- Email: [email protected]
Effects of mannitol and dextran on interstitial pulmonary edema
JOURNAL
OF
SCRGICAL
EFFECTS
MICHAEL
E.
12, 236239
RESEARCII,
OF
REIF,
(1972)
MANNITOL AND PULMONARY M.D.,
JAMES AND
R.
DEXTRAN EDEMA
MCCURDY,
LAZAR
J.
PROGRESSIVE PULMONARY INSUFFICIENCY characterized by reduced pulmonary compliance and hypoxia has been termed the “wet-lung syndrome” because of the extensive interstitial pulmonary edema usually found at autopsy [5]. This syndrome can follow a variety of insults including trauma, sepsis, and resuscitation from burns and shock. Although the use of crystalloid infusion therapy has frequently been incriminated as an etiological factor, we have recently shown that the pulmonary effects of interstitial edema induced by hemodilution differ considerably from the effects of hydrostatic edema [I]. Using the isogravimetric perfused canine lung preparation, interstitial edema produced by progressive venous constriction was found to simulate more closely the clinical problem of reduced compliance, hypoxia, and increased pulmonary capillary pressure. In this report, the effectiveness of mannitol and low molecular-weight dextran were compared to determine the response of the edematous lung t,o these osmotic agents.
The isogravimetric perfused canine lung preparation has been described previously utilizing healthy adult mongrel dogs anesthetized with pentobarbital (30 mg./kg.) and exsanguiFrom the Departments of Surgery and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104 and Veterans Administration Hospital, Oklahoma City, Oklahoma 73104. This investigation supported in part by U. S. Navy Contract NOOO14-68-A-0946 and the Markle Foundation. Submitted for publication Jan. 7, 1972. 234 Q 1972 by Academic
Press,
Inc.
JACQliELINE
INTERSTITIAL
J.
COAT&ON,
PH.D.,
M.D.
nated to prime the perfusion system [3]. The lungs were perfused with deoxygenated blood and ventilated with ambient air. Perfusion pressures for maximum flow without weight gain averaged a mean pulmonary arterial pressure of 18 mm. Hg and venous pressure of 0 mm. Hg. Peak inflation pressures less than 18 cm. water and end-expiratory pressures of 2-3 cm. HZ0 were employed to maintain normal residual volume. Isogravimetric pulmonary capillary pressures were determined by the stop-flow technique. Interstitial pulmonary edema \vas induced by progressive venous constriction in IO-gram increments at intervals of 15 min. to a total fluid load of 60 grams representing a weight gain approximately equal to the original wet weight of the lung. Blood gases and pH were measured in an analyzer (Instrumentation Laboratories Model 113) calibrated with known gas mixtures prior to each determination. Effective compliance was calculated from peak inflation pressure and tidal volume measured by a Wright respirometer. The ability to reverse pulmonary interstitial space edema was evaluated in 14 perfused lungs. In four control preparations venous constriction was released without further treatment permitting a negative pressure produced by siphon drainage ranging from -1 to -6 mm. Hg. Measurements of lung weight, pulmonary capiIIary and perfusion pressures, and blood gases were repeated 1 hour after release of venous constriction. Two osmotic diuretics were evaluated in the remaining studies using 10% mannitol in four preparations and low molecular-weight dextran in six lungs after re-
METHODS
Copyright
M.D.,
GREENFIELD,
ON
REIF
ET
AI,.:
INTERSTITIAL
PULlCOXARY
lease of venous constriction. Physiological dosages of these agents were calculated on the basis of perfusate volume and lung weight using an average of 15 grams of dextran and 1.5 grams of mannitol. The drugs were added to the perfusate immediately after release of venous const’riction and measurements were made 1 hour later. Light and electron microscopy were utilized t’o compare the effects of the osmotic agents to control lungs on the basis of sequential biopsy specimens. Biopsy material was fixed in Carnoy’s and Bouin’s soWions, embedded in Paraplast, and stained with H. and E., Giemsa, van Gieson elastica, PAS, and fibrin PTAH stains. For electron microscopy, the material was fixed in Zetterquist’s fixative, dehydrated in alcohol1 embedded in Spurr and Epon 812, and stained with lea,d cit.ra,te and uranyl acetate.
CONTROL I DEXTRAN
2. Isogravimetric pulmonary capillary pressure (PC,) response to edema induced by venous constriction shows a significant rise in each group. After release of venous constriction, both untreated control and dextran groups return toward normal level. Mannitol treatment however results in further increase in PC,. Fig.
RESULTS After release of venous constriction, the control lungs continued to gain weight averaging an additional 12.5 grams at the end of 1 hour (Fig. 1). Continued weight gain also was observed after treatment with t’he osmotic agents averaging an additional 11 grams with dextran and 87 grams with mannitol. The weight gain with mannitol was significantly greater (p < .005) than in the untreated or dextran groups. Pulmonary capillary pressures measured prior to venous constriction were within the normal range as reported previously [3] averaging 6.6 mm. Hg (Table I). After the fluid load the PCi increased in each group to values nearly double the control (Fig. 2). After release of venous constriction for 1 hour, PCi decreased in the control group from a mean of 12 mm. Hg to 9 mm. Hg. A comparable change was observed with dextran which produced a decrease from 13 mm. Hg to 8.3 mm. Hg mean
100 -
a0 -
WEIGHT CHANGE (GMS)
”
-
4.
_
CONTROL
DEXTRAN
MANNITOL
Fig. 1. After release of venous constriction, the perfused lungs continued to gain weight as shown by the I-ertical bars representing the average increase for each group. Table
1. Comparison
of
Perfused Lungs
Response
to Induction
and 1 Hour After
of Hydrostatic Treatment (T)
Edema.
hfannitol
Untreated
PCi (mm. Hg f SEM) Pulmonary venous POZ (mm. Hg f SEMI Effective compliance (ml./cm. Hz0 k SEM)
235
EDEMA
(E) from
Control
YaIues
(C)
Destran
-
C
E
T
C
E
T
C
E
T
7.5 0.29 S6. 2. 7
12.0 1.08 65. 4.6
9.0 1.68 38. 3.5
6.3 0.60 9s.a 4.4
10.5 0.63 so. 3.6
12.0* 0.71 39.1 3.3
6.1 0.42 89. 3.3
10.9 0.54 so . 1.S
s.3 0.31 65.t 2.c7
60. 10.
46. 7.
45. 7.
59.
46. 7.
2s.** 71
69. s.
69. 4.
* p < .05 compared to untreated; ** p < ,025 compared to untreated; t p < ,005 for change after edema compared
6.
to untreated.
100. 13.
236
JOURNAL
OF
SURGICAL
RESEARCH,
90 al PQ2 m m Hg
70 60
PRE-EDEMA
POST-EDEMA
POST-TREATMENT
Fig. 3. Changesin pulmonary venousoxygen tension in responseto interstitial edemaproducedby venous constriction. A decline was observed in each group which continued in control lungs after release of venous constriction. The decreaseof 41 mm. Hg after the addition of mannitol was significantly greater (p < ,005) than that in the other groups,and the decrease of 15 mm. Hg after dextran was significantly
lrss(p < .005).
VOL.
12,
NO.
4,
APRIL
1972
mean to 65 mm. Hg which was significantly less (p < .005) decline than after mannitol or no treatment. Effective compliance decreased 30-36% in all groups with edema formation and an additional 16% with mannitol treatment which differed significantly from untreated lungs (p < ,025). There was essentially no change from the post#edemalevel in both the control and dextran-treated groups (Fig. 4). Light and electron microscopy revealed focal changes of atelectasis, alveolar space edema, and perivascular space widening in all postedema, pretreatment specimens. With dextran treatment, minimal if any perivnscular space widening occurred (Fig. 5) while mamiitol produced diffuse and more marked perivascular space widcning (Fig. 6) . l>IBCT’SSION
60 -
MANNITOL
50 PERCENT 40 DECREASE IN EFFECTIVE 30 COMPLIANCE 20 IO 0 PRE-EDEMA
POST-EDEMA
POST-TREATMENT
Fig. 4. Percentage of decrease in effective compliance observed after hydrostatic edema which did not
changein the dextran and control groupsafter release of venous constriction.Bfter mannitol treatment, an additional 16%decrease wasnoted (p < ,025). not significantly different from untreated or control values. In contrast an incrase was observed after the administration of mannitol from 10.5 mm. Hg to 12 mm. Hg mean (Fig. 2) which differed significantly (p < .05) from the untreated group. Prior to venous constriction, pulmonary venous oxygen tension (PVO,) ranged from 80-110 mm. Hg in t,he 14 perfused lungs. In the control group, PV02 decreased after induction of edema to 65 mm. Hg and declined 27 mm. Hg furt’her to 38 mm. Hg after release of constriction. Mannitol treatment resulted in a greater fall of 41 mm. Hg (p < .005) after edema from 80 mm. Hg mean to 39 mm. Hg (Fig. 3). After dextran treatment, PVOS decreased only 15 mm. Hg from 80 mm. Hg
The management of l)ntients with the Iyetlung syndrome has been largely empirical and based on supportive measures. Primary sul)port by a positive-pressure ventilat,or usually must be modified to include positive end-expiratory pressure (PEEP) in order to permit continued alveolar patency and gas exchange during the ventilatory cycle [8]. In spite of this, reduced pulmonary compliance and arteriovenous shunting persist for days or weeks mitil the excessive interstitial fluid can be mobilized from the lung. In addition, the use of PEEP has been criticised because of adverse effects on cardiac output and a corresponding net decrease in tissue oxygen delivery [4]. Also respirator therapy itself has been shown to have an adverse effect on fluid mobilization since it promotes fluid retention by an unknown mechanism [7]. C’onscquently diuretic and osmotic agents bar-e been utilized clinically to promote reabsorption of edema fluid with varying results [6]. In the present study the degree of fluid loading induced by venous constriction was shown to be irreversible when venous pressure was returned to normal or negative values. The difficulty in ret’ricving fluid driven into the interstitial space has been noted previously and is probably compounded by the osmotic effects of the proteins deposited in the interstitial space [2]. In view of this it is not surprising
‘
HEIF
ET
AL.
: INTEHSTITL4L
that, pulmonary venous oxygen tensions continued to decline in the control lungs while effective compliance remained decreased and
PULMOSBIIY
EDEMA
237
only a slight improvement in pulmonary capillary pressure was observed. The deleterious effect of mannitol was unex-
Fig. 5. Dextrawtreated specimen 1 hour after indllction of hydrostatic edema and release of venous The endothelium lining the capillaries (c) is attenuated. The perivascular space (I’) appears normal and width. An immatrxe alveolar type IT cell (9T 11) projects in the normal alveolar space (A). and uranyl acetate, ~8400.
constriction. in contents Lead citrate
238
JOURNAL
OF
SURGICAL
RESEARCH,
petted and significant resulting in a marked additional weight gain, increased pulmonary capillary pressure, and further decrease in pulmonary venous oxygen tension and compli-
Fig. 6. Mannitol-treated specimen 1 hour tion. The perivascular space (P) is markedly (C) are lined by attentuated endothelium
VOL.
12,
ante. The turbing in age and edema. In
NO.
4,
APRIL
1’37%
ultrastructural changes were disview of focal endothelial cell dammore marked perivascular space contrast, the low molecular-weight
after induction of hydrostatic edema and release of venous constricedematous. The alveolar spaces (A) are compressed. The capillaries that, is disrupted (arrow). Uranyl acetate and lead citrate, X12.170.
REIF
ET
AL.:
INTERSTITIAL
dextran appeared to have some beneficial effects limiting the fall in pulmonary venous oxygen tension while producing comparable changes in compliance and PCi to the control group. The change in oxygen tension could be attributed to improved rheological properties of blood after dextran although there was also ultrastructural evidence of a reduction in perivascular space edema. One explanation for these differences in effects may be found in the differing molecular weights of the two agents since mannitol with a molecular weight of 182 is much more likely to have extravasated into the interstitial space while dextran with an average molecular weight of 40,000 is more likely to have remained intravascular exerting a beneficial osmotic effect, The entry of mannitol into the interstitial space would certainly compound the problem as it continued to exert an osmotic effect across the capillary membrane. SUMMARY Pulmonary interstitial edema in the isogravimetric perfused canine lung produced by venous constriction results in decreased compliance and pulmonary venous POZ, and increased pulmonary capillary pressure. Release of venous constriction is associated with further deterioration in pulmonary venous POS, and no improvement in lung weight or compliance although PCi returns toward normal. Addition of 15 grams LMW dextran minimizes the fall in PVO? and shows less perivascular edema microscopically, but does not otherwise differ from untreated controls. In contrast, deleterious effects are noted after the addition
PULMONARY
EDEMA
239
of 1.5 grams mannitol shown by marked weight gain, increased PCi, decreased PVOz, and decreased compliance. In addition, elect’ron microscopy shows focal endothelial cell damage and more marked perivascular space edema. The adverse effects of mannitol may relate to its smaller molecular weight facilitating entry into the interstitial space. REFEREKES 1. Greenfield, L. J., Reif, M. E., Coalson, J. J., McCurdy, J. R., and Elkins, R. C. Comparative effects of interstitial pulmonary edema produced by venous hypertension or hemodilution in perfused lungs. Surgeru (In press) 2. Gump, F. E., Mashima, Y., Ferenczy, A., and Kinney, J. M. Pre and postmortem studies of lung fluids and electrolytes. J. Trauma 11:474, 1971. 3. Harrison. L. H., Beller, J. E., Hinshaw, L. B., Coalson, J. J., and Greenfield, L. J. Effects of endotoxin on pulmonary capillary permeability, ultrastructure, and surfactant. Surg. Gynec. O&et. 129:723-733, 1969. 4. Lutch, J., Glazier, J. B., and Murray, J. F. Effects of continuous positive pressure breathing on systemic oxygen transport and tissue oxygenation. Amer. Rev. Resp. Di.s. 103:912, 1971. 5. Martin. A. M., Jr., Soloway, H. B., and Simmons, R. 1,. Pathologic anatomy of the lungs following shock and t,rauma. J. Trauma 8:687, 1968. 6. Skillman. J. J., Parikh, B. M., and Tanenbaum, B. J. Pulmonary arteriovenous admixture, improvemcnt with albumin and diureeis. Amer. J. Surg. 119:440,1970. Sladen, A.. Laver, M. B., and Pontoppidan, H. Pulmonary complications and water retention in prolonged mechanical ventilation. New Eng. J. Med. 279 :448, 1968. Uzawa, T.. and Ashbaugh, D. G. Continuous positive pressure breathing in acute hemorrhagic pulmonary edema. J. Appl. Physiol. 26:427, 1969.
OF
SCRGICAL
EFFECTS
MICHAEL
E.
12, 236239
RESEARCII,
OF
REIF,
(1972)
MANNITOL AND PULMONARY M.D.,
JAMES AND
R.
DEXTRAN EDEMA
MCCURDY,
LAZAR
J.
PROGRESSIVE PULMONARY INSUFFICIENCY characterized by reduced pulmonary compliance and hypoxia has been termed the “wet-lung syndrome” because of the extensive interstitial pulmonary edema usually found at autopsy [5]. This syndrome can follow a variety of insults including trauma, sepsis, and resuscitation from burns and shock. Although the use of crystalloid infusion therapy has frequently been incriminated as an etiological factor, we have recently shown that the pulmonary effects of interstitial edema induced by hemodilution differ considerably from the effects of hydrostatic edema [I]. Using the isogravimetric perfused canine lung preparation, interstitial edema produced by progressive venous constriction was found to simulate more closely the clinical problem of reduced compliance, hypoxia, and increased pulmonary capillary pressure. In this report, the effectiveness of mannitol and low molecular-weight dextran were compared to determine the response of the edematous lung t,o these osmotic agents.
The isogravimetric perfused canine lung preparation has been described previously utilizing healthy adult mongrel dogs anesthetized with pentobarbital (30 mg./kg.) and exsanguiFrom the Departments of Surgery and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104 and Veterans Administration Hospital, Oklahoma City, Oklahoma 73104. This investigation supported in part by U. S. Navy Contract NOOO14-68-A-0946 and the Markle Foundation. Submitted for publication Jan. 7, 1972. 234 Q 1972 by Academic
Press,
Inc.
JACQliELINE
INTERSTITIAL
J.
COAT&ON,
PH.D.,
M.D.
nated to prime the perfusion system [3]. The lungs were perfused with deoxygenated blood and ventilated with ambient air. Perfusion pressures for maximum flow without weight gain averaged a mean pulmonary arterial pressure of 18 mm. Hg and venous pressure of 0 mm. Hg. Peak inflation pressures less than 18 cm. water and end-expiratory pressures of 2-3 cm. HZ0 were employed to maintain normal residual volume. Isogravimetric pulmonary capillary pressures were determined by the stop-flow technique. Interstitial pulmonary edema \vas induced by progressive venous constriction in IO-gram increments at intervals of 15 min. to a total fluid load of 60 grams representing a weight gain approximately equal to the original wet weight of the lung. Blood gases and pH were measured in an analyzer (Instrumentation Laboratories Model 113) calibrated with known gas mixtures prior to each determination. Effective compliance was calculated from peak inflation pressure and tidal volume measured by a Wright respirometer. The ability to reverse pulmonary interstitial space edema was evaluated in 14 perfused lungs. In four control preparations venous constriction was released without further treatment permitting a negative pressure produced by siphon drainage ranging from -1 to -6 mm. Hg. Measurements of lung weight, pulmonary capiIIary and perfusion pressures, and blood gases were repeated 1 hour after release of venous constriction. Two osmotic diuretics were evaluated in the remaining studies using 10% mannitol in four preparations and low molecular-weight dextran in six lungs after re-
METHODS
Copyright
M.D.,
GREENFIELD,
ON
REIF
ET
AI,.:
INTERSTITIAL
PULlCOXARY
lease of venous constriction. Physiological dosages of these agents were calculated on the basis of perfusate volume and lung weight using an average of 15 grams of dextran and 1.5 grams of mannitol. The drugs were added to the perfusate immediately after release of venous const’riction and measurements were made 1 hour later. Light and electron microscopy were utilized t’o compare the effects of the osmotic agents to control lungs on the basis of sequential biopsy specimens. Biopsy material was fixed in Carnoy’s and Bouin’s soWions, embedded in Paraplast, and stained with H. and E., Giemsa, van Gieson elastica, PAS, and fibrin PTAH stains. For electron microscopy, the material was fixed in Zetterquist’s fixative, dehydrated in alcohol1 embedded in Spurr and Epon 812, and stained with lea,d cit.ra,te and uranyl acetate.
CONTROL I DEXTRAN
2. Isogravimetric pulmonary capillary pressure (PC,) response to edema induced by venous constriction shows a significant rise in each group. After release of venous constriction, both untreated control and dextran groups return toward normal level. Mannitol treatment however results in further increase in PC,. Fig.
RESULTS After release of venous constriction, the control lungs continued to gain weight averaging an additional 12.5 grams at the end of 1 hour (Fig. 1). Continued weight gain also was observed after treatment with t’he osmotic agents averaging an additional 11 grams with dextran and 87 grams with mannitol. The weight gain with mannitol was significantly greater (p < .005) than in the untreated or dextran groups. Pulmonary capillary pressures measured prior to venous constriction were within the normal range as reported previously [3] averaging 6.6 mm. Hg (Table I). After the fluid load the PCi increased in each group to values nearly double the control (Fig. 2). After release of venous constriction for 1 hour, PCi decreased in the control group from a mean of 12 mm. Hg to 9 mm. Hg. A comparable change was observed with dextran which produced a decrease from 13 mm. Hg to 8.3 mm. Hg mean
100 -
a0 -
WEIGHT CHANGE (GMS)
”
-
4.
_
CONTROL
DEXTRAN
MANNITOL
Fig. 1. After release of venous constriction, the perfused lungs continued to gain weight as shown by the I-ertical bars representing the average increase for each group. Table
1. Comparison
of
Perfused Lungs
Response
to Induction
and 1 Hour After
of Hydrostatic Treatment (T)
Edema.
hfannitol
Untreated
PCi (mm. Hg f SEM) Pulmonary venous POZ (mm. Hg f SEMI Effective compliance (ml./cm. Hz0 k SEM)
235
EDEMA
(E) from
Control
YaIues
(C)
Destran
-
C
E
T
C
E
T
C
E
T
7.5 0.29 S6. 2. 7
12.0 1.08 65. 4.6
9.0 1.68 38. 3.5
6.3 0.60 9s.a 4.4
10.5 0.63 so. 3.6
12.0* 0.71 39.1 3.3
6.1 0.42 89. 3.3
10.9 0.54 so . 1.S
s.3 0.31 65.t 2.c7
60. 10.
46. 7.
45. 7.
59.
46. 7.
2s.** 71
69. s.
69. 4.
* p < .05 compared to untreated; ** p < ,025 compared to untreated; t p < ,005 for change after edema compared
6.
to untreated.
100. 13.
236
JOURNAL
OF
SURGICAL
RESEARCH,
90 al PQ2 m m Hg
70 60
PRE-EDEMA
POST-EDEMA
POST-TREATMENT
Fig. 3. Changesin pulmonary venousoxygen tension in responseto interstitial edemaproducedby venous constriction. A decline was observed in each group which continued in control lungs after release of venous constriction. The decreaseof 41 mm. Hg after the addition of mannitol was significantly greater (p < ,005) than that in the other groups,and the decrease of 15 mm. Hg after dextran was significantly
lrss(p < .005).
VOL.
12,
NO.
4,
APRIL
1972
mean to 65 mm. Hg which was significantly less (p < .005) decline than after mannitol or no treatment. Effective compliance decreased 30-36% in all groups with edema formation and an additional 16% with mannitol treatment which differed significantly from untreated lungs (p < ,025). There was essentially no change from the post#edemalevel in both the control and dextran-treated groups (Fig. 4). Light and electron microscopy revealed focal changes of atelectasis, alveolar space edema, and perivascular space widening in all postedema, pretreatment specimens. With dextran treatment, minimal if any perivnscular space widening occurred (Fig. 5) while mamiitol produced diffuse and more marked perivascular space widcning (Fig. 6) . l>IBCT’SSION
60 -
MANNITOL
50 PERCENT 40 DECREASE IN EFFECTIVE 30 COMPLIANCE 20 IO 0 PRE-EDEMA
POST-EDEMA
POST-TREATMENT
Fig. 4. Percentage of decrease in effective compliance observed after hydrostatic edema which did not
changein the dextran and control groupsafter release of venous constriction.Bfter mannitol treatment, an additional 16%decrease wasnoted (p < ,025). not significantly different from untreated or control values. In contrast an incrase was observed after the administration of mannitol from 10.5 mm. Hg to 12 mm. Hg mean (Fig. 2) which differed significantly (p < .05) from the untreated group. Prior to venous constriction, pulmonary venous oxygen tension (PVO,) ranged from 80-110 mm. Hg in t,he 14 perfused lungs. In the control group, PV02 decreased after induction of edema to 65 mm. Hg and declined 27 mm. Hg furt’her to 38 mm. Hg after release of constriction. Mannitol treatment resulted in a greater fall of 41 mm. Hg (p < .005) after edema from 80 mm. Hg mean to 39 mm. Hg (Fig. 3). After dextran treatment, PVOS decreased only 15 mm. Hg from 80 mm. Hg
The management of l)ntients with the Iyetlung syndrome has been largely empirical and based on supportive measures. Primary sul)port by a positive-pressure ventilat,or usually must be modified to include positive end-expiratory pressure (PEEP) in order to permit continued alveolar patency and gas exchange during the ventilatory cycle [8]. In spite of this, reduced pulmonary compliance and arteriovenous shunting persist for days or weeks mitil the excessive interstitial fluid can be mobilized from the lung. In addition, the use of PEEP has been criticised because of adverse effects on cardiac output and a corresponding net decrease in tissue oxygen delivery [4]. Also respirator therapy itself has been shown to have an adverse effect on fluid mobilization since it promotes fluid retention by an unknown mechanism [7]. C’onscquently diuretic and osmotic agents bar-e been utilized clinically to promote reabsorption of edema fluid with varying results [6]. In the present study the degree of fluid loading induced by venous constriction was shown to be irreversible when venous pressure was returned to normal or negative values. The difficulty in ret’ricving fluid driven into the interstitial space has been noted previously and is probably compounded by the osmotic effects of the proteins deposited in the interstitial space [2]. In view of this it is not surprising
‘
HEIF
ET
AL.
: INTEHSTITL4L
that, pulmonary venous oxygen tensions continued to decline in the control lungs while effective compliance remained decreased and
PULMOSBIIY
EDEMA
237
only a slight improvement in pulmonary capillary pressure was observed. The deleterious effect of mannitol was unex-
Fig. 5. Dextrawtreated specimen 1 hour after indllction of hydrostatic edema and release of venous The endothelium lining the capillaries (c) is attenuated. The perivascular space (I’) appears normal and width. An immatrxe alveolar type IT cell (9T 11) projects in the normal alveolar space (A). and uranyl acetate, ~8400.
constriction. in contents Lead citrate
238
JOURNAL
OF
SURGICAL
RESEARCH,
petted and significant resulting in a marked additional weight gain, increased pulmonary capillary pressure, and further decrease in pulmonary venous oxygen tension and compli-
Fig. 6. Mannitol-treated specimen 1 hour tion. The perivascular space (P) is markedly (C) are lined by attentuated endothelium
VOL.
12,
ante. The turbing in age and edema. In
NO.
4,
APRIL
1’37%
ultrastructural changes were disview of focal endothelial cell dammore marked perivascular space contrast, the low molecular-weight
after induction of hydrostatic edema and release of venous constricedematous. The alveolar spaces (A) are compressed. The capillaries that, is disrupted (arrow). Uranyl acetate and lead citrate, X12.170.
REIF
ET
AL.:
INTERSTITIAL
dextran appeared to have some beneficial effects limiting the fall in pulmonary venous oxygen tension while producing comparable changes in compliance and PCi to the control group. The change in oxygen tension could be attributed to improved rheological properties of blood after dextran although there was also ultrastructural evidence of a reduction in perivascular space edema. One explanation for these differences in effects may be found in the differing molecular weights of the two agents since mannitol with a molecular weight of 182 is much more likely to have extravasated into the interstitial space while dextran with an average molecular weight of 40,000 is more likely to have remained intravascular exerting a beneficial osmotic effect, The entry of mannitol into the interstitial space would certainly compound the problem as it continued to exert an osmotic effect across the capillary membrane. SUMMARY Pulmonary interstitial edema in the isogravimetric perfused canine lung produced by venous constriction results in decreased compliance and pulmonary venous POZ, and increased pulmonary capillary pressure. Release of venous constriction is associated with further deterioration in pulmonary venous POS, and no improvement in lung weight or compliance although PCi returns toward normal. Addition of 15 grams LMW dextran minimizes the fall in PVO? and shows less perivascular edema microscopically, but does not otherwise differ from untreated controls. In contrast, deleterious effects are noted after the addition
PULMONARY
EDEMA
239
of 1.5 grams mannitol shown by marked weight gain, increased PCi, decreased PVOz, and decreased compliance. In addition, elect’ron microscopy shows focal endothelial cell damage and more marked perivascular space edema. The adverse effects of mannitol may relate to its smaller molecular weight facilitating entry into the interstitial space. REFEREKES 1. Greenfield, L. J., Reif, M. E., Coalson, J. J., McCurdy, J. R., and Elkins, R. C. Comparative effects of interstitial pulmonary edema produced by venous hypertension or hemodilution in perfused lungs. Surgeru (In press) 2. Gump, F. E., Mashima, Y., Ferenczy, A., and Kinney, J. M. Pre and postmortem studies of lung fluids and electrolytes. J. Trauma 11:474, 1971. 3. Harrison. L. H., Beller, J. E., Hinshaw, L. B., Coalson, J. J., and Greenfield, L. J. Effects of endotoxin on pulmonary capillary permeability, ultrastructure, and surfactant. Surg. Gynec. O&et. 129:723-733, 1969. 4. Lutch, J., Glazier, J. B., and Murray, J. F. Effects of continuous positive pressure breathing on systemic oxygen transport and tissue oxygenation. Amer. Rev. Resp. Di.s. 103:912, 1971. 5. Martin. A. M., Jr., Soloway, H. B., and Simmons, R. 1,. Pathologic anatomy of the lungs following shock and t,rauma. J. Trauma 8:687, 1968. 6. Skillman. J. J., Parikh, B. M., and Tanenbaum, B. J. Pulmonary arteriovenous admixture, improvemcnt with albumin and diureeis. Amer. J. Surg. 119:440,1970. Sladen, A.. Laver, M. B., and Pontoppidan, H. Pulmonary complications and water retention in prolonged mechanical ventilation. New Eng. J. Med. 279 :448, 1968. Uzawa, T.. and Ashbaugh, D. G. Continuous positive pressure breathing in acute hemorrhagic pulmonary edema. J. Appl. Physiol. 26:427, 1969.