Saline compared to plasma volume replacement after volume depletion in sheep: Lung fluid balance

ORIGINAL INVESTIGATIONS

Saline Compared to Plasma Volume Replacement After Volume Depletion in Sheep: Lung Fluid Balance Charles R. McKeen, Ronald E, Bowers, Thomas R. Harris, Jane E. Hobson, and Kenneth L, Brigham We bled anesthetized sheep until they were severely hypotensive, and immediately infused enough nor-

mal saline or autologous plasma to restore systemic blood pressure in order t o define differences between the effects of crystalloid and colloid infusions on lung fluid balance. Forces favoring fluid filtration in the pulmonary microcirculation w e r e highest just after the infusion period. Lung lymph flow tripled after saline but increased only 50% after plasma infusion. Lymph f l o w rate correlated well w i t h the sum of Starling f o r c e s throughout the study w h e t h e r saline or plasma was infused, and the

citated animals w e r e the only ones to develop significant increases in postmortem w e t - t o - d r y lung w e i g h t r a t i o s ( c o n t r o l s = - 4 . 3 6 ~ 0 . 0 5 ; saline == 4.86 ± 0.17, P < .05; plasma = 4.34 ± 0.19,

P - NS). A f t e r volume depletion, saline eliminated the lymph-to-plasma ascetic pressure gradient w h i l e plasma helped to preserve it. Regardless of the type of fluid used to restore circulating volume, hydrostatic pressure was the major determinant of transvascular fluid fiitretion in the lungs. Lung lymph f l o w correlated m o r e closely w i t h f o r c e s affecting fluid filtration than w i t h lung w a t e r c o n t e n t .

relationship was similar to that w h e n lung vascular pressures w e r e mechanically elevated. Saline-resus-

© 1986 b y G r u n e & S t r a t t o n , Inc.

N SPITE OF several studies in animals and humans relevant to the subject, controversy Ipersists about the effects of hemodilution on lung

induced anesthesia with enough pentobarbital to cause apnea, intubatcd the trachea, and maintained anesthesia via a scmicloscd rebreathing system with a mixture of compressed air and oxygen (FIo~ - 0.3 to 0.6) and an average of I% to 2% halothane. Airway pressure ranged from 0 to 7 cm HyO during inspiration. Each sheep then had two thoraceramics and a neck and groin dissection for cannulating the pulmonary artery, [eft atrium, external jugular vein, carotid artery, femoral artery, and the efferent duct from the caudal mcdiastinal lymph node. W¢ iigated the tail of this node to eliminate nonpulmonary lymph. At the conclusion of all surgical procedures, we placed animals in the prone position and continued inhalation anesthesia. In sheep prepared this way, the lymph collected is largely from the lungsn'~l and the protein concentration of the lymph appears to reflect protein concentrations in the lung perimicrovascular space) TM

fluid balance and about the relative efficacy of saline and plasma resuscitation from hemorrhagic shock. T M To compare effects of isoncotic with effects of hypooncotie intravenous fluids without the complications of lung microvascular damage, which might accompany prolonged shock, zT'is we infused either saline or plasma following acute volume depletion in anesthetized sheep using systemic arterial pressure as the index of adequate volume replacement. Both fluids restored systemic blood pressure, but lung lymph flow increased much more with saline and extravascular lung water increased with saline but not with plasma. In both cases, lung lymph flow correlated with filtration forces but saline caused more filtration because it eliminated the transmicrovascular oncotic pressure gradient. We conclude that following acute hemorrhage, if systemic blood pressure is used as the index of adequate volume replacement, saline resuscitation causes pulmonary edema but plasma resuscitation does not. The different effects are explained by different effects on the forces

affecting fluid filtration. MATERIALS A N D METHODS

D e s c r i p t i o n o f S h e e p Preparation We made all experiments in anesthetized yearling sheep, prepared acutely over two to four hours in the manner previously described for preparing sheep chronieallyJ~':' We Journal of Critical Care, Vo! 1, No 3 (September), 1986: pp 133-141

Experimental Protocols General Wc estimated the level of the left atrium in each sheep in the prone position and fixed strain gauges (Micron Instruments, Los Angeles) at this level. We recorded mean pressures in the pulmonary artery, left atrium, and From the Center for Lung Research, Departments of Medicine and Surgery, Vanderbilt University School of Medicine, Nashville, Tenn. Supported by Grant Nos. HL 19153 (SCOR in Pulmonary Vascular Diseases) and 5 7"32 IlL 07123 (Training Grant) from the National Heart. Lung and Blood Instilute. and Private Grants from the Bernard Werthan, Sr Fund for Pulmonary Research and the Hugh J. Morgan Fund .[or Cardiology donated by the Martha Washington Straus-Harry H. Straas Foundation, Inc. Address reprint requests to Kenneth L. Brigham, MD, B-1308, Medical Center North, Vanderbiit University School of Medicine, Nashville, TN 37232. ©1986 by Grune& Stratton, Inc. 0883-9441/86/0103--0001 $05.00/0 133

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thoracic aorta continuously using an electronic recorder (Hewlett-Packard Co; Pale Alto, Call0 and measured lung lymph flow each 15 minutes by recording the volume drained into a tube fixed to the animal's side. We measured total protein concentration in each 15-minute lymph sample during experimental intervention (but in samples pooled each 30 minutes during baseline). We also measured total protein concentration of a sample of peripheral blood plasma drawn each 60 minutes during baseline and each 30 minutes during experimental interventions. A stable baseline of at least 60 minutes preceded any experimental intervention. We bled sheep from the femoral artery cannula over ten minutes until the systolic blood pressure was 40 to 50 torr. We then infused either normal saline or autologous plasma over 30 minutes into the jugular vein cannula in quantity sufficient to restore systemic systolic pressure to baseline levels. We continued observations for another 90 minutes and then excised the lungs for postmortem measurements of lung water.

Control sheep were prepared in an identical manner, and the same experimental variables were followed for three hours after preparation. Indicator dilution studies were done twice on three animals during the observation period. Collection ofautologous plasma. In sheep designated to receive plasma resuscitation, we cannulated a carotid artery and an external jugular vein under sterile conditions with silastic tubing 1 week prior to the acute experiment. We collected approximately 500 mL of whole blood on each of two occasions in a collection bag containing acid-citratedextrose, separated the plasma by centrifugation (4,000 RPM for ten minutes), transferred the plasma to a separate collecting bag, and quickly froze it at - 70 °C. The packed red cells were then relnfused along with 500 mL of normal saline through a blood component infusion filter (code 4C2100, Fenwall Laboratories; Dcerfield, ill). We did not phlebotomize the sheep for two to three days prior to the acute study. Before infusion, we warmed plasma to 37 °C in a water bath and infused through a blood component infusion filter. We m~asured the total protein concentration of the autologous plasma and cultured it for bacteria. Postmortem lung water measurements. Ninety minutes after either saline or autologous plasma infusion, we killed the sheep and measured the postmortem ¢xtravascular lung water content. We killed six sheep after saline infusion and five sheep after autologous plasma infusion, For control, we quickly killed nine sheep acutely anesthetized with pentobarbital and removed the lungs while airway pressures were maintained at 20 cm H20. We homogenized the lung and measured 5ter activity in samples of the homogenate and blood drawn at death in a gamma spectrometer (model 3002 Packard Instruments; Downer's (:;rove, I11). and wc measured the fractional water content oftbe samples of homogenate and blood by drying to constant weight in a 70 °C oven, Assuming a water content and radioactivityconcentration in blood drawn at death equal to those of residual lung blood, we calculated extravascular lung water by the formulas of Pcarc~ et al.~ We expressed values as the ratio of the quantity of extravascular water to the dry weight of bloodless lung. 5tCr-erythrocytcs wcrc injected near the beginning of the experiment ~ that serial measurements of blood volume could be mad, (set: below).

MCKEEN ET AL

There is some e~idence in sheep that substantial amounts of StCr may elate from [abc!ed ¢rythrocytes in rive over several hours.26 I f this occurred in our experiments, our estimates of

residual blood in lungs postmortem may be inaccurate.

Other Methods Protein analysis. We measured total protein concentration in lymph and blood plasma with an automated system (AutoAnalyzer, Technicon Instruments; Tarrytown, NY) by a modified biuret method27; duplicate determinations differed by less than 5%. Indicator dilution studies. We did single-pass indicator studies to measure cardiac output and extravascular lung water during the steady-state baseline period, during hypotension, immediately after volume replacement, and ninety minutes later. 2s We did studies this way nine times: five times in sheep receiving saline and four times in sheep receiving autologous plasma. We did control studies on two sheep at two different times during three hours of continuous anesthesia after acute preparation. We have described the indicator methods before, j9"2°'29A bolus of ):tSl-albuminand 3H-water was injected through the right atrial catheter. From the radioactivity measured in arterial samples taken at 1.0-second intervals after isotope injection and in the injected mixture, we calculated car~[~c output and extravascular lung water volume by the ~:.ezn transit time method. Blood gas measuremems. We measured Po~. Pco~, and pH in samples of arterial blood collected anaerobical!y during steady-state baseline, during hypotension, at ,t~Je ~ll,J of fluid resuscitation, and at the end of the experiment ~,:':ha blood gas analyzer (Instrumentation Laboralorics, Modci No. 513; Lexington, Mass). Blood volume measurements. We used autotogous ~t~rlabeled erythrocytes to determine blood volume c~i~g¢~. There is some evidence in sheep that substantial amounts of 5tCr elute from labeled erythrocytes in rive over several hours, 26 so that blood volumes at the later times in our experiments may be inaccurate. We labeled sheep red cells by mixing gently 50 uci of StCr and 15 mL of heparinized whole blood collected from the animal during the acute preparation for 30 to 45 minutes at room temperature. Afterwards wc centrifuged the blood at 2,000 RPM for 15 minutes, removed the plasma, and washed the labeled cells repeatedly by resuspending them in normal saline and centrifuging as above until the supernatant was clear. Our injectat¢ was the labeled cells r~uspended in normal saline restored to the original 15 mL volume. We saved 0.5 mL of the injectate to count and injected the remainder into the sheep. After 45 to 60 minutes of equilibration, 5 mL of whole blood was collected in EDTA Vacutainer Brand Blood Collection Tubes (Becton, Dickinson and Co; Columbus, Neb) every 15 to 30 minutes throughout the experiment. We counted two 0.5 mL aliquots of injeetate diluted with 5 mL of saline and one 0.5 mL aliquot of the sheep's unlabeled blood for 20 minutes in a gamma spectrometer. The remainder of the experimental blood sample was for total protein determination. Blood volume was then calculated by dividing by the total number of ~Cr counts injected. Statistics. We tested significance of differences between steady-state baseline and experimental measurements made

PLASMA VOLUME DEPLETION IN SHEEP

13E"

in the same animals in the same experiment using a paired t-test and between measurements made in different animals with a t-test for independent groups. ~° We derived the correlation between experimental variables for different animals under different test conditions using the methods described by Armitage. 31 We considered a P value less than 0.05 significant.

SYSTOLIC AORTIC PRESSURE ( torr ;

mean :I: S,E.M,)

5o~

PULh~ONARY ARTERY

RESULTS

Control animals remained stable and had no significant change in the variables measured throughout the time course of the experiment. Arterial blood Po,, Pea.., and pH did not change significantly from baseline in any of the experimental groups. Experimental results are summarized in Figs I and 2. Systemic blood pressure was effectively restored and maintained at baseline levels by both saline and plasma infusion. Pulmonary artery pressure increased only an average 3 cm H20 above control levels at the end of the infusion period and was near baseline by the end of the experiment. Average left atrial pressure increased minimally with plasma and 4 cm H20 with saline by the end of resuscitation. The data

MEAN PRESSURE

20' 15"

(cm H20 ; mean + S.E.M.)

#o-~

LEFT ATRIUM

O"

LUNG LYMPH FLOW i normalized to baseline ; mean _* S,E.M. }

2,0-

I. O-

0.5

ko

t.5

TIME SYSTOLIC

PULMONARY

ARTERY

M AN

PRESSURE ( cm H 2 0 ; mean + S,E.M.)

2.5

3.0

3.5

Fig 2. Hemodynamics and lung lymph f l o w during hemorrhagic shock a n d plasma r e s u s c i t a t i o n ( m e a n ± SEI.

lOOl

AORTIC 801 PRESSURE 60 ( torr ; mean ± S,E.M.) 40 zo

2.0

( hours )

15 I

4.0.

3.(P LUNG LYMPH FLOW ( normalized to 2.0" baseline I mean ± S,E.M,) hO-

0.5

1,0

h5

TIME

2,0

2.5

3.0

3.5

( hours )

Fig 1. Hemodynamics end lung lymph f l o w during hemo r r h a g i c shock a n d n o r m a l s a l i n e r e s u s c i t a t i o n (meah ± SE).

are summarized in Table 1 for critical periods during the experiment. Arterial blood gases did not change significantly from baseline. Cultures of the plasma infused grew no gram-negative organisms. The protein content of the autologous plasma infused was not significantly different from baseline plasma protein measurement. Figures I and 2 also show changes in lung lymph flow rates. After saline infusion lymph flow increased threefold, while with plasma resuscitation, lymph flow increased only 1.5 times baseline. Both lymph flow rates peaked approximately 30 minutes after volume replacement and still tended to be elevated at the end of the experiment although lymph flow rate after saline infusion was declining. As shown in Table 1, the lymph flow rates at the end of the experiment were significantly higher than baseline after volume replacement with saline but not after plasma. Figure 3 shows the mean cumulative volume of lymph in excess of baseline for the two groups, indicating the higher lymph volume after saline volume replacement. The average blood volume measurements and

136

McKEEN EY AL

Table 1. Summary o f Hemodynamio and Lung Lymph Data During Hamorrh~glc Shack and Fluid Resuscitation W i t h Normal Ssllne or Autologous Plasma Mesrl Pressure {cm HaD)

Sheep N

Weight (kgl

Res~s'ctt~t~n Fluid

7

38 ± 2

Normal saline

6

40 ± 4

Autologous plasma

Condition Baseline Shock After rt~sus~itation End of experiment Baseltne Shock After resuscitation Endof experimsnt

Sy~toliCAortic

Pulmonsry Artery

|.~It Atrium

Pressur~ (Ton)

17 ± 2 14 ± 2 t 21 ~: 2~

6 ± 2 3 ± It 10 ± 2~"

93 ± 4 46 ± 3 t 97 ± 7

19 ± 2

6 ± 2

24 ± 2

6 ± 1

16 ± 2 27 ± 2

--2 ± It 7 ± 2

26 ± 2

~, ± 2

LungFIow.Lymph (Normalizedto Baseline}

Total P~otein Concentration (g/dL| LyTnph

Pl:sma

1.0 ± 0. I 1,2 ± 0.2 1.6 ± 0,2

4.0 ± 0.3 3.9 :~ 0.3 3.3 ± 0,2~

6.1 ± 0 . 4 5.0 ± 0.3t" 3.4 ± O.21"

90 ± 6

2.0 ± 0,2 t

2.6 ± 0 , 3 t

4.3 ± 0.3 t

100 ± 5

1,O ± 0.0

4,2 ± 0.8

6.0 ± 0.6

0,9 ± 0.1 1 .O ± O. 1

4,4 ± 0,8 t 4.3 ± 0.7

5,6 ± 0,5 t 5.5 ± 0.6

1.6 ± 0,3

4.4 ± 0.5

6.0 ± 0.5

51 ± 3 t 98 ± 6 101 ± 4

Values oro given as mean ± SE. =Four of seven sheep resuscitated with normal saline had lung lymph collected; four of six sheep resuscitated with autologous ptasma had lung lymph collected, tSignificantly different from baseline (P < .05),

fluid volumes infused are shown in Fig 4. An average volume of normal saline equal to two to three times the volume of blood loss was required for resuscitation in comparison to an average volume of plasma "equal to 75% of the volume of blood loss. Plasma infusion increased blood volume by an amount equal to the volume of plasma infused, but with saline, blood volume increased

20~

!

15-

I

I0

Fig 3. T o t a l v o l u m e (mL| o f lymph in e x c e s s o f baseline value during two hours following saline ( D ) ( n - a) o r plasma reausc'mtion (1~) (n - - 4 ) f r o m hemorrhagi c shock. Values are given as mL (mean ± SEM).

only about 60% of the infused saline volume. By the end of the experirfient, blood volume was 10% greater than baseline after saline infusion but 5% to 10% Iov~er than baseline after plasma infusion. Indicator dilution studies are summarized in Fig 5. During hypotension, cardiac output fell and pulmonary vascular resistance more than doubled, but these values had returned to near baseline levels by the end of the experiment, except for cardiac output after saline infusion which was almost 50% greater than baseline. By the end of the experiment when pulmonary vascular resistance was again at baseline values, extravascular lung water measurements averaged 27% greater than baseline with saline infusion but nearly 20% lower afte r autologous plasma. This was confirmed by postmortem lung water measurements in the same animals (listed in Table 2), which were significantly elevated after saline infusion but not after plasma infusion. Figure 6 illustrates mean changes with time in the sum of measurable forces affecting fluid filtration and lung lymph flow for the saline volume replacement experiments. We calculated mierovascular pressure (Pray) as Ppa + 0.4 ( P p a - Pla), where Ppa refers to pulmonary artery pressure and Pla refers to left atrial pressure. 32 We recognize that changes in the pre°

PLASMA VOLUME DEPLETION IN SHEEP

137

A

2°]A

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,.50.B 1.25-

,.; " ,.;

Lo" 3:5

.

-

-

TIME (hours)

-

i

AUTOLOGOU$ PL&SMA

1.00-

0.7"50.50-

Fig 4. Change in blood volume relative to baseline values during hemorrhagic shock and fluid resuscitation (mean ± SE). A, normal saline ( n - 5): average volume blood shed, 432; average volume fluid infused, 1,488. B, autologous plasma ( n - 4 } : average volume blood shed, 744; average volume fluid infused. 581.

capillary to postcapillary resistance ratio may make this formula inaccurate during volume depletion and repletion, but our data do not permit an estimate of the magnitude of such changes and we thought that microvascular pressure estimated from the widely used formula would be better than using either pulmonary arterial or left atrial pressure alone. We considered the transmural oncotic gradient to be the difference between plasma and lymph oncotic pressures calculated from total protein measurements by the equation of Landis and Pappenheimer. 33 The sum of forces favoring filtration peaked at the end of the saline infusion while lung lymph flow peaked 30 minutes later. Both forces favoring filtration and lymph flow returned toward baseline levels by the end of the experiment. We have shown a 30-minute lag between changes !n ~lungvascular pressure and the lymph response in early studies. ~4 Figure 7 shows the relationship between the suin of filtration forces

I aASELmE ~,l,~s~,,,,

oe~ERv~r,CN

Fig 5. Average changes in indicator dilution measurements of cardiac output (A), pulmonary vascular resistance, (B), and extravascular lung water content (C) during hemorrhagic shock and fluid resuscitation (normalized to baseline for each study). (~), saline resuscitated animals; (lYJ}, animals resuscitated with autologous plasma. All values are normalized to baseline values. *Significantly different from baseline (P < .05). +Significantly different from normal saline (P < ,05).

and lung lymph flow (which has been offset 30 minutes to reflect the time delay). The good correlation implies that filtration forces are the principal determinants of lymph" flow. Figure 7 also shows the same correlations for autologous plasma volume replacement studies and for a previously reported study in which pulmonary vascular pressure was increased mechanically.2° We adjusted the normalized lymph flow rates so that all baseline conditions would arise from the origin, simplifying the comparison of the slopes Table 2. Postmortem Lung Water for Control Sheep and for Sheep After Saline or Plasma Resuscitation Condition Control After saline After plasma infusion

N

Extravascu~a~LungWater/ Dry Weight of BloodlessLung

7 6 5

4,36 ± 0.05 4.86 ± O. 17" 4.34 ± 0.19

Values are given as mean ± SE. *Significantly different from baseline (P < ,05)

138

McKEEN ET AL

20"

/~'" ~ , ~

" 3

-2

10-

0"

-I0

'

i

,

•

o.5

..... -

,

,.5

21o

TiME

(hours

~

0

3.o }

Fig 8. Mean change in net filtration forces, sum of press~tr6s (~P) end lung lymph flow during hemorrhagic shock and saline r e s u s c i t a t i o n , ( ~ P PIs-t-0.4 [Pps - pla] + lymph oncotic pressure -- plasma oncotic pressure), (0----0), mean change in sum of Starling forces from baseline (cm HzO). ( H ) , mean lung lymph flow (mL/15 min)

of the regression lines. Over the range of values of the mechanically increased hydrostatic pressure study, the slopes were not significantly different, indicating that pulmonary microvascular permeability was not altered in our experiments. Figure 8 shows the changes in hydrostatic and oncotic pressure for saline and plasma studies. After volume replacement with saline, microvasdular hydrostatic pressure rose initially 50% above baseline but gradually fell to only 20% above baseline. During the same time the oncotic pressure gradient fell after saline infusion to near zero and eventually recovered to only 60% of the baseline value. In comparison, following autologous plasma infusion, the hydrostatic pressure rose an average 20% above baseline levels but stabilized at 10% below baseline while the oncotic gradient fell only 25% and recovered another 10% by the end of the experiment.

DISCUSSION Although it is not clear that even prolonged hemorrhagic shock causes lung microvascular

injury, 17'~8'3sJ~ in these experiments, we deliberately made hemorrhage a single brief event, beginning resuscitation immediately in order to concentrate our investigation on hydrostatic and oncotic pressure changes in an intact pulmonary circulation during volume depletion and replacement. During hypotension due to volume depletion we saw, as have others, 3'4'" a marked increase in pulmonary vascular resistance. When either saline or plasma was infused, while systemic blood pressure was only gradually increasing toward baseline levels, pulmonary hydrostatic pressures were already above baseline and had become the dominant filtration force. Faster fluid infusion in the early volume replacement period, when pulmonary vascular resistance is still high, might magnify the pulmonary vascular pressure rise and lead to greater fluid filtration. Clinically, this suggests that the lung may accumulate fluid during volume replacement before systemic pressure returns to normal and that the edema may be worse if volume is replaced quickly. Several investigators have specifically addressed the question of* whether pulmonary edema seen following hemorrhagic shock is due to increased permeability in the microcirculation. Compounding the already difficult problems of modeling clinical shock and resuscitation, several different animal preparations have been used as well as different periods of shock and resuscitation. Compared to most of these experiments, we maintained animals hypotensive for a very short period, hoping to minimize any possibility of vascular injury. Our study is consistent with others ~'4'~7who have found no change in vascular permeability but attribute increased lung water to elevated filtration forces. Our data do not address the question of whether permeabiJity changes with prolonged shock, Hypoproteinemia has also been said to

NORa**=,$AUNt:Rcsusctmrlo~

NORMALI ZED LUNG LYMPH FLOW MINUS ONE I

~ ~

"~, ~ -o.#,~ ZN¢~'£,¢~¢o~v~osr~r~c p~ESSURt:

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N,46. f.O.6t

"5

0

5

I0

15

20

25

CHANGE IN SUM OF STARLING FORCES FROM BASELINE ( e m i l 2 0 )

Fig 7. Correlation of lung lymph flow to net fi;tration forces (sea Fig 6) for mechanically inc,-eesed pulmonary vascular pressure end h e m o r rhagic: shock with either normal saline or auto|ogous plasma resuscitation.

PLASMA VOLUME DEPLETION IN SHEEP

t.5"

139

A •..j*.°

1.0

0,5

0"

1.25"

,oo .711-

°""

,50"

.25"

o.~

i

t.n

z.o

TIME

(hours)

z,n

n.o

3,~

Fig 8. Changes in lung microvascular hydrostatic pressure and the transmirrovascular oncotic pressure gradient relative to baseline values during hemorrhagic shock and normal saline (A) (n - 41 o r autologous plasma rest|stirsties (B) (n - 4) {mean ± SEL The hydrostatic gradient is lung microveacular pressure (ie, we assumed perimicroveacular pressure - 0), ( H ) , hydrostatic gradient; ( 0 - - - 0 ) , oncotic gradient.

increase the conductivity of exchange vessels in the lungsJ 7 Our animals developed hypoproteinemia during shock and especially during resuscitation with saline, but increases in transvascular fluid filtration were completely explained by alterations in Starling forces. Recent reports indicate that apparent increases in lung vascular permeability caused by hypoproteinemia may be artifacts of the preparations usedJ s Both animal and clinical studies related to the empiric question of whether crystalloid or colloid solutions are preferable for resuscitation have been reviewed extensively in the literature. 14The studies are .not consistent mechanistically. Some workers ha~'e reported increased vascular permeability with colloid solutions; 5 while others have notJ In-light of our study using fresh frozen

autologous plasma, effects of the materials infused in these studies on lung vascular permeability need to be ruled out before concluding that increased permeability resulted from the oncotic load. Heterologous plasma may cause immunologic reactions and even homologous plasma when stored at 4 *C, and not freshly frozen, may contain substances that affect vascular permeability) ~-4' With microvascular permeability unaltered by brief hypotension, it follows that more infused colloid would remain intravascular than crystalloid thereby increasing the efficacy of a given volume of colloid in restoring systemic blood pressure. The efficiency of normal saline in expanding blood volume in our study was similar to our previous report in which comparable volumes of saline were infused in awake normotensire sheepJ 4 The colloid volume required to resuscitate animals in our studies was less than the volume of blood shed, probably because of systemic vasoconstriction. Guyton and Lindsey found that hypoproteinemia in dogs resulted in a shift to the left of the relationship between lung water and left atrial pressure, 42 but whether infusion of crystalloid solutions in amounts used clinically causes pulmonary edema is not clear. Some workers feel that the lung is "spared" from edema due to hypoproteinemia compared to other organs.14 We saw increased extravascular lung water in animals infused with saline, but the amount of edema was small, not enough to produce abnormalities in lung function. The edema resulted from increased transvascular fluid filtration in the lungs due to loss of the oneotic pressure gradient in the pulmonary microcirculation in the face of increasing hydrostatic pressure. The early change in protein concentration during saline infusion was predominantly intravascular. Because of this, we analyzed the relationship of plasma protein concentration (which can be measured clinically) t o the plasma-lymph oneotic pressure gradient (the actual oncotic driving force). We found the correlation coefficients of plasma protein concentration with oncotic pressure gradient for saline and plasma infusion were 0.83 and 0.69, respectively. These high correlations support several repoi'ted clinical studies4r'4s using the gradient between pulmonary artery wedge pressure and plasma col-

140

loid oncotic pressure as a predictor o f p u l m o n a r y e d e m a . This relationship is p r o b a b l y limited to cases o f unaltered vascular permeability and o f p r e d o m i n a t e l y intravascular protein changes, t+ T h e data we report here are exactly what ~vould be predicted from c u r r e n t knowledge o f factors affecting lung fluid balance, namely, that if e x c h a n g e vessel permeability is not altered, fluid filtration (and thus e d e m a ) will be governed by t h e t r a n s m i c r o v a s c u l a r h y d r o s t a t i c a n d oncotic pressure gradients. L a r g e volumes o f saline ~iilute intravascular protein and result in more increase in fluid filtration a n d m o r e accumulation o f lung w a t e r than with infusion o f isoncotic fluids during the acute response. However, if severe fluid overload is avoided, the a m o u n t of e d e m a resulting from saline resuscitation is small, p r o b a b l y not sufficient to interfere with gas exchange. O u r studies do not address a n y possible l o n g - t e r m d i f f e r e n c e s between plasma and saline resuscitation. W h a t e v e r fluid

McKEEN ET AL

is used for resuscitation f r o m h e m o r r h a g i c shock, careful attention should be paid to p u l m o n a r y vascular pressures, especially in the resuscitation period when p u l m o n a r y vascular pressures m a y be elevated out o f proportion to systemic pressures. W e conclude that b r i e f periods of h e m o r r h a g i c hypotcnsion do not alter microvascular permeability in the lungs but arc associated with increased p u l m o n a r y vascular resistance. H e m o r r h a g c also reduces intravascular oncotic pressure, which is f u r t h e r reduced by crystalloid resuscitation. W h e n the transvascular oncotic gradient is diminished, vascular hydrostatic pressure becomes the m a j o r d e t e r m i n a n t of fluid filtration. L u n g lymph flow (transvascular fluid filtration) increases more and extravascular flttid a c c u m u l a t i o n is g r e a t e r a f t e r crystalloid resuscitation than a f t e r colloid because of the d i m i n ished oncotic gradient in the face of increased p u l m o n a r y vascular pressures.

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PLASMA VOLUME DEPLETION IN SHEEP

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