Ill
Alveolar Hypoxia Increases Lung Fluid
Filtration in Unanesthetized Newborn
Lambs
MICHAEL A. BRESSACK AND RICHARD D. BLAND
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SUMMARY We studied the pulmonary vascular response to hypoxia and associated transvascular
flux of fluid into the lungs of newborn lambs. After a 2-hour baseline period, 14 unanesthetized lambs,
1-3 weeks old, breathed 10-12% oxygen in nitrogen for 3-6 hours. We measured steady state lung
lymph flow, pulmonary arterial and left atrial pressures, blood flow to the lungs, and the concentration
of protein in lymph and plasma. As Pao2 decreased from 81 ± 3 torr to 32 ± 1 torr, pressure in the
pulmonary artery almost doubled, left atrial pressure was unchanged, and pulmonary blood flow
increased by 14%. Calculated pulmonary vascular resistance increased by 69%. Contrary to results of
previous experiments performed with mature sheep, lymph flow increased by 80%, and the concentration of protein in lymph decreased during hypoxia. These results suggest that hypoxia increased the
pulmonary transvascular gradient of hydraulic pressure in the lambs, increasing filtration of fluid into
the lungs. Possible explanations are that pulmonary vasconstriction during hypoxia (1) occurred distal
to the sites of transvascular fluid flux or (2) redistributed the increased blood flow to fewer lung
vessels, thereby increasing intravascular pressure at the sites of fluid exchange. Postmortem lung
blood content was significantly less than that of control lambs, but there was no difference in
extravascular lung water content or lung histology, suggesting that pulmonary lymph flow kept pace
with transvascular filtration of fluid and prevented pulmonary edema. The concentration of protein in
lymph relative to that in plasma decreased with hypoxia, and the ratio of [albumin] to [globulin] in
lymph was unchanged, indicating that sustained alveolar hypoxia of this magnitude had no demonstrable effect on the sieving characteristics of the pulmonary endothelium of the lambs. Circ Res 46:
111-116, 1980
A REDUCED supply of oxygen, such as that experienced at high altitude, sometimes induces pulmonary edema in the absence of heart failure. Pulmonary edema at high altitude is more common in
infants and children than it is in adult humans
(Hultgren et al., 1961; Scoggin et al., 1977), suggesting that lung maturation may be an important
element in the adaptive response to hypoxia.
Bland et al. (1977) reported that alveolar hypoxia
had no effect on pulmonary lymph flow or the
concentration of protein in lymph of eight awake
sheep breathing 10% oxygen for 4 hours compared
to measurements made during a 2-hour control
period in which the sheep breathed air. Even when
hypoxia was sustained for 2 days in three of the
sheep, lymph flow did not increase.
To see if the pulmonary microcirculation of
lambs and sheep might react differently to hypoxia,
From the Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco.
Supported in part by National Heart and Lung Institute Pulmonary
Specialized Center of Research (SCOR) Grant HL 19185. Dr. Bressack
was a trainee supported by National Heart, Lung, and Blood Institute
Pulmonary Faculty Training Center Grant HL 07159. This work was
completed during Dr. Bland's tenure as an Established Investigator of the
American Heart Association.
Parts of this work were presented at meetings of the Western Society
for Pediatric Research, Carmel, California, February 1979, and the American Federation for Clinical Research, Washington, DC, May 1979.
Address for reprints: R.D. Bland, M.D., Cardiovascular Research
Institute, University of California, San Francisco, California 94143.
Received June 25, 1979; accepted for publication October .'I, 1979
we assessed lung fluid balance in 14 unanesthetized
lambs, 1-3 weeks old, breathing 10-12% oxygen for
3-6 hours after a 2-hour steady state period in air.
Contrary to results with sheep, pulmonary lymph
flow increased and the concentration of protein in
lymph decreased significantly in the lambs, suggesting that hypoxia caused an increase in the pulmonary transvascular pressure gradient, thereby
increasing filtration of fluid into the lungs of the
lambs. As in previous studies, there was no evidence
of altered pulmonary microvascular permeability to
protein during hypoxia.
Methods
Preparation of Lambs for Experiments
Using methods previously described (Staub et
al., 1975; Bland and McMillan, 1977), we surgically
prepared 14 newborn lambs (average birth weight,
3.7 ± 0.3 kg) to collect lung lymph and measure
average pulmonary arterial, left atrial, and aortic
blood pressures. Each lamb had two thoracotomies,
the first at 1-2 days of age and the second 3-7 days
later. We use halothane and nitrous oxide anesthesia and ventilated the animals with a piston-type
respirator (model 607, Harvard Apparatus Co., Inc.)
during surgery. Before and after surgery, and between experiments, the lambs remained with their
ewes for feeding and warmth.
In the first operation we placed polyvinyl cathe-
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CIRCULATION RESEARCH
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ters (Tygon Tubing) in the thoracic aorta, pulmonary artery, and both atria. In the second operation
we resected the systemic contribution to the caudal
mediastinal lymph node and inserted a heparincoated (TDMAC Processing, Polyscience Inc.) polyvinyl catheter (internal diameter, 0.38 mm) into
the efferent duct of that node for collection of nearly
pure pulmonary lymph. Previous studies showed
that this fluid is not contaminatd by lymph of
systemic origin (Staub et al., 1975). We tunneled
the catheter beneath the pleura and through the
chest wall, securing it to the skin with a suture and
protecting it with a canvas pouch. In addition, we
placed a 4 X 2 cm silicone (Silastic, Dow Corning
Corp.) balloon and a polyvinyl catheter in the
pleural space for subsequent measurement of
pleural pressures and postoperative drainage of
fluid and air. The lambs had at least 3 days to
recover from surgery, and experiments did not begin
until the lymph was free of visible blood and flowing
at a steady rate.
Description of Experiments
The average weight of the lambs at the time of
experiments was 6.5 ± 0.5 kg; their average age was
14 ± 1 days. During studies, the lambs were awake
and unmedicated, resting on a canvas sling that did
not interfere with respiratory movements. We administered gas mixtures through a plastic bag
around the lamb's head. Each lamb received isotonic saline, approximately 5 ml/hr per kg body
weight, intravenously during experiments, an
amount that yielded no significant change in body
weight, vascular pressures, or concentrations of protein in plasma. The design of the 17 experiments
was similar to that of the previous studies performed with sheep (Bland et al., 1977): after a 2hour control period in air, the lambs breathed 1012% oxygen in nitrogen during a steady state period
lasting 3 or 6 hours. In 11 experiments the lambs
were hypoxic for 3 hours; in six experiments we
extended the study period to 6 hours.
During all experiments we measured pressures
continuously in the pulmonary artery, left atrium,
thoracic aorta, and pleural space, using calibrated
pressure transducers (Statham P23 Dc, Statham
Instruments, Inc.) and a six-channel amplifier-recorder (Grass model 7B, Grass Instruments Co.).
Zero reference level for measurement of vascular
pressures was a line drawn on the lamb's skin at
the level of the left atrium at the time of surgery;
for measurement of pleural pressure, zero reference
was atmospheric pressure.
We measured the flow of lymph to the nearest
0.01 ml at 30-minute intervals for at least 2 hours
during a steady state baseline period, and then for
3 or 6 hours with thelamb breathing 10-12% oxygen
in nitrogen. The change in the inspired oxygen
concentration was sufficient to keep the partial
pressure of oxygen in arterial blood at 30-35 torr.
We collected samples of lymph and blood in heparinized test tubes every 30 minutes, taking blood at
VOL. 46, No. 1, JANUARY 1980
the midpoint of each lymph collection period. During control and experimental periods we measured
respiratory frequency, heart rate, and rectal temperature, and obtained samples of arterial blood at
frequent intervals for measurement of packed cell
volume (hematocrit), pH, and blood gas tensions.
We measured pulmonary blood flow (cardiac output) by indicator dilution (Rudolph, 1974) using
cardiogreen dye (Hynson, Wescott, and Dunning,
Inc.) and calculated pulmonary vascular resistance
as (pulmonary arterial pressure — left atrial pressure)/pulmonary blood flow.
Postmortem Studies
At the conclusion of experiments on each lamb,
we injected pentobarbital sodium, 20 mg/kg, into
the right atrium, placed the lamb supine, ventilated
the lungs with 10% oxygen in nitrogen via the
respirator, and rapidly split the sternum to excise
the lungs. We clamped the hili of both lungs at endinspiration, at an airway pressure of 25 cm H2O,
with the heart still beating, and removed the lungs
for measurement of blood content, extravascular
water, and dry lung tissue weight. We did this with
nine lambs immediately after a 4- to 6-hour period
of steady state hypoxia, and compared the results
to measurements made on lungs of control lambs
killed during ventilation with air. Control and experimental lambs had undergone the same surgical
procedures.
We rapidly froze in liquid nitrogen part of the
inflated- lung tissue of six lambs and prepared a
section from each for microscopy by the method of
Storey and Staub (1962).
Analytic Methods
We centrifuged samples of lymph and blood and
measured the concentration of protein in the supernatant fluid by the biuret method (Henry et al.,
1957), with protein fractionation by cellulose acetate electrophoresis (Microzone 110, Beckman instruments, Inc.). We measured the pH and partial
pressure of gases in arterial blood with a blood gas
analyzer (Acid-Base Analyzer PHM 71, Radiometer
Co.), with calibration at 40°C, the normal body
temperature of lambs.
We calculated the weight of extravascular lung
water per gram of dry lung tissue, exclusive of blood,
for all lambs by a modification (Erdmann et al.,
1975) of the method described by Pearce et al.
(1965). We expressed pulmonary blood flow (cardiac
output), lung lymph flow, and lymph protein flow
(lymph flow X lymph protein concentration) relative to the weight of dry, bloodless lung tissue. We
also expressed protein flow in relation to the concentration of protein in the plasma of each animal.
Statistical Analysis
We used the paired £-test (Snedecor and Cochran, 1972) to compare measurements made during
air breathing with those obtained during steady
state hypoxia, accepting P < 0.05 as indicative of
LUNG FLUID BALANCE IN HYPOXIC NEWBORN LAMBS/Bressack and Bland
113
the changes in pleural pressure. These alterations
in the pattern of breathing produced a decrease in
the partial pressure of carbon dioxide in arterial
blood (Pacoa) and an increase in pH. Heart rate
increased with hypoxia, but there was no change in
aortic blood pressure.
Lung Lymph
Flow
(ml-rf'g" 1 )
Proiein
Concentration
(q-dl' 1 )
Vosculor
Pressure
(torr)
Hours
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FIGURE 1 Effects of 6 hours of hypoxia on lung lymph
flow, concentrations of protein in lymph and plasma,
and average vascular pressures of an unanesthetized 2week-old lamb.
significant differences. Measurements of postmortem lung blood and lung water content in hypoxic
and control lambs were compared by the unpaired
t-test. All summary results in the text and the tables
are expressed as the mean ± one standard error of
the mean.
Effects of Hypoxia on Lung Fluid and Protein
Transport
Table 2 shows the data related to lung fluid and
protein transport. Average pressure in the pulmonary artery (Ppa) almost doubled during hypoxia,
while average pressure in the left atrium (Pla) did
not change. Pulmonary blood flow increased, on
average, by 14%, and calculated pulmonary vascular
resistance increased by 69%. These circulatory effects were associated with an 80% increase in the
flow of pulmonary lymph and a concomitant decrease in the concentration of protein in lymph
from 3.8 ± 0.2 g/dl to 3.2 ±0.1 g/dl. During hypoxia,
average lymph protein flow increased by 45% above
the control value. The concentration of protein in
plasma was unaffected by hypoxia; the ratio of the
concentration of protein in lymph to that in plasma
decreased significantly from 0.65 to 0.54. Hypoxia
did not significantly change the concentration of
albumin relative to globulin in lymph or plasma.
Figure 1 shows the results of a typical experiment
in which a lamb breathed 11% oxygen in nitrogen
for 6 hours after a 2-hour control period in air.
Hypoxia produced an abrupt increase in the flow of
lymph, with an associated decrease in the concentration of protein in lymph, as pressure in the
pulmonary artery doubled. Vascular pressures, protein concentrations, and lymph flow returned to
baseline with resumption of air breathing.
Because the effects of hypoxia for 3 hours were
indistinguishable from those observed in the longer
experiments, we pooled (in Tables 1 and 2) the data
for the 17 experiments.
Postmortem Findings
Table 3 shows the content of blood and extravascular water in the lungs of nine lambs killed after
4-6 hours breathing 10-12% oxygen, compared to
measurements made on the lungs of 10 control
lambs killed without preceding hypoxia. Lung blood
per gram of dry lung tissue was significantly less in
the hypoxic lambs, but there was no significant
difference in lung water content. Consistent with
these findings, we observed by light microscopy
that the lungs of hypoxic lambs were more pallid
than those of control lambs; as shown in Figure 2,
there was no evidence of alveolar or interstitial
edema or hemorrhage in the lungs of lambs made
hypoxic for 4-6 hours.
Effects of Hypoxia on Respiration and
Circulation
Table 1 is a summary of the effects of hypoxia on
respiration and systemic circulation in the 14 lambs.
The decrease in the partial pressure of oxygen in
arterial blood (Pao2) from 81 ± 3 torr to 32 ± 1 torr
caused tachypnea and hyperpnea, as indicated by
Previous studies have demonstrated that measurement of pulmonary lymph flow and the concentration of protein in lymph is a sensitive index of
the net transvascular movement of fluid and protein
in the lung (Staub, 1971, 1974; Brigham et al, 1974;
Results
Discussion
TABLE 1 Effects of Hypoxia on Respiration and Systemic Circulation in 14 Lambs
Control
Hypoxia
Respiratory
frequency
(breaths/min)
Pao2
(torr)
PacoL.
(torr)
81
±3
38
±1
7.44
±0.01
±2
32*
28*
±1
7.50*
±0.01
±3
+1
Results are expressed as mean ± SK.
* Significant difference, P < 0.05.
50
67
Mean pleural
pressure (torr)
Pleural pressure difference
between end-inspiration and
end-expiration (torr)
-3
±0.4
4
±1
196
±7
79
±2
-5*
±0.4
9*
±1
236*
±8
78
±2
Heart rate
(beaus/min)
Mean aortic blood
pressure (torr)
114
TABLE
CIRCULATION RESEARCH
2 Data Pertaining to Lung Water and Protein Transport in 14 Lambs
Vascular pressures
(torr)
Lamb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Mean
±SE
VOL. 46, No. 1, JANUARY 1980
Ppa
18—
16—
16—
17—
17—
20—
18—
16—
15—
17—
13—
15—
16—
16—
16—
±1
34
33
28
37
27
31
31
32
29
35
23
33
30
32
31:):
±1
Protein concentrations (g/dl)
Pla
Lymph
Plasma
2— 3
2—2
3—2
3—3
1—0
2— 1
3—2
1— 1
2—2
1— 1
1— 1
3—4
4—5
1— 4
2—2
±.3 ±.5
3.0 — 2.4
3.7— 2.9
4.3 — 3.6
3.8— 3.1
3.0 — 2.9
3.4 — 2.8
3.3 — 2.4
3.6— 2.8
4.0 — 3.3
3.9 — 3.4
4.2 — 3.8
4.3 — 3.3
3.7— 3.2
5.2 — 4.3
3.8 — 3.2:):
±.2 ±.1
4.7 — 4.6
6.5— 6.7
6.8 — 6.7
5.9 — 5.7
5.7 — 5.7
5.3 — 5.5
6.2 — 6.0
5.2— 5.1
5.9 — 5.9
5.8 — 6.2
5.9 — 6.2
5.9 — 5.9
5.8 — 5.8
6.9 — 6.9
5.9— 5.9
±.2 ±.2
Lymph: Plasma
blood flow
(ml/min)"
— 0.53
— 0.44
— 0.54
— 0.54
— 0.51
— 0.50
— 0.40
— 0.55
— 0.56
— 0.55
— 0.61
— 0.56
— 0.55
— 0.69
— 0.54:):
±.02
98 — 127
147— 197
101 — 114
99— 138
112— 160
77 — 90
89—91
176— 185
66— 92
102— 113
84— 108
118— 147
153 — 183
82 — 93
108 — 123f
±8
±10
0.64
0.57
0.62
0.65
0.53
0.64
0.54
0.70
0.68
0.67
0.71
0.73
0.63
0.76
0.65
±.02
[Albumin): [globulin |
Pulmonary
Lymph flow
(ml/hr)"
Lymph
Plasma
0.06 — 0.08
0.05 — 0.05
0.09—0.18
0.10— 0.15
0.17— 0.22
0.08— 0.17
0.11 — 0.25
0.11 — 0.23
0.06—0.12
0.14 — 0.29
0.13— 0.18
0.06 — 0.10
0.21 — 0.40
0.07— 0.10
0.10—0.18:):
±.01 ±.02
0.80 — 0.86
0.84 — 0.88
0.88— 1.21
0.85— 1.01
1.07— 1.12
0.87 — 0.68
0.89 — 0.93
0.96— 1.06
0.94 — 1.06
0.94 — 0.97
1.12— 1.19
0.76 — 0.75
1.18— 1.54
1.22— 1.14
0.95— 1.03
±.04 ±.06
0.61 — 0.62f
0.61 — 0.62
0.60 — 0.83
0.66 — 0.64
0.70 — 0.68
0.53 — 0.47
0.46 — 0.51
0.63 — 0.62
0.58 — 0.64
0.71 — 0.76
0.67 — 0.64
0.53 — 0.55
1.03— 1.16
0.66 — 0.58
0.64 — 0.67
±.04 ±.05
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* Per g of dry lung tissue, exclusive of blood, measured postmortem.
f Numbers to the left of the arrow are measurements made before hypoxia, those to the right are measurements during hypoxia.
% Significant difference, P < 0.05.
TABLE 3 Blood and Extravascular Water in the Lungs*
Experimental
conditions
No. of lambs
Weight of dry lung
tissue (g)
Hypoxia for 4-6 hr
Breathing air
10
Lung blood/dry
lung tissue
Extravascular lung
water/dry lung tissue
20.5
±1.7
1.50
±0.18
4.54
±0.13
20.5
±1.4
2.22
±0.25
4.72
±0.14
t
* For lambs killed after breathing 10-12% oxygen in nitrogen for 4-6 hours and for control lambs without
preceding hypoxia; results are expresoed per unit of dry lung tissue, exclusive of blood, measured postmortem.
t Significant difference, P < 0.05.
Staub et al., 1975; Erdmann et al., 1975; Bland et
al., 1977), assuming that the concentration of protein in lymph approximates that in the pulmonary
interstitium (Nicolaysen et al., 1975; Vreim et al.,
FIGURE 2 Photomicrograph of a section of frozen lung,
taken at an inflation pressure of 25 cm H>O, from a lamb
killed after breathing 11% oxygen for 6 hours. Lung
architecture is normal, and there is no visible fluid
within the air spaces or surrounding blood vessels. Magnification is 8.5X.
1976). In newborn lambs, about two-thirds of the
pulmonary lymph flows through the caudal mediastinal lymph node into the thoracic duct (Humphreys et al., 1967).
The 80% increase of pulmonary lymph flow that
we observed in lambs breathing 10-12% oxygen in
nitrogen for 3-6 hours shows that alveolar hypoxia
increases transvascular filtration of fluid into the
lungs of awake newborn lambs. The associated decrease of the concentration of protein in lymph,
without a change in plasma protein concentration,
suggests that the increased filtration of fluid was
the result of an increased transmural pressure gradient in the pulmonary microcirculation. The 45%
increase in net protein flux is consistent with a
pressure-evoked difference in fluid filtration (Erdmann et al, 1975; Bland and McMillan, 1977).
Based on the data of Erdmann et al. (1975), an
80% increase in lymph flow and a decrease in
[lymph protein]: [plasma protein] from 0.65 to 0.54
would result from a 6 to 7 torr increase of pulmonary
microvascular pressure (Pmv). If we calculate Pmv
as Pla + 0.4 (Ppa - Pla) (Gaar et al., 1967), Pmv
increased in the lambs by 6 torr during hypoxia.
That is, the changes that we observed in lymph
flow and lymph protein concentration were consist-
LUNG FLUID BALANCE IN HYPOXIC NEWBORN LAMBS/Bressack and Bland
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ent with a pressure-induced change in lung fluid
filtration.
Hypoxia did not increase pulmonary microvascular permeability to protein, in that the concentration of protein in lymph decreased during hypoxia.
Had vascular permeability been affected, we would
have expected the concentration of protein in
lymph to remain stable or increase (Brigham et al.,
1979; Bressack et al., 1979) as the flow of lymph
increased. The fact that [albumin] : [globulin] in
lymph did not decrease with hypoxia is further
evidence that the sieving characteristics of the pulmonary endothelium did not change appreciably in
these animals (Brigham et al., 1979; Bressack et al.,
1979).
It is not likely that hypoxia increased lung fluid
filtration solely by recruiting new vessels, thereby
increasing vascular surface area for exchange of
fluid in the lung. Had this been the major source of
the increased flow of lymph, the concentration of
protein in lymph would have been unchanged, and
the content of blood in the lungs of hypoxic lambs
should have been greater than that of control animals. Our finding of decreased blood in the lungs of
lambs that were killed during hypoxia is consistent
with the observation of Stahlman et al. (1967) who
from indicator dilution curves estimated pulmonary
blood volume in lambs before and during hypoxia.
The reduced pulmonary blood volume in hypoxia
probably reflects a constricted lung vascular bed.
Is it possible that hypoxia decreased intracellular
fluid within the lung, diluting the concentration of
protein within the pulmonary interstitium, and enhancing the flow of lymph? This is unlikely, in that
lung water content was not significantly different
after 6 hours of hypoxia than it was in control
lambs; neither was there any difference in lung
architecture microscopically between the two
groups of lambs. Furthermore, the sustained nature
of the increased lymph flow is more consistent with
altered filtration of fluid from the bloodstream,
rather than cellular dehydration.
The outcome of these experiments, and similar
ones performed on adult sheep (Bland et al., 1977),
indicate that the pulmonary microcirculation of
newborn and mature sheep respond differently to
alveolar hypoxia. In sheep, a decrease in the partial
pressure of oxygen in arterial blood from 97 ± 2 torr
to 38 ± 1 torr caused pulmonary vascular resistance
to increase by 54%, with no change in the rate of
flow or the concentration of protein of lung lymph.
In lambs, hypoxia of a similar degree induced a 69%
increase in pulmonary vascular resistance, with a
substantial increase in the transvascular flow of
fluid into the lungs. Pulmonary edema did not
occur, presumably because lymph flow kept pace
with transvascular filtration of fluid.
Our observations do not define the mechanism
by which hypoxia increased the pulmonary transvascular gradient of hydraulic pressure in lambs
without doing so in sheep, but certain possibilities
115
are noteworthy. Pulmonary arterial pressure and
cardiac output under baseline conditions were
greater in lambs than in sheep, and it is possible
that the pulmonary microcirculation of the lambs
had a smaller reserve capacity to accommodate the
increased flow of blood caused by hypoxia.
Hypoxia could have caused pulmonary venous
constriction in the lambs without doing so in mature
sheep. Work by Naeye (1965) suggested that hypoxia produces such an effect in calves, but does
not do so in mature dogs. Rivera-Estrada et al.
(1958) and Morgan et al. (1968) presented evidence
that, even in adult dogs, most of the increase in
pulmonary vascular resistance that occurs during
hypoxia is the result of increased venous tone. Most
investigators, however, have found that hypoxia
produces predominantly arteriolar constriction
(Kato and Staub, 1966; Bergofsky et al., 1968; Glazier and Murray, 1971; Malik and Kidd, 1976). In
studies of lambs that were beyond the newborn
period and weighed 25-38 kg, Hyman and Kadowitz
(1975) showed that lobar ventilation with 5% oxygen
in nitrogen increased pulmonary arterial pressure,
without a comparable increase in pulmonary venous
pressure, suggesting that the constrictive response
was predominantly pre-venous. The apparent inconsistency of this observation and our results could
stem from differences in the degree of hypoxia or in
the age and maturity of the animals that were
studied. We cannot exclude the possibility that
water may leave the pulmonary vascular bed
through small arterioles in hypoxic lambs, as
Whayne and Severinghaus (1968) suggested, but if
this is the case, it would appear to be an age-related
phenomenon, in that lymph flow did not increase
in adult sheep (Bland et al., 1977).
An alternative explanation for the increased flow
of lymph in hypoxic lambs is that intense constriction of pulmonary arteries during hypoxia diverts the increased flow of blood to fewer vessels in
the lung, thereby increasing the transvascular pressure gradient within those vessels. That is, redistribution of blood flow may transmit a greater percentage of pressure in the pulmonary artery to
vessels that participate in fluid exchange. Hultgren
and Grover (1968) invoked this theory to account
for the development of pulmonary edema in humans who ascend to high altitude. Such an explanation is consistent with our findings of reduced
lung blood in lambs with hypoxia.
In previous experiments with sheep, hypoxia led
to hyperpnea, but did not cause an increase in
respiratory frequency (Bland et al., 1977); in lambs
hypoxia was associated with tachypnea, as well as
hyperpnea and a decrease in mean pleural pressure.
Another consideration, therefore, is that the
breathing pattern elicited by hypoxia enhanced pulmonary transvascular filtration of fluid in lambs by
decreasing lung tissue pressure. Although this explanation for our findings is possible, recently Haberkern and Bland (unpublished observations) re-
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produced the respiratory pattern observed in the
hypoxia experiments by allowing eight lambs to
breathe 10% carbon dioxide in air for several hours,
inducing both tachypnea and hyperpnea, without
an appreciable change in the steady state flow of
pulmonary lymph.
In sheep, hypoxia caused an increase in the concentration of protein in plasma (Bland et al., 1977),
thereby increasing the transvascular gradient of
protein osmotic pressure, a change that tends to
inhibit filtration of fluid into the lungs. This change
did not occur in lambs during hypoxia, presumably
because they did not have an associated diuresis. It
is possible that this difference in the response to
hypoxia may account partly for the failure of lymph
flow to increase in hypoxic sheep as it did in hypoxic
lambs.
We conclude from these experiments that sustained alveolar hypoxia does not increase pulmonary microvascular permeability to protein in
lambs, but does increase the pulmonary transvascular pressure gradient, thereby enhancing filtration of fluid into the lungs. In normal lambs, the
flow of lymph keeps pace with filtration, such that
pulmonary edema does not occur.
Speculation. It is possible that by imposing an
additional stress, such as exercise (Whayne and
Severinghaus, 1968; Viswanathan et al., 1969), an
intravascular infusion of fluid (Courtice and Korner,
1952), or raised pulmonary venous pressure (Haddy
et al., 1950) in the presence of hypoxia, we could
have induced pulmonary edema in the lambs. Likewise, during absorption of liquid from the lungs at
birth, with concurrent hypoxia it is possible that
the combination of increased transvascular and
transepithelial filtration of fluid might exceed the
reserve capacity of the microcirculation and lymphatic system in the lungs. In this way, perinatal
hypoxia might produce pulmonary edema and respiratory distress.
Acknowledgments
We thank Luther Dong for his technical assistance, and
Marilyn Biagini for her secretarial help.
References
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M A Bressack and R D Bland
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Circ Res. 1980;46:111-116
doi: 10.1161/01.RES.46.1.111
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