmonary edema
(18). These changes in pulmonary sur-
face activity may appear very rapidly, in
some instances after only 5 min of hyper-
ventilation (8). Both overinflation and in-
crease in surface forces induced by
HIPPV would lead to an augmentation
in vascular transmural pressure.
An increase in transmural pressure of
extra-alveolar vessels results in an en-
larged cross section and, therefore, could
lead to pore stretching (19). This may ex-
plain the increased hydraulic conductivity
found in isolated rabbit (20) and dog (21)
lungs with high (more than 30 mmHg)
outflow pressures or in dog lungs venti-
lated for 20 min with an airway pressure
exceeding 42 cmH 2 0 (11). Whether the
resulting vascular mural stress would be
sufficient to allow a protein leakage of
consequence remains doubtful, because
the average filtration coefficient mea-
sured with atrial pressures within the
range of 50 to 60 cmH 2 0 was only 2 times
the control level (21). Then, an increase
in transmural pressure as the sole mech-
anism would lead to a hydrostatic-type
edema with low protein content. How-
ever, Webb and Tierney (1), using light
microscopy, observed that interstitial
edema fluid contained protein, as was
shown by its deep eosinophilic staining.
After 5 min of HIPPV, the increase
in fractional albumin uptake could be ex-
plained either by an augmented filtration
rate or by an abnormal protein permea-
bility. Fractional albumin uptake is simi-
lar to transvascular protein flux meas-
urements (22), i.e., the quantity of pro-
tein that crosses the vascular barrier
during a given time. Only the range of
magnitude of its changes would separate
hydrostatic from high permeability
edema. But a twofold increase in frac-
tional albumin uptake, as observed in
Group II, would occur in the case of the
hydrodynamic mechanism for a filtration
rate approximately 12 times the control
level if one neglects the delayed lymphatic
output (23) during such a short period
(in 5 min of HIPPV, nearly twice more
albumin moved into interstitial spaces
than during 30 min under control condi-
tions). Such an increase is unlikely, and
is not consistent with the absence of sig-
nificant increase in Qwl. The significant
increase in dry lung weight is a further
HYPERVENTILATION AND MICROVASCULAR INJURY
Fig. 4. 20-min HIPPV rat. Very altered alveolar septum with 3 capillaries. Ai the right side, the epithelial lining
is destroyed, denuding the basement membrane (arrows). Hyaline membranes (HM) composed of cell debris
and fibrin (f) are present. Two endothelial cells (En) of another capillary are visible inside the interstitium (In).
At the lower left side, a monocyte fills the lumen of a third capillary with a normal blood-air barrier.
argument for a high protein extravasa-
tion, excluding the hydrodynamic edema
as the unique hypothesis. Light micro-
scopic examination shows that HIPPV
edema began at the extra-alveolar level,
according to the pattern described by
Staub and colleagues (24). Because fixa-
tion was done from the alveolar side, we
were unable to draw any conclusion from
the aspect ofthe alveolar lining fluid. The
ultrastructural endothelial lesions were
nonspecific and were identical to those
encountered in many types of experimen-
tal high permeability edema (13, 14).
However, these lesions were never found
in hemodynamic edema (25-27).
After to min of HIPPV, the physio-
logic and anatomic alterations remained
identical.
There was a striking increase in all
edema and permeability indexes after 20
min of HIPPV, together with dramatic
changes in anatomic aspect. Alveolar
flooding, when present, consisted of al-
most pure plasmatic extravasation as was
evidenced by the high 1251 albumin activ-
ity found in tracheal fluid. These deteri-
orations, reflected by the signs of pul-
monary microvascular injury, cor-
responded to additional ultrastructural
lesions that are frequent in advanced
stages of permeability edema (13, 25) and
in human ARDS (28). Because we never
observed epithelial degeneration with
desquamation leading to the denudation
of the basement membrane and hyaline
membrane formations in Groups II and
III, it is likely that these lesions were the
consequence of the progression of lung
injuries that led to irreversible damage.
This is consistent with the fact that most
of the resistance to protein flux into al-
veoli is due to the low epithelial permea-
bility (29, 30).
The HIPPV edema is essentially ex-
tracellular as indicated by the steady
values of cellular weight and anatomic
findings. These results differ from previ-
ous observations in toxic or inflamma-
tory pulmonary edemas (13). The linear
relationships (figure 2A and B) that ex-
ist between Qwl and dry lung weight or
fractional albumin uptake suggest that
it was always the same kind of pulmo-
nary edema, i.e., with the same high pro-
tein content, whatever the extent of the
lesions or their localization, depending
on the HIPPV duration.
To our knowledge, no ultrastructural
study had been done after HIPPV result-
ing in alveolar edema. There was no
histologic nor ultrastructural changes in
lungs of goats ventilated at 13 cmH 2 0
peak airway pressure for 2 wk (31). On
the other hand, a loss in alveolar type
I cell continuity and interstitial but not
alveolar edema were found in some rab-
bits ventilated with a peak inspiratory
pressure of 20 cmH2 0 for 6 h (32). The
occurrence of permeability-type edema
883
in intact animals during HIPPV is con-
sistent with the increased hydraulic con-
ductivity and decreased protein reflection
coefficient found in isolated dog lung
lobes during HIPPV above 42 cmH 2 0
peak airway pressure (11). Thus, HIPPV
may also impair epithelium permeabil-
ity. Alveolar epithelial permeability to
nonelectrolytic hydrophilic solutes was
found to closely depend on pulmonary
distention (33, 34). Prolonged in situ seg-
mental overinflation with 40 cmH 2 0
pressure produced a protein-permeable
epithelium in the rabbit (to). The rele-
vance of this latter finding to HIPPV
edema remains, however, uncertain be-
cause it was not confirmed when the
whole lung was submitted to the same
airway pressure that corresponded to a
relative distention many times smaller
(10).
In summary, 2 phenomena may be in-
volved in HIPPV edema: parenchymal
injuries and increased microvascular
transmural pressure. Our results suggest
that parenchymal injuries begin at the en-
dothelial side and rapidly spread to the
epithelium. These lesions may compound
their effects with those of overinflation
and/or increased surface tension to pro-
duce pulmonary edema (35-37). These
results may be of concern in the manage-
ment of acute respiratory failure when
mechanical ventilation with high inspira-
tory pressures could lead to an overin-
flation of open alveoli as a result of un-
even distribution of compliance.
Further studies are necessary to deter-
mine whether and at which stage this
edema remains reversible, the possible ef-
fects of PEEP, and to understand the
mechanisms that lead to parenchymal le-
sions.
Acknowledgment
The writers thank Mrs G. Martet and R.
Villechevrolle for their excellent technical as-
sistance, Mrs F. Bouchonnet for her help in
preparing the results, and Miss F. Miklovic
for editorial assistance.
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