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Vol. 84, Issue 3, 1011-1023, March 1998
1 Département d'Anesthésie-Réanimation 2 and 2 Unité Mixte de Recherche 5525 du Centre National de la Recherche Scientifique, Faculté de Médecine de Grenoble, Université Joseph Fourier, 38 700 La Tronche, France; and 3 Department of Physiology, University of South Alabama, Mobile, Alabama 36688
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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On the basis of
changes in capillary filtration coefficient
(Kfc) in 24 rabbit lungs, we determined whether elevations in pulmonary venous
pressure (Ppv) or blood flow (BF) produced differences in
filtration surface area in oleic acid-injured (OA) or control (Con)
lungs. Lungs were cyclically ventilated and perfused under zone 3 conditions by using blood and 5% albumin with no pharmacological modulation of vascular tone. Pulmonary arterial, venous, and capillary pressures were measured by using arterial, venous, and double occlusion. Before and during each
Kfc-measurement
maneuver, microvascular/total vascular compliance was measured by using
venous occlusion.
Kfc was measured
before and 30 min after injury, by using a Ppv elevation of 7 cmH2O or a BF elevation from 1 to
2 l · min
1 · 100 g1 to obtain a similar
double occlusion pressure. Pulmonary arterial pressure increased more
with BF than with Ppv in both Con and OA lungs [29 ± 2 vs. 19 ± 0.7 (means ± SE) cmH2O;
P < 0.001]. In OA lungs
compared with Con lungs, values of
Kfc (200 ± 40 vs. 83 ± 14%, respectively; P < 0.01) and microvascular/total vascular compliance ratio (86 ± 4 vs. 68 ± 5%, respectively; P < 0.01) increased more with BF than with Ppv. In conclusion, for a given OA-induced increase in hydraulic conductivity, BF elevation increased filtration surface area more than did Ppv elevation. The steep pulmonary pressure profile induced by increased BF could result in the
recruitment of injured capillaries and could also shift downstream the
compression point of blind (zone 1) and open injured vessels (zone 2).
capillary permeability; pulmonary vascular compliance; filtration surface area; isolated rabbit lung; permeability pulmonary edema
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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SIMILAR INCREMENTS in pulmonary filtration pressure, when generated by an elevation in blood flow (BF) or an elevation in pulmonary venous pressure (Ppv), may induce different effects in transvascular filtration. A pathological increase in Ppv induces a relatively homogeneous increase in all pressures along the pulmonary vascular tree, whereas a physiological increase in BF widens the arteriovenous pressure difference by increasing essentially pulmonary arterial pressure (Ppa). These two hemodynamic conditions may involve differences in the filtration surface area, even though the average pulmonary capillary pressure (Ppc) increases are similar. In a previous study in anesthetized dogs, pulmonary BF was increased by using an extracorporeal circuit while increases in Ppc were minimized by lowering left atrial pressure, although the lung perfusion was maintained in zone 3 condition; that is, Ppa > Ppv > alveolar pressure (PA). The characteristics of the increase in lung lymph flow and protein transport, an estimate of fluid and protein transcapillary transport, were within the range usually associated with an elevation in Ppc alone (15). In Ppc-induced increases in lung transvascular filtration, the increase in lung lymph flow is associated with a decreased lymph/plasma total protein concentration ratio (42). These data suggest that there is no significant additional vascular recruitment for transvascular filtration in zone 3 conditions when pulmonary BF is increased in normal lung. Newman et al. (33) had a similar interpretation of the increased lung lymph flow and decreased lymph/plasma total protein concentration ratio observed in exercising sheep during an increased cardiac output.
The effects of an elevated BF on filtration surface area were further studied by Shibamoto et al. (41) by using the capillary filtration coefficient (Kfc) in isolated dog lungs. The filtration coefficient is measured by the increase in the transvascular filtration rate for a given increment in Ppc. It is the product of hydraulic conductivity and filtration surface area. Therefore, if hydraulic conductivity remains constant, the filtration coefficient will reflect filtration surface area. This was shown by Townsley et al. (45), who observed a linear decrease in filtration coefficient with reduction in lung mass in normal dog lungs. Shibamoto et al. (41) observed that filtration coefficients were similar in normal dog lungs whether Ppc was increased by high flow or by simultaneous elevation of Ppa and Ppv with unchanged flow. In contrast, Shibamoto et al. (41) observed in paraquat-injured lungs a higher filtration coefficient at increased BF compared with increased Ppv; that is, a higher recruitment with increased BF for the same level of injury. These results were interpreted as indicating a significant derecruitment of filtration surface area in the injured lung. In their study, BF progressively decreased with the progress of the paraquat injury, due to the constant-pressure mode of perfusion. By the end of the experiment, BF was only 15-32% of baseline level. Because decreases in cardiac output of this magnitude are not observed in acute respiratory distress syndrome patients, a constant-BF mode of perfusion is expected to better mimic the hemodynamic situation during acute lung injury in a clinical setting. Also, a constant-BF model could explain the large increase in capillary permeability induced by relatively subtle changes in the redistribution of BF among injured capillaries in the heterogeneous injury induced by oleic acid (OA) (39). Therefore, the present study used an isolated lung preparation, with a constant-BF mode of perfusion, to examine the modifications of surface filtration area in lung injured by either Ppv or BF elevation.
In the present study, the filtration coefficient was measured in normal and in OA-injured rabbit lung by using similar increments in Ppc that were caused by either Ppv or BF increases. To better mimic the clinical situation in the damaged lung, we maintained throughout the experiment cyclic ventilation under zone 3 condition of perfusion and a constant pulmonary BF.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Lung Preparation
New Zealand White adult rabbits (2.7 ± 0.09 kg) were anesthetized with pentobarbital sodium (30 mg/kg body wt) administered via a marginal ear vein. Anesthesia was maintained with reinjection of barbiturate as needed. A tracheotomy was performed, and the animals were mechanically ventilated (Braun 74072) with room air by using a tidal volume (VT) of 6 ml/kg and a respiratory rate of 40 breaths/min. Heparin (300 IU/kg) was administered via the ear vein and allowed to distribute for 5 min before animals were exsanguinated through a carotid artery cannula. The anticoagulated autologous blood (80-100 ml), diluted in Earl's buffer solution (150 ml) containing 5% bovine serum albumin, resulted in hematocrit values between 10 and 20% and was used to prime the perfusion system. After animals were exsanguinated, the chest was opened by a midsternal incision. Polyethylene cannulas (3.5 mm ID) were inserted into the pulmonary artery through an incision of the right ventricle and into the left atrium and secured with ligatures. A small bulldog clamp was positioned on the pulmonary artery to prevent air bubbles from entering during the cannulation procedure. The pulmonary circulation was washed free of blood, with the use of physiological saline solution at a slow rate (~20 ml/min), to minimize ischemia/reperfusion injury until the lungs were extracted and connected to the perfusion circuit. A suture was placed around the ventricles to occlude their lumen. After a thorough ligature of all connections with the surrounding tissues, the heart and lungs were removed en bloc and weighed. The isolated lungs were then suspended by a string tied around the tracheal cannula from a counterbalanced force transducer (model FT 03; Grass) to perform continuous weight measurement; the lungs were covered with plastic film to prevent evaporation. The perfusion circuit consisted of a 60-ml venous reservoir, a roller pump (model 7523-02; MasterFlex), a heat exchanger, and a 60-ml bubble trap (arterial reservoir) placed upstream from the arterial cannula. Ppa and Ppv were measured at side ports of the arterial and venous cannulas by using identical pressure transducers (model 5299 702; Viggo-Spectramed) referenced to the top of the lung. Perfusion was started just after the cannulas were connected, and lungs were perfused at constant flow (0.96 ± 0.07 l · min1 · 100 g1). To provide a
homogeneous lung perfusion, Ppv was transiently elevated
to 10 cmH2O during 5 min. No papaverine or other substance was used to maintain normal
vasomotor tone and reactivity. After a brief inflation (intratracheal
pressure <25 cmH2O) to reverse any atelectasis, the lungs were cyclically ventilated with a gas mixture containing 22% O2-5%
CO2-73%
N2 at a rate of 34 cycles/min, a
VT of ~3 ml/kg body wt, and an
end-expiratory pressure of 3 cmH2O. The minute
ventilation was 100 ml · min1 · kg
body wt1. Blood gases were
maintained within the normal range. Ppv was set at 5 cmH2O by adjusting the height of
the outflow reservoir at a higher level than positive end-expiratory
airway pressure (3 cmH2O), i.e.,
under zone 3 condition (Ppa > Ppv > airway pressure) in all regions
of the lung. We repeatedly assessed hematocrit, blood gases, and
temperature during the course of the experiment. Lung-weight changes,
Ppa, Ppv, and intratracheal pressure were continuously monitored,
digitized, and recorded by using a personal computer (Macintosh IIsi)
through a MacLab interface. Ppv and Ppa were sampled at 100 Hz during the measurement of the vascular occlusion traces. The
sampling rate was set at 1.7 Hz for acquisition of the weight-gain
curve to be used in the estimation of the
Kfc.
Lung Hemodynamic Measurements
Capillary pressure measurements were performed by using arterial, venous, and double occlusion by manually clamping the arterial, the venous, and both cannulas, respectively. Before each occlusion, ventilation was turned off during expiration to increase the signal-to-noise ratio. To estimate pulmonary arterial occlusion pressure (Pao), a monoexponential fitting was carried out on the Ppa curve between 0.2 s after the arterial occlusion and the time at which Ppa had fallen to 10% of the preocclusion arteriovenous pressure difference. Pao was obtained by extrapolation of the exponential fit back to the instant of occlusion. Pulmonary venous occlusion pressure (Pvo) was obtained by the extrapolation of a linear fit of the Ppv trace 0.2 s after occlusion back to the instant of occlusion. Pulmonary double occlusion pressure (Pdo) was measured as the common level reached by Ppa and Ppv after a double occlusion. These occlusion pressures were interpreted by using a model of the pulmonary circulation in which most of the compliance is in the capillary bed and most of the resistance resides in the small arteries and veins of small muscules. Pao and Pvo are the pressures prevailing in the arterial microvessels downstream from the major site of arterial resistance and in the venous microvessels upstream from the major site of venous resistance in the pulmonary circulation (17). The Pdo is the prevailing pressure in the capillaries. The pressure drops between Ppa, Pao, Pdo, Pvo, and Ppv were all defined as a percentage of total arteriovenous pressure difference. These pressure drops were respectively expressed as arterial for Ppa
Pao (
Pa), middle
for Pao Pvo (Pm), and venous for Pvo Ppv (Pv).
The total dynamic vascular compliance
(CT) was calculated by using
the mean slope of the Ppa and Ppv curve between 0.2 and 1 s after the
time of venous occlusion. The microvascular compliance (Cmv)-to-CT ratio
(Cmv/CT) was calculated
according to the method of Linehan et al. (28) as
![Cmv/C<SC>t</SC> = (4{[(Pai − Ppv)/(Ppa − Ppv)] − 0.75})<SUP>1/2</SUP>](/content/vol84/issue3/fulltext/1011/img001.gif)
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Cmv was calculated from CT × Cmv/CT.
At constant PA, the fraction of
the lung in zone 3 vs. zone 2 can be estimated by using the
transmission of incremental elevation in Ppv (Ppv) to arterial
pressure (Ppa) (7). In these experiments, the Ppa-to-Ppv ratio
(Ppa/Ppv) was determined by an elevation in Ppv of 5 cmH2O during 5 s. Ppv was then
returned to its original level.
Pulmonary Kfc
The pulmonary Kfc was used as an index of both hydraulic conductivity and filtration surface area. To measure Kfc, Ppv was step raised by 7-8 cmH2O from an initial isogravimetric state (the lung was neither gaining nor losing weight) and was maintained at this level until the vascular volume changes were completed (at least 15 min after the elevation in Ppv). The elevation in Ppv results in an initial large weight gain for a few seconds followed by a slower rate of weight gain. Kfc can be measured on the slow phase of the weight curve by using either the time 0 extrapolation (12) or the slope technique (36). The slope of the weight curve between 9 and 10 min [(wt /t)t9-10] after the step rise in Ppv was used to measure
Kfc. This slope was divided by the difference in Pdo, the prevailing Ppc, measured before and at the end of the
Kfc maneuver such
as
![<IT>K</IT><SUB>fc</SUB> = [(&Dgr;wt /&Dgr;<IT>t</IT>)<SUB>9–10</SUB>]/&Dgr;Pdo](/content/vol84/issue3/fulltext/1011/img002.gif)
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Protocol
As shown in Fig. 1, after weight and hemodynamics were stabilized (~30 min), a first series of hemodynamic measurements was performed, including occlusion pressures (arterial, venous, and double) andPpa/Ppv. The baseline
Kfc was then
measured by using an elevation in Ppv, as previously described. A
second series of the same hemodynamic measurements was performed during
the Kfc-measurement
maneuver (at the end). Ppv was then lowered back to its initial level,
and a new isogravimetric state was attained 10-15 min later. The
lung preparations were randomly assigned to one of four groups. In two
groups, 40 µg of OA were then infused into the pulmonary artery. A
period of observation lasting 30 min was completed, and a third series
of hemodynamic measurements was then obtained. A final
Kfc measurement
was performed, and a fourth series of hemodynamic measurements was
performed during the
Kfc-measurement
maneuver (at the end).
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Four groups (n = 6 in each group) were designed as follows.
Control pressure (ConP). A Ppv elevation of 7-8 cmH2O was used for the final Kfc measurement in this group.
Control blood flow (ConBF). BF was doubled for the final measurement of Kfc in this group.
OA-injured group with Ppv elevation (OAP). A Ppv elevation of 7-8 cmH2O was used for the final Kfc measurement in this group.
OA-injured group with BF elevation (OABF). BF was doubled for the final measurement of Kfc in this group.
The total time of perfusion of the lung preparation was ~2.5 h. At the end of the study, the heart and lungs were again weighed before and after dissection of the heart and main stem bronchi. This allowed us to calculate the lung weight before lung perfusion. Data are reported as mean values ± SE. Pooled data were analyzed with one-way and two-way analyses of variance (ANOVA), with repeated-measures analysis of sequential measurements. When the F ratio of pooled-data ANOVA reached a significant value, differences between ConP and ConBF groups or between OAP and OABF groups were tested by using pairwise contrast tests (1). A difference at the 5% level was considered statistically significant.| |
RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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No significant differences between groups were observed in blood gases, hematocrit, and mean intratracheal end-expiratory pressure throughout the experiment. Mean initial values of blood gases for all groups were PCO2 = 37 ± 1 Torr; PO2 = 137 ± 3 Torr; and pH = 7.40 ± 0.01. Mean hematocrit of the perfusate was 16.5 ± 0.7%. Mean intratracheal end-expiratory pressure was 2.9 ± 0.2 cmH2O.
The hemodynamic data for all groups were analyzed sequentially in two ways. First, steady-state data (before Kfc-measurement maneuver) were analyzed (Table 1). Second, the modifications induced by Kfc-measurement maneuver were analyzed (Table 2).
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Analysis of Steady-State Data
Baseline conditions.
No significant differences in steady-state hemodynamic values were
present between groups during baseline (Table 1). Mean values of
pulmonary vascular pressure, resistance, compliance, and Ppa/Ppv
for all groups during baseline are given below. Ppa was 15.1 ± 0.6 cmH2O; Ppv was 5.5 ± 0.2 cmH2O; and Pao, Pdo, and Pvo
were 10.6 ± 0.5, 8.7 ± 0.2, and 7.9 ± 0.2 cmH2O, respectively. The Pa
represented 48 ± 6% of the total arteriovenous pressure difference. The Pm and Pv bed accounted for 25 ± 3 and 27 ± 3%, respectively, of the total pressure gradient. Baseline BF was 0.92 ± 0.06 l · min1 · 100 g1 of initial lung weight.
Total vascular resistance (RT)
was 10.9 ± 0.8 cmH2O · l1 · min · 100 g. CT was 2.2 ± 0.15 ml · cmH2O1 · 100 g1, with a predominance of
microvascular fractional compliance
(Cmv/CT) at 72 ± 3%. Ppa/Ppv was 0.77 ± 0.05, reflecting a large zone 3 predominance.
Evolution with time and OA infusion (t = 30 min).
Steady-state values of Ppa, Ppv, Pdo, and Pvo did not change with time
in all groups. Only Pao increased moderately in all groups (from 10.5 ± 0.5 to 11.4 ± 0.6 cmH2O). A modest increase in Pm
was observed with time in all groups (33 ± 3 vs. 26 ± 3%), associated with a decrease in Pa (42 ± 3 vs. 48 ± 3%). The
total arteriovenous pressure difference did not change significantly with time in all groups (9.6 ± 0.6 vs. 10.3 ± 0.8 cmH2O). This implies a stable
RT throughout the study. No
significant changes with time were observed in
CT and
Cmv/CT in all four groups (2.1 ± 0.2 vs. 2.2 ± 0.1 ml · cmH2O1 · 100 g1 and 74 ± 3 vs. 72 ± 3%, respectively). No changes with time were observed in
Ppa/Ppv. This implies a stable zone 3 condition throughout the
study.
Pv increased in the OA-injured group (30 ± 2 vs. 27 ± 2%), whereas it decreased in the Con
group (21 ± 2 vs. 26 ± 2%). No changes in total arteriovenous
pressure difference were observed after OA injury. OA injury did not
affect CT,
Cmv/CT, or Ppa/Ppv.
Analysis of Modifications Induced by Kfc Maneuver
Pulmonary vascular pressures.
As a whole, the changes in vascular pressures were influenced more by
the hemodynamic stimulus used for the final
Kfc-measurement maneuver (BF or Ppv elevation) than by the presence of OA-induced injury (Table 2). Indeed, the vascular pressure profile along the
pulmonary vascular tree was quite different, depending on whether the
final Kfc was
measured by using an elevation in BF or an elevation in Ppv (see Fig.
2). The arteriovenous
pressure difference increased with BF elevation (the mean value of Ppa Ppv in ConBF and OABF groups increased from 12.1 ± 1.3 to
22.9 ± 2.2 cmH2O;
P = 0.0001) compared
with a decrease with Ppv elevation (the mean value of Ppa Ppv
in ConP and OAP groups decreased from 8.5 ± 0.8 to 6.7 ± 0.5 cmH2O). This modification in the
longitudinal pressure profile with BF or Ppv elevation led to
modifications in segmental pressures. Although the levels attained by
Pao [18.6 ± 1.6 vs. 16.4 ± 0.4 cmH2O; not significant (NS)]
and Pdo (14.3 ± 0.6 vs. 15.4 ± 0.5 cmH2O; NS) during the final
Kfc maneuver were
not different during BF or Ppv elevation, the level attained by Pvo was
lower during BF elevation than during Ppv elevation (11.5 ± 0.5 vs.
14.2 ± 0.4 cmH2O,
respectively; P = 0.001) (Fig. 2).
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Pulmonary vascular resistances.
In all groups, RT decreased
(from 11.8 ± 1.2 to 10.6 ± 1.1 cmH2O · l1 · min · 100 g, P = 0.01) when vascular pressure was increased during the final
Kfc-measurement
maneuver, whether this increase was caused by BF or Ppv elevation.
Pulmonary vascular compliances.
In all groups, CT
decreased with increased pressure during the final
Kfc maneuver
(from 2.2 ± 0.2 to 1.6 ± 0.1 ml · cmH2O1 · 100 g1;
P = 0.0001), but this decrease in
CT was less pronounced in the
flow groups (from 2.1 ± 0.2 to 1.7 ± 0.2 ml · cmH2O1 · 100 g · 1)
than in the Ppv groups (from 2.3 ± 0.3 to 1.5 ± 0.2 ml · cmH2O1 · 100 g1;
P = 0.03).
Cmv/CT was not different,
whether BF or Ppv elevation was used. As a consequence, in all groups,
calculated Cmv (calculated from
CT × Cmv/CT) decreased with
increased pressure during the final
Kfc maneuver
(from 1.6 ± 0.1 to 1.1 ± 0.1 ml · cmH2O1 · 100 g1;
P = 0.0001), but this decrease in
calculated Cmv was less pronounced in the BF groups (from 1.5 ± 0.1 to 1.3 ± 0.1 ml · cmH2O1 · 100 g1) than in the Ppv
groups (from 1.7 ± 0.3 to 1.0 ± 0.1 ml · cmH2O1 · 100 g1;
P = 0.001).
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Zonal characteristics.
During the final
Kfc-measurement
maneuver, Ppa/Ppv did not change during the BF increase (0.78 ± 0.04 vs. 0.79 ± 0.05), whereas it increased during the Ppv
elevation (from 0.78 ± 0.04 to 0.91 ± 0.02;
P = 0.03), implying an increased
amount of zone 3 lung in the latter maneuver.
Kfc.
No significant differences between groups were present during baseline
(Table 2). The
Kfc mean value
for all groups was 0.117 ± 0.01 ml · min1 · cmH2O1 · 100 g1 of initial lung weight.
13 ± 19%). In
contrast (see Fig. 4),
Kfc in the
OA-injured groups demonstrated a marked increase (200 ± 40%) when
BF rather than Ppv elevation (85 ± 15%) was used for its
measurement (P = 0.002).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The aim of the present study was to assess in injured lung the effect of a BF elevation on filtration coefficient; this measurement reflects the combination of fluid transvascular permeability and filtration surface area. In contrast to a previous study by Shibamoto et al. (41), BF was maintained in conditions approaching those of a supine patient with an injured lung, i.e., cyclic ventilation, intact vascular tone, vascular pressure pulsatility, and zone 3 condition of perfusion, allowing the lung weight to increase. The results of the present study support those of Shibamoto et al., although the present results were obtained in a different species (rabbit instead of dog), by using a different injury model (OA instead of paraquat), and under different BF conditions (constant-flow vs. constant-pressure perfusion). The filtration coefficient, that is the product of hydraulic transvascular conductivity and filtration surface area, increases more in the injured lung after a BF elevation than after a Ppv elevation. These results suggest that capillaries that present a high level of injury are recruited after a BF elevation and that, in such circumstances, some of them may be blind, i.e., fed by upstream vessels and not drained, because of downstream obstruction.
Pulmonary Hemodynamics
Perfusion conditions.
That zone 3 condition (Ppa > Ppv > PA) prevails under controlled
ventilation is more likely in injured lung than in normal lung because
of a decreased tissue pulmonary compliance (6). To obtain zone 3 condition of perfusion, Ppv was established at 3 cmH2O higher than
PA, with vascular pressures
zeroed at the top of the lung. The partition of the lungs between zones
was controlled in all experiments by measuring the transmission of an
incremental elevation in Ppv to Ppa as proposed by Brower et al. (7).
This method is based on the assumption that alveolar vessels behave
like Starling resistors. When extramural pressure exceeds the
intraluminal pressure at the outflow end of the alveolar vessels (Ppa > PA > Ppv), an increment in
Ppv will not affect inflow pressure; that is, Ppa. Thus Ppa/Ppv
equals 0 in lung perfused in zone 2. If intraluminal pressure exceeds
extramural pressure (Ppa > Ppv > PA), then the increment in Ppv
will affect Ppa. Thus Ppa/Ppv equals 1 in lung perfused in zone
3. Ppa/Ppv for the entire lung is then an estimate of the
fraction of the lung that is in zone 3. This functional estimate of the
zone 3 condition of the lung is valid as long as the increment in Ppv does not appreciably increase vascular conductance, or modify extramural pressure. In the present study, baseline measurements of
Ppa/Ppv showed an average value of 0.77, reflecting a large zone
3 predominance. The same order of Ppa/Ppv value was obtained by
Brower et al. (7) in zone 3 condition of perfusion. We suggest that
Ppa/Ppv is not equal to 1 in this type of experiment, because some vessel vasomotor tone was maintained, resulting in an average critical opening pressure higher than
PA. This suggests a critical opening pressure higher than PA,
or independent of PA in some regions of the lung, and indicates that some reserve for recruitment persists even if the lung is perfused under zone 3 condition.
Pm) observed in the present study in isolated lungs from
rabbits represented a greater proportion (25 ± 3%) of the total
longitudinal pressure gradient than observed in intact dog lungs (9,
10, 18, 22). This enlargement of Pm, which is attributed to a
reduction in vascular tone (9) and pressure pulsatility (37), persisted
in our preparation, although no vasodilators were added to the
perfusate and although pressure pulsatility was maintained by using a
noncompliant arterial blood reservoir.
Evolution with time and OA injury.
The absence of changes in RT and
CT in either
normal or OA-injured lung implies the stability of the experimental
preparation and the lack of important derecruitment or reduced
distensibility with time. This stability of the OA-induced injury
compared with that observed in intact dog (48) may relate to species
differences, constant pulmonary BF, or dose of OA. Low doses of OA
injury and maximal BF, similar to the low range of control cardiac
outputs in anesthetized rabbit (4), were used in the present study to
avoid large changes in pulmonary hemodynamics that are often associated
with an early and massive hemorrhagic edema when vessel vasomotor tone
is maintained (39). The Pv increased as a function of
time only in the OA-injured groups, as previously reported in studies
of the effects of OA in dog (21) and in rabbit (29).
Transvascular Permeability and Filtration Surface Area
The main finding of the present study was that an elevation in perfusate flow increased Kfc to a greater extent than did Ppv elevation in OA-injured lung. Possible explanations of this phenomenon include: the Kfc measurement technique, an increase in hydraulic conductivity, a displacement of the major site of filtration, or an increase in filtration surface area.Kfc measurement.
Kfc has been
evaluated in numerous studies as the rate of weight gain
(wt/t) after a given increment
in capillary pressure. The weight-gain transient includes increases in
both blood volume and filtration, with increases in blood volume being
more important in the early part of the weight-gain curve (19). Drake
et al. (12) recommend discarding the first 3 min of the weight curve to
eliminate the contribution of the blood-volume increase, and a
logarithmic extrapolation of
wt/t to time
0 to compensate for adjustment of tissue Starling
forces. Because vascular stress relaxation may persist up to 20 min
after an increase in capillary pressure (19), Parker et al. (36) used
measurements of filtration based on the hemoconcentration of the
perfusing blood (35). No significant differences were reported between
the Kfc values derived from the densitometric technique and those derived from the
late slope of weight-gain curves (after 10 min of increased capillary
pressure). In the present study, the
Kfc values using the time 0 extrapolation
technique were correlated to CT,
whereas such a correlation was not observed when
Kfc was measured
by using the late-slope technique. We therefore used the latter
technique, because it is likely to be less influenced by the early
vascular volume changes involved by the influence of BF elevation and
Ppv elevation that are specific to the present study. Changes in
Kfc were highly
correlated by using the two techniques
(r = 0.69, P = 0.0002), although
Kfc values
measured by using the late constant weight-gain technique were 47 ± 4% of the Kfc
values measured by using the time 0 extrapolation technique. This percentage was comparable to that of
Parker et al. (39 ± 4%) (36).
BF dependency of hydraulic conductivity. That an increased BF may induce an alteration of capillary permeability in the lung by overperfusion of the residual lung is suggested by the data of Ohkuda et al. (34) after microembolization in the sheep. Shear stress caused by an increase in blood velocity is given as an explanation for the increased lung lymph flow observed in such a situation. However, this mechanism was considered less likely by the same group, because no increase in permeability was observed when overperfusion was induced mechanically by lung mass resection and transfusion (26). Townsley et al. (45) observed no increase in global Kfc as a function of lung resection in normal dog lungs submitted to constant flow until 80% of the lung mass was removed. They concluded that moderate increases in blood velocity are without effect on hydraulic conductivity. This conclusion in normal lung cannot be extended, without caution, to the injured lung. In the present study, higher regional BF may have contributed to the increased Kfc in the OA-injured lungs because of redistribution of BF, but the lack of change in vascular resistance in the OABF group compared with the OAP group suggests that any shear stress effect would be small.
Displacement of the major site of filtration. The site of maximal filtration is determined by the combination of the local permeability of the vascular wall and of the local intravascular pressure. The major hemodynamic difference between BF and Ppv groups in the present study was an enlargement of the arteriovenous pressure difference. The flow elevation entails a high Ppa and a low Ppv for a given increment in capillary pressure, favoring the filtration in the arterioles compared with the venules. On the contrary, the Ppv elevation entails a high Ppv and a moderate increase in Ppa for a similar increment in capillary pressure, favoring the filtration in the venules compared with the arterioles. Any increase in extra-alveolar vascular pressure on either the arterial or venous side could lead to a multiplicative effect on filtration if combined with an increased extra-alveolar permeability on the same side. A high permeability of the extra-alveolar vessels (2) is proposed as one explanation for the high extra-alveolar/alveolar filtration ratio that is observed in zone 1 condition even in normal lung. However, no differences in extra-alveolar permeability between the arterial and venous sides are observed in either dog (2, 16, 23) or rabbit lung (25). The data of the present study support the concept of an equivalent permeability of the arteriolar and venular extra-alveolar vessels, as differences in Kfc between the flow and Ppv groups were minor in normal lung.
In contrast, the extra-alveolar permeability may be different on the arterial and venous side in the injured lung, depending on the type of injury. Histological findings suggest that the damage in specific types of acute lung injury, i.e., induced by air emboli, is restricted to the arteriolar segment in dog (31) and sheep (3). However, previous histological findings after OA injury in dog suggest minimal damage to extra-alveolar vessels but instead injury primarily of capillaries (11, 32). Moreover, in isolated rabbit lung, Lamm et al. (25) found different extra-alveolar Kfc values with different types of injury, i.e., OA infusion, intratracheal instillation of HCl, or air emboli infusion, when measured in zone 1 condition. In contrast, similar increases in Kfc were observed with the three types of injury perfused in zone 3 condition. OA increased capillary and venous Kfc, but OA did not increase the arterial Kfc. Thus a displacement of the site of filtration toward the arterioles seems unlikely in the present study.BF dependency of filtration surface area: recruitment vs.
distension.
The data of the present study support the assertion that an increase in
BF was associated with recruitment, whereas an increase in Ppv was
associated with distension. As shown by the simplified model described
above (see Appendix), recruitment
and distension produce different effects on
RT and
CT. Although recruitment and distension both decrease RT,
they differ in their effects on
CT. Recruitment is associated
with an increase in CT, whereas
distension is accompanied by a decrease in
CT (Fig.
5). In the present study, CT and calculated Cmv decreased
less with increased BF compared with increased Ppv, whether in normal
or injured lung, supporting the occurrence of recruitment with
increased flow associated with no change in the zonal condition of
perfusion (no change in Ppa/Ppv). On the contrary, the present
data support the occurrence of distension with increased Ppv associated
with an increase in zone 3 vs. zone 2 of perfusion (increase in
Ppa/Ppv). That recruitment is linked to an increase in BF rather
than to an increase in Ppv is supported by the data of other studies.
Wagner et al. (46) showed that capillary recruitment under zone 2 condition occurs primarily by increases in Ppa, whereas an increase in
Ppv has relatively little effect on recruitment. Wang et al. (47),
using fluorescent videomicroscopy of subpleural microvessels, concluded
that capillary blood volume did not change with the transition from
zone 2 to zone 3. Such an observation is also consistent with the data
of Effros et al. (13) that raising flow in zone 2 lungs increases the
permeability-surface area product for a
K+ analog and functional capillary
surface area more than a shift from zone 2 to zone 3 condition of
perfusion by raising left atrial pressure. In the in situ rabbit lung
perfused under zone 3 condition, Toivonen and Catravas (43) observe
that capillary surface area, as evaluated by the angiotensin-converting
enzyme mass, increases with BF and Ppa.
|
BF dependency of filtration surface area in normal lung.
A change in Kfc
implies a change in filtration surface area when hydraulic conductivity
is stable, the latter being expected from normal lung. In the present
study, the mean value of
Kfc in normal
lung was not significantly different, whether using increased
BF or Ppv. In previous studies in normal
dog lungs, Kfc
remained unchanged despite a fivefold decrease in BF with the use of
vasoconstrictors (38) or changing BF over a range from 0.03 to 2.5 l · min1 · 100 g1 under isogravimetric
zone 3 condition (41). However, conflicting results were obtained in
dog lungs by Ehrhart et al. (14). They reported that
Kfc increased by
fivefold when the BF was increased fivefold. These conflicting data may
be explained in part by the important increase in effective filtration
pressure at the end of the filtration period, approaching the high
level where a pressure-induced increase in
Kfc has been
observed in similar preparations (38, 44).
BF Dependency of Filtration Surface Area in Injured Lung Cmv/CT
Microvascular compliance increases. In the present study, RT was essentially unchanged in the OA-injured lung whether after Ppv or BF elevation. On the contrary, the percentage of Cmv/CT in the injured lung decreased after Ppv elevation, whereas it increased after BF elevation (Fig. 3). These changes suggest a phenomenon of capillary recruitment with BF elevation that is specific to the injured lung. Such capillary recruitment helps in interpreting the cause of an increase in filtration coefficient. If the OA-induced increase in hydraulic conductivity is considered similar in the pressure and flow groups, the observed differences in Kfc after Ppv or BF elevation reflect differences in filtration surface area linked to differences in capillary recruitment. The increased Kfc and increased Cmv/ CT suggest that BF recruits injured capillaries that were previously closed to perfusion.
If a simple Starling resistor model is used, critical opening of a vessel results when the intravascular pressure exceeds the extravascular surrounding pressure, i.e., PA or vascular vasomotor tone. There is some evidence that vascular vasomotor tone is increased in OA-injured lung compared with normal lung (39). Because the Ppa was higher during BF elevation than during Ppv elevation, intravascular pressures that exceed the critical opening pressure of additional capillaries are more likely. Although Pao was not statistically different in the two groups, there was a tendency for Pao to be higher in the flow group compared with the Ppv group in both normal and injured lungs. This modest increase in Pao could induce the consistent increase in Cmv/CT observed in the present study. Another explanation for the recruitment is the shear stress of the endothelium generated by a high BF. It may be associated with an elevation of nitric oxide production by endothelial cells (27), which may decrease vasomotor tone and decrease the critical opening pressure. This mechanism may explain the fact that CT decreased less during Kfc measurement in the high-BF group compared with high-Ppv group in both normal and injured lungs. The vasodilatation induced by nitric oxide is proportional to the preexisting vasoconstriction (27) associated with OA injury. The increase in flow may have entailed a vasodilatation of the injured microcirculation and an increase in Cmv/CT.Does the recruitment of blind vessels coexist with the recruitment
of open vessels (Fig. 6)?
Indeed, a difference in filtration pressure cannot explain the increase
in capillary recruitment and in
Cmv/CT ratio after BF compared
with Ppv elevation, because Pdo of a similar magnitude was observed in
both groups during the
Kfc-measurement
maneuvers. Another possible explanation is a shift of the zonal
condition of perfusion from zone 2 to zone 3. Because the initial
values of Ppa/Ppv were not equal to 1, the Pdo elevation during
the Kfc-measurement
maneuver could increase capillary recruitment by changing zonal
condition from zone 2 to zone 3. However, the increase in BF did not
result in an increase in Ppa/Ppv, and hence in the amount of zone
3 perfusion, in either normal or injured lungs. We therefore suggest
that increasing BF may have increased both zone 2 and zone 3 conditions
at the expense of zone 1. Moreover, because the
RT and the fractional Pm
gradient did not decrease after BF elevation, we suggest that the newly
recruited vessels were few but were more permeable than those that were
already perfused.
|
Ppv gradient in the OA-injured
lung compared with the normal lung (see Table 1). This venous obstacle
may be the result of a venospasm by inflammatory mediators and
thromboxane (21, 39). It may also be the result of the displacement of
capillary thrombi from capillaries to veins when flow increases. Such
thrombi, formed of fibrin, platelets, and cells debris, are reported in
ultrastructural studies of OA-injured dog lung as soon as 1 h after OA
infusion (11). Whatever the reason for venous
obstruction, BF increase could result in the recruitment of nonflowing
injured vessels and in an increase in
Cmv/CT, because stagnant blood
would pool in the arterial and middle part of the vessels. Stagnation
of blood in open capillaries could dramatically affect filtration by
affecting Starling forces for filtration across injured capillaries. Interstitial protein concentration around such capillaries could approach plasma protein concentration because the reflection
coefficient for proteins is lowered by injury. This could result in a
low transvascular oncotic pressure gradient in injured lung compared with normal lung. Moreover, because these injured capillaries would
have no BF, while remaining open at their arterial end, the filtration
pressure would equilibrate with pulmonary arteriolar pressure. Thus
filtration would actually be greater in those blind capillaries with
stagnant blood than in flowing capillaries. The opening of blind
vessels to pulmonary arteriolar pressure would be consistent with
observations, made in dogs with heterogeneous OA-induced edema, that
areas with the greatest increase in pulmonary transcapillary escape
rate for proteins are also the areas with the greatest reduction in BF
(40). Thus the arterial opening of blind vessels remains, at the
present time, a possible explanation that warrants a further specific
demonstration.
A similar mechanism could apply to vessels perfused under zone 2 conditions. The steep pressure gradient observed during increased flow
involves a high Ppa and a low Ppv that can result in a distension of
the arterial ends of arterioles and capillaries and in a downsteam movement of the compression point toward the venous ends of capillaries and venules. Such a hemodynamic regimen could increase
Cmv/CT and surface filtration
area. This mechanism would be consistent with observations reported by
Effros et al. (13), that raising flow in zone 2 lungs increases the
pulmonary surface area product for a
K+ analog in normal lung. The
application of the above mechanism to the increased
Kfc in the
OA-injured lung subjected to an increased BF remains speculative and
deserves further study.
Implications for the In Vivo Studies of Capillary Permeability
An increment in Ppc and a full recruitment of filtration surface area are required to test the permeability of pulmonary microcirculation by using the lymph protein washdown method in in vivo preparations (42). These requirements are usually met by an elevation in Ppv. Because this is usually done by inflating a left atrial balloon and results in a decreased cardiac output, the Ppa increases relatively little compared with Ppv, such that capillary recruitment may actually be partially offset. However, in normal dog lung, the pulmonary lymphatic flow and protein concentration response is not very different whether the increment in capillary pressure is generated by an elevation in cardiac output or in Ppv (15). In contrast, the situation may be very different in lung injury. A recruitment of injured capillaries by BF may occur, as evidenced by the increase in lung water observed with high cardiac output in OA-induced pulmonary edema in dog (20). Further work is needed to validate the response of the in vivo models of lung injury to high cardiac output states.Clinical Implications
Recent studies suggest that reduction of high-permeability pulmonary edema in the early phase of acute respiratory distress syndrome decreases morbidity (30). Even a small increase in Ppc results in an increase in pulmonary edema formation when a capillary injury is present. Increases in filtration surface area may also have important consequences on transcapillary filtration when injured capillaries are filled with blood whether perfused or not perfused. Data from the present study suggest that an increase in cardiac output and Ppa would aggravate high-permeability pulmonary edema to a greater extent than an increase in Ppv would. Circumstances where cardiac output is elevated, i.e., transfusion and the early phase of septic shock, could be more detrimental in high-permeability pulmonary edema formation than circumstances, i.e., left ventricular failure, where Ppv is elevated. Accordingly, the conclusion of the present study lends further support to the therapeutic importance of maintaining a low Ppa in high-permeability pulmonary edema (5).In conclusion, the filtration coefficient was measured in normal and in OA-injured rabbit lung by using similar increments in capillary pressure, obtained either by an elevation of Ppv or by an elevation of BF. A greater increase in filtration coefficient was obtained in OA-injured lungs by increasing BF than by Ppv elevation. We suggest that an increase in BF and Ppa, compared with an elevation of Ppv, enhances the arterial opening of few but seriously injured capillaries, with the possibility that some of them may be nonflowing because of a downstream obstruction. These mechanisms may apply to clinical situations where a high-permeability pulmonary edema is present.
| |
APPENDIX |
|---|
We designed a simplified model of the lung vasculature to predict to what extent RT and CT would change with recruitment or distension. The model includes n flow channels in parallel and n possible increments in vessel diameter. The theoretical curves of RT and CT are drawn first in relation to the recruitment of n flow channels with a set diameter (D) if only recruitment occurs, where Ci and Ri are compliance and resistance of the ith channel.
|
|
RT = K1/D4 and CT = K2/D + K3/D2, if only distension occurs, where K1 is a blood viscosity and vessel-length-related constant, K2 and K3 are adjustment constants, and D is the vessel diameter (24).
| |
ACKNOWLEDGEMENTS |
|---|
We thank Michèle Delaire for valuable technical assistance.
| |
FOOTNOTES |
|---|
Address for reprint requests: F. Grimbert, PRETA, Département de Physiologie, Faculté de Médecine de Grenoble, 38 700 La Tronche, France (E-mail: Francis.Grimbert{at}imag.fr).
Received 25 February 1997; accepted in final form 7 November 1997.
| |
REFERENCES |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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, 
) or
pulmonary venous pressure (Ppv; 
, 
). Ppa, pulmonary arterial
pressure; n, no. of experiments.
* Significant difference between groups at end of blood flow or
Ppv elevation during final
Kfc-measurement maneuver.
Significant difference linked to BF or Ppv elevation during
Kfc-measurement
maneuver in OA-injured lungs.
) in model of pulmonary
circulation including n parallel dilatable channels, some of which are unperfused. If full recruitment occurs, RT decreases with no. of
open channels, whereas CT
increases. If distension of already open channels occurs, both
RT and
CT decrease.
