Lung Injury Edema in Dogs

INFLUENCE OF SYMPATHETIC ABLATION

IRA M. DAUBERand JOHN V. WEIL, University of Colorado Health SciencesCenter, Cardiovascular Pulmonary Research Laboratory,Department of Medicine, Denver, Colorado 80262

A B S T R A C T Increased vascular permeability char-acterizes lung injury pulmonary edema and rendersfluid balance in the injured lung especially sensitive tochanges in hydrostatic pressure. Pulmonary edema isoften associated with increased sympathetic nervoussystem activity which can lead to pulmonary venocon-striction. This postcapillary venoconstriction could raisemicrovascular pressure and might therefore increaseedema in the injured lung. Weproduced lung injuryedema in dogs with oleic acid and directly measuredsmall (<2 mm) pulmonary vein pressure. We foundthat the small pulmonary vein pressure was increasedfrom 9.8±0.5 mmHgto 12.6±0.5 mmHg(n = 10) byoleic acid injury edema. The increase was not due toa rise in left atrial pressure since the small pulmonaryvein-left atrial pressure gradient also increased. To testif this increase in the postcapillary pressure gradientwas sympathetically mediated, we either unilaterallyablated the stellate ganglion or produced unilateralalpha adrenergic blockade with phenoxybenzaminebefore giving oleic acid. Both of these "antisympa-thetic" interventions prevented the increase in pul-monary vein pressure caused by oleic acid edema inthe protected lung but not in the intact contralaterallung. These interventions produced a 30±6.8% reduc-tion in the amount of edema caused by oleic acid.Restoring the increase in small vein pressure by inflatinga balloon in the left atrium of dogs with bilateral stellateganglion ablations abolished the reduction in edemaproduced by antisympathetic treatment. However, thedecrease in edema was not significantly correlated withthe reduction in pulmonary vein pressure. Thus, themechanism of the effects of these antisympathetic in-terventions remains unclear. We conclude that lunginjury edema causes sympathetically mediated pul-

Address correspondence to Dr. Dauber.Received for publication 29 March 1983 and in revised

form 27 July 1983.

monary venoconstriction and that antisympathetic in-terventions significantly reduce lung injury edema andmicrovascular pressure.

INTRODUCTION

Pulmonary edema due to lung injury is characterizedby increased vascular permeability (1-3). This increasedpermeability not only promotes edema formation byreducing the oncotic gradient that normally acts tokeep fluid within the vascular compartment (1-5), butalso causes a dramatic increase in the rate of trans-vascular fluid flux in response to increased hydrostaticpressure gradients (2-8). Thus, edema can be causedby much smaller increases in microvascular pressurein an injured lung than in a normal lung with intactpermeability (1, 2, 6-9).

Pulmonary edema is associated with increased sym-pathetic nervous system activity (10-14). Increasedsympathetic activity can lead to systemic and pulmo-nary vasoconstriction (10, 12, 15, 16). In particular,pulmonary veins have been shown to constrict in re-sponse to sympathetic nervous system stimulation (17-20) and to circulating catecholamines (17, 20-23). Ifpulmonary venoconstriction occurred in the setting oflung injury edema, the resulting increase in microvas-cular pressure, even if small, might significantly con-tribute to edema formation, since fluid balance in theinjured lung is especially sensitive to changes in mi-crovascular pressure. Previous studies have shown sig-nificant reductions in lymph flow (6, 7, 24) or extra-vascular lung water (25, 26) even with small reductionsin microvascular pressure in a setting of lung injuryedema.

Therefore, we carried out a series of studies designedto test the hypothesis that lung injury edema leads tosympathetically mediated pulmonary venoconstrictionthat increases microvascular pressure and contributessignificantly to edema formation.

J. Clin. Invest. © The American Society for Clinical Investigation, Inc. * 0021-9738/83/12/1977/10 $1.00Volume 72 December 1983 1977-1986

1977

METHODSProtocolIn chloralose-anesthetized (50 mg/kg loading dose followed

by 0.5 mg/kg per h infusion) mongrel dogs (weight, 24.1±1.8kg), we measured pulmonary artery and systemic pressure,heart rate, and green-dye dilution cardiac output by insertingcatheters via the femoral artery and internal jugular vein.Tidal volume and respiratory rate on a ventilator (HarvardApparatus Co., Inc., S. Natick, MA) with 3 cm positive end-expirator pressure added were used to adjust initial arterialblood gases to pH 7.30 and Pco2 30 (Corning Radiometermodel 165/2, Corning Medical and Scientific, Corning GlassWorks, Medfield, MA) on room air, and were not changedthereafter. In addition, catheters were placed directly in theleft atrium and a small pulmonary vein of each lung (seedescription below) via a left thoracotomy, after which thechest was closed and a chest tube to water seal was left inplace. Shunt measurements were made periodically by ven-tilating the animal with 100% oxygen for 20 min and thenmeasuring the oxygen content (Lex-02-Con, Lexington In-struments Corp., Waltham, MA) of pulmonary and femoralarterial blood samples. Pressures were measured with StathamP23DB transducers (Statham Medical Instruments, Hato Rey,Puerto Rico) zeroed to the level of the respective cathetertip by fluoroscopy. The small pulmonary vein pressures weremeasured on a Statham Medical Instruments P23AA trans-ducer calibrated with a slanted water manometer. All pressureresults were recorded at 15-min intervals and mean valuesover 20 heartbeats calculated on-line by a digital computer(No. 1200, Data General Corp., Lexington, MA). Green-dyedilution cardiac outputs (Waters Associates [Millipore Corp.,Milford, MA] densitometer B-402A) were also calculated on-line by computer. All pressure recordings were monitoredby an oscillograph.

After stable base-line measurements of pulmonary artery,left atrial, bilateral small pulmonary vein, and systemic pres-sures, and of cardiac output, shunt, and arterial blood gasesover 1 h, each animal was given 0.05 ml/kg oleic acid (SigmaChemical Co., St. Louis, MO) intravenously. Control dogswere given saline instead. Wefound that oleic acid tendedto preferentially produce lesions in the lower lobes, presum-ably owing to streaming and/or gravitational effects causinglocalized oleic acid deposition. To produce a more homo-geneous injury, we rotated the dog from supine to right andleft lateral decubitus positions and gave one-third of the totaloleic acid dose in each position. By gross examination thisappeared to produce a more homogeneous injury than dida single injection.

Measurements were made over 4 h and at the end of thattime the animals were killed by rapid exsanguination. Thelungs were excised and extravascular lung water correctedfor residual blood volume was determined (see descriptionbelow).

Specific methodsSmall pulmonary vein pressure measurements. At tho-

racotomy, a No. 5 National Institutes of Health multiple side-hole catheter (outer diameter, 1.7 mm, USCI Co, Billerica,MA) was positioned fluoroscopically in a small (<2 mm)pul-monary vein of each lower lobe near the costophrenic anglevia retrograde passage through the left atrial appendage (27).A length of PE 200 polyethylene tubing was attached to theadvancing distal end of the catheter before insertion to actas a "nose." This nose was then wedged as far distally aspossible while allowing the side-holes to remain unwedged

and in an area of free flow in the vein. Recording of smallvein pressure via the side-holes was begun after the followingcriteria were met: (a) a free flow of contrast dye (Hypaque60%, Winthrop Laboratories, New York) injected throughthe side-holes back to the left atrium (i.e., side-holes notwedged) was observed by fluoroscopy; (b) an undamped pres-sure tracing was obtained on the oscillograph; (c) the positionof the catheter in the distal lower lobe was verified fluoros-copically; (d) the distal diameter of a column of contrast dyeproduced by injecting via the catheter side-holes was 2 mmor less; and (e) small vein pressure was shown to be inde-pendent of left atrial and pulmonary artery pressure by brief(30 s) direct stellate ganglion stimulation (electrostimulator[model 58C; Grass Instrument Co., Quincy, MA]: 20 V, 2 ms,20 Hz) with shielded electrodes. Thereafter, the position ofthe catheters, free-flow of injected dye, and adequacy ofpressure tracings were rechecked before each measurementof small vein pressure during the experiment.

Extravascular lung water. Autologous erythrocytes weretagged in vitro with 100 uCi 5"Cr (New England Nuclear,Boston, MA) and injected intravenously 20 min before killingeach animal. After death, each lung was clamped at thehilum and rapidly excised. The entire lung was weighed andthen homogenized in a blender (Waring Products Div., Dy-namics Corp. of America, New Hartford; CT) after addingan equal weight of distilled water. An aliquot of each ho-mogenate was counted for 5"Cr activity in a gammacounter(model 5253, Auto-Gamma Spectrometer, Packard InstrumentCo., Inc., United Technologies, Downer's Grove, IL) as wasa sample of whole blood drawn from the animal just beforedeath. The remaining homogenate of each lung was driedto constant weight at 55°C in an oven. Extravascular lungwater corrected for residual blood content was determinedby modification of the method of Pearce et al. (28) and ex-pressed as grams of extravascular lung water per gram blood-less dry lung.

StatisticsChanges from base line within each group were tested for

significance by a paired t test. Comparisons between lungswith antisympathetic interventions and their contralateralintact lungs were also tested by a paired t test. Comparisonsbetween experimental groups were made by a one-way anal-ysis of variance. Correlations between pressures and lungwater were established by linear regression analysis. All valuesare reported as mean±SE. Weaccepted P < 0.05 as statis-tically significant.

Experimental groups

CONTROLANIMALS (n = 5)

Control animals received no oleic acid. All animals un-derwent either unilateral or bilateral stellate ganglion abla-tion. Since there was no difference in hemodynamic or lungwater measurements in animals with unilateral or bilateralablations, these results were pooled.

OLEIC ACID AND"ANTISYMPATHETIC"TREATMENT(n = 10)

To carefully assess the effect of antisympathetic interventionon animals treated with oleic acid, the intervention (eitherstellate ganglion ablation or alpha adrenergic blockade) wasperformed unilaterally. This allowed comparison of groups

1978 I. M. Dauber and J. V. Weil

of lungs with each animal having one intact lung and onelung in which an antisympathetic intervention had been per-formed. The following three experimental groups thereforerefer to groups of lungs rather than animals.

Two different antisympathetic interventions were per-formed unilaterally before oleic acid administration. Bothinterventions were designed to produce a functional ratherthan a total sympathectomy.

Stellate ganglion ablation (n = 5). Either the right orthe left stellate ganglion of the sympathetic chain was iden-tified at thoracotomy in the posteromedial portion of thethorax at the level of T1 and widely ablated under directvision with disruption of the sympathetic chain and cardi-othoracic nerves. Since there is both contralateral and ipsilat-eral sympathetic innervation of the lung this probably pro-duced a functional unilateral rather than a complete anatomicsympathectomy.

Alpha blockade (n = 5). Phenoxybenzamine (SmithKline& French Laboratories, Philadelphia, PA), 0.05 mg/kg, wasgiven by slow infusion directly into either the right or theleft pulmonary artery by fluoroscopic direction of the infusioncatheter. Localized alpha adrenergic blockade produced byinfusion of phenoxybenzamine has been previously used inthe systemic circulation (29). Phenoxybenzamine producesalpha blockade by avidly and tightly binding to the alphareceptor by alkylation (30). This may explain its ability toproduce a blockade that is most intense at the site of ad-ministration. This differential blockade was demonstrated inthe present study by prevention of the rise in small pulmonaryvein pressure in response to stellate ganglion stimulation (thisresponse has previously been shown to be alpha adrenergicallymediated [17]) on the side of the infusion and the preservationof this response in the contralateral lung. Before infusion ofthe phenoxybenzamine, the small pulmonary vein constrictionin response to 2 min of supramaximal ipsilateral stellate gan-glion stimulation (20 V, 2 ms duration, 20 Hz) was measuredin each lung and expressed as the increase in the small pul-monary vein to left atrial pressure gradient. 1 h after thephenoxybenzamine infusion, blockade was tested by repeatingthe stellate ganglion stimulation of each lung. Only animalsin which there was a 75% inhibition of the small pulmonaryvein-left atrial pressure increase in the lung infused withphenoxybenzamine and a <25% decrease in the constrictorresponse of the contralateral lung were considered to havesuccessful unilateral alpha blockade. Thereafter, adequacyof blockade was periodically tested by briefly (1 min) re-peating the stellate ganglion stimulation in the alpha blockedlung. In each case the effect was shown to last for the durationof the experiment.

Intact (n = 10). The intact contralateral lungs of theanimals of the two antisympathetic groups served as the com-parison group for the effects of oleic acid.

BILATERAL STELLATE-GANGLIONABLATIONANDMECHANICALLYELEVATEDLEFTATRIAL PRESSURE(n = 5)

Both stellate ganglia were identified by thoracotomy andwidely ablated with interruption of the sympathetic chainand cardiothoracic nerves at that level. After placement ofthe left atrial and bilateral small pulmonary vein catheters,a Foley catheter (No. 12) was placed in the left atrium. 1 hafter administration of oleic acid the left atrial balloon wasinflated in order to raise the small pulmonary vein pressureto the same level as that which had been measured afteroleic acid in the intact, contralateral lungs of animals with

PRESSURE ml P y

(mm Hg) Small Pulmonary10 Vein

Lef t Atrium5JW0 timulation

0 2 4 6 8 1TIME (minutes)

FIGURE 1 Stellate ganglion stimulation causes pulmonaryvenoconstriction. Results from a representative dog show thatdirect unilateral stellate ganglion stimulation (20 V, 2 ins,20 Hz) increases small (<2 mm) pulmonary vein and pul-monary artery pressure. The simultaneous decrease in leftatrial pressure is reflected in the PV-LA gradient increase.

unilateral antisympathetic treatment. Balloon inflation wasthereafter adjusted to maintain a constant small pulmonaryvein pressure.

RESULTS

In preliminary studies we examined the response ofsmall pulmonary vein pressure to stellate ganglionstimulation (20 V, 2 ms duration, 20 Hz; Fig. 1). Therewas a rapid increase in both pulmonary artery andsmall pulmonary vein pressure with a simultaneous de-crease in left atrial pressure. This response has beendemonstrated by Kadowitz et al. (17).

The increase in small vein pressure was small (3.5± 1.8mmHg); however, there was a larger increase in thepulmonary vein to lef t atrial pressure gradient (5.6±2.2mmHg), because lef t atrial pressure decreased. Mostof the increase in pulmonary artery pressure appearedto be due to the increase in small vein pressure.

Because small pulmonary vein pressure can changepassively with changes in left atrial pressure (i.e., with-out a change in the small pulmonary vein-left atrialpressure gradient), we calculated the small pulmonaryvein-left atrial pressure gradient (PV-LA).' This gra-dient reflects changes in small vein pressure that areindependent of changes in left atrial pressure.

Hemodynamic and lung water data are summarizedin Tables I and II. Oleic acid administration caused asmall but significant increase in the small pulmonaryvein pressure (Fig. 2). This increase in small vein pres-

' Abbreviation used in this paper: PV-LA, pulmonary vein-left atrial pressure gradient.

Pulmonary Venoconstriction Increases Lung Injury Edema 1979

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TABLE IISummary of Pulmonary Vein Pressure and Lung Water Data by Individual Lungs

PWv

Dog No. Initial Final &[PV-LAJ EVLW EVLWincrease

mmHg g/g bloodless dry %

I. Control (n = 5)

right left right left right left right left right

12.6 10.7 13.010.0 10.5 10.3

9.5 11.1 11.710.7 12.3 12.012.0 11.8 12.7

11.1±0.3

11.010.113.214.012.3

12.0±0.4

-0.3 -0.41.4 0.70.2 0.1

-0.5 -0.1-0.3 -0.5

+0.1+0.2

II. Oleic acid and unilateral anti-sympathetic treatment (n = 10)

intact treated intact treated

9.68.2

10.48.5

10.511.911.9

8.77.9

10.0

10.8 12.99.0 11.49.8 12.78.3 13.0

10.6 14.312.4 13.513.2 14.0

9.3 9.38.5 12.88.9 11.7

10.09.2

10.811.413.811.410.7

8.710.310.5

Mean (±SE) 9.8 10.1 12.6 10.7±0.5 ±0.5 ±0.5 ±0.4

intact treated

3.9 -0.22.9 -0.11.8 0.52.6 1.23.3 2.74.2 1.62.7 -1.91.5 0.33.3 0.20.8 0.7

2.7 0.5±0.3 ±0.4

intact treated intact

6.255.825.555.986.647.377.625.166.245.98

5.55 81.34.65 69.25.27 61.35.38 73.85.43 93.06.31 114.25.55 121.55.29 50.05.34 81.45.29 73.8

6.26 5.42 82.0±0.24 ±0.13 ±7.0

treated

61.335.253.256.457.883.461.353.855.253.8

57.5+3.7

III. Oleic acid and bilateral stellate ganglion ablation and elevated left atrial pressure (n = 5)

right left right left

9.4 8.4 14.5 14.411.1 12.0 15.0 15.310.9 13.5 15.1 17.110.5 11.0 16.3 15.713.4 12.8 14.2 14.6

11.3±0.5

15.2±0.3

right left

--1.0 -0.1--1.2 -1.8

L 0.9 0.3-1.2 -2.3-2.0 -1.0

-0.9±0.3

right

7.887.726.447.147.33

7.27+0.14

left right

7.63 129.16.94 124.46.94 87.27.02 101.67.63 113.1

Initial and final measurements of small pulmonary vein (Pspv) pressure; changes in small pulmonary vein-left atrial pressure gradient [A(PV-

LA)] from initial to final measurement; extravascular lung water (EVLW), and percentage increase in EVLWcompared with mean controlEVLW(EVLW increase) for individual lungs within groups were made. Values are reported as right and left in animals where both lungsreceived the same experimental treatment and all values are pooled to calculate group means (Groups I and III). Values are reported as

intact and treated where lungs were treated differently and mean values of each group of lungs shown (Group II).

e Stellate ganglion ablation.I Alpha adrenergic blockade.

sure was not associated with a change in left atrial animals receiving no oleic acid, this was because of an

pressure and the PV-LA gradient therefore increased. increase in left atrial pressure since there was no in-

In contrast, whereas small vein pressure increased crease in the PV-LA gradient. Cardiac output decreasedslightly during the experiment in the lungs of control from base line in oleic acid-treated animals, but not in

Pulmonary Venoconstriction Increases Lung Injury Edema 1981

82,08082,28092,28091,680

9,480

Mean (±SE)

left

2.55 -3.55 -3.55 -3.93 -3.47 -

3.433.583.613.383.30

3.44±0.11

72,28073,08081,980e

9,980e91,080

111,780112,580112,9801

121,180112,7811

32,38121,98122,58131,181

3,481

Mean (±SE)

left

121.8101.7101.7104.1121.8

111.3±4.1

Oleic Acid Treated

12

PRESSURE(mm Hg) 8

4.

PV-LA=4.3±0.4mmHg Lef t atrium

PV-LA=7.0 ±0Q4(mm Hg)

BASE LINE AFTEROLEIC ACID

FIGURE 2 Small pulmonary vein pressure increases in lunginjury edema. Pulmonary vein pressure increases 4 h afterproduction of lung injury edema with oleic acid (n = 10).Left atrial pressure is unchanged.

control animals. Pulmonary artery pressure increasedafter oleic acid and this increase was greater than couldbe accounted for by the increase in pulmonary veinpressure.

The increase in the small vein pressure and PV-LAgradient after oleic acid could be prevented by eitherunilateral stellate ganglion ablation or by unilateralalpha blockade with phenoxybenzamine (Fig. 3). Bothof these antisympathetic interventions also produceda decrease in the amount of edema caused by oleicacid. Wedefined edema as the increase in extravascularlung water caused by oleic acid. This amounted to a30.2±6.7% decrease with stellate ganglion ablation anda 29.5±12.2% decrease with alpha blockade (Fig. 4).The amount of edema correlated with the small pul-monary vein pressure when all oleic acid-treated lungswere compared (Fig. 5). However, there was not asignificant relationship between extravascular lung wa-

8-

PV-LAPRESSUREGRADIENT6-

(mm Hg)

4.

Intact (n= 10)

<P0.05

Anti Sympathetic Rx(n=1o)

Control (n=5)

BASE LINE AFTER OLEIC ACID

FIGURE 3 Unilateral antisympathetic treatment prevents theincrease in small pulmonary vein pressure caused by lunginjury edema. Either unilateral stellate ganglion ablation (n= 5) or unilateral alpha adrenergic blockade with phenox-ybenzamine (n = 5) prevents the increase in pulmonary veinpressure (PV-LA pressure gradient) caused by oleic acid lunginjury edema in the intact contralateral lungs (n = 10) ofthe same animals.

INTACT STELLATE INTACT PHENOXYBENZAMINEGANGLION TREATEDABLATION

FIGURE 4 Unilateral antisympathetic treatment decreaseslung injury edema. The increase in extravascular lung water(EVLW) caused by oleic acid is reduced by unilateral stellateganglion ablation (n = 5) and by unilateral alpha adrenergicblockade with phenoxybenzamine (n = 5) when comparedwith the EVLWof intact contralateral lungs of the sameanimals. o, P < 0.05.

ter and vein pressure within the antisympathetic in-tervention group alone. Control lungs showed no cor-relation between lung water and small vein pressure.

As noted, the increase in small vein pressure causedby oleic acid was small. To determine whether such asmall increase in vein pressure could account for thelarge increase in lung edema observed, we mechanicallyraised vein pressure by inflating a left atrial balloonafter oleic acid administration and bilateral stellateganglion ablation. The small vein pressure was in-creased due to the increase in left atrial pressure withan accompanying slight decrease in the PV-LA gra-dient. Although the small pulmonary vein pressure wasactually higher in this group than in the intact oleicacid-injured lungs, the relationship between vein pres-

EVLW

(9g' blooddry lung

10

*Intact + Oleic AcidOSGA+ Oeic AcidAAlpha Blockade + Oleic AcidABilateral SGA+Increased LAP

+ Oleic Acid

15 20PVP (mm Hg)

FIGURE 5 Lung water content correlates with small pul-monary vein pressure in lung injury edema. In oleic-acidlung injury, extravascular lung water (EVLW) correlates withpulmonary vein pressure (PVP) when compared among intactlungs (n = 10), lungs with stellate ganglion ablation (SGA)(n = 5), alpha adrenergic blockade (n = 5), or mechanically-increased left atrial pressure (LAP) plus stellate ganglionablation (n = 10). P < 0.05, r = 0.776, n = 30.

1982 I. M. Dauber and J. V. Weil

16-

* Intoct (nl 10)o SGA(n-5)

Alpha Blockadeln'5)*0

0

0

. °0 * 0

slope 8.4±2.2r*0.70P<0.05

0.10 12 14

PVP (mn

FIGURE 6 The decrease in lung injantisympathetic treatment is abolishdecrease in pulmonary vein pressure.monary vein pressure (PVP) by antireduces oleic acid lung injury edemater, EVLW). (Right) Mechanicallycreasing left atrial pressure (LAP) abedema caused by antisympathetic treaablation). The EVLW-PVP relationsin both comparisons.-

sure and extravascular lung watEcomparable to that in the other Itof the increase in lung water withpressure was identical (8.6±2.29lung water per millimeter of m

Fig. 6.Gas exchange data are summar

tial gas exchange parameters were

experimental groups and shunt fceptably low level. All animals hametabolic acidosis which we atttime under anesthesia, mechanic;tensive surgery. Although acidosisvascular tone, the degree of acidexperimental groups and therefcsource of difference between thgases showed a decrease in theincrease in shunt fraction in t]groups, but these changes were

the groups.

A SGIA+#LAP(nD5) n IqrT qIoN* Intact (n 10)

"A A^ These studies indicate that lung injury edema produced/ t by oleic acid (26, 31) causes an increase in small pul-

monary vein pressure. The pressure increase appears

to be sympathetically and alpha adrenergically me-

*/* diated since it could be prevented by antisympathetic*/ Slo-.6±2.2 treatment, either by stellate ganglion ablation or by

r .76 alpha adrenergic blockade with phenoxybenzamine.';o 92 4 16 The increase in vein pressure is small. However, pre-

n Hg) venting the pressure increase by antisympathetic treat-ment was associated with a significant decrease in the

jurby edema caused by amount of edema produced by oleic acid injury. Sinceled by preventing the

(Left) Decreasing pul- a graded relationship between vein pressure and edema[sympathetic treatment was not present within the antisympathetic group, a(extravascular lung wa- non-pressure-mediated antisympathetic effect on

elevating PVP by in- edema is also possible. Weprevented the decrease in

olishes the reduction in vein pressure produced by stellate ganglion ablationItment (stellate ganglion

hip has the same slope by mechanically elevating left atrial pressure with aballoon. Preventing the vein pressure from decreasingabolished the decrease in edema caused by stellate gan-

glion ablation.Zr in these lungs was Pulmonary edema is associated with increased sym-

ungs. In fact, the rate pathetic nervous system activity (10-13). The preciseincreasing small vein stimulus for sympathetic activation is not clear but it

vs. 8.4±2.2% excess could arise within the lung, reflecting activity of irritantercury) as shown in or mechanical receptors (32) or could represent a sys-

temic response to acute injury perhaps triggered byized in Table III. Ini- hypoxemia or hypotension. The small pulmonary veinnot different between pressure appeared to increase approximately 1 h afterraction was at an ac- oleic acid administration but this was not a consistentLd an initial moderate finding.ributed to prolonged Constriction of pulmonary veins to a wide variety

al ventilation, and ex- of stimuli has been shown by both direct and indirectcan affect pulmonary measurements. Direct measurements of pulmonary vein

losis was similar in all pressure in vivo have shown constrictor responses to

re we doubt it was a norepinephrine (17), histamine (17, 22), prostaglandine groups. Final blood F2a (17), ice-water immersion (18), aortic chemore-

arterial Po2 and an ceptor stimulation (19), serotonin (22), acetylcholinehe oleic acid-treated (22), and endotoxin (33). In vitro studies of pulmonarynot different between veins have demonstrated similar responses (17, 22, 34).

Venoconstriction had been demonstrated in response

TABLE IIISummary of Gas Exchange Data

Initial (FL = 1.0) Final (Flo, = 1.0)

Group pH PCo. Po, Qs/Qt pH Pox PA Qs/Qt

I (n = 5) 7.28±0.05 28±1 422±15 0.05±0.01 7.33±0.04 33±3 390±25 0.07±0.01II (n= 10) 7.34±0.03 26±1 395±22 0.05±0.01 7.27±0.04 30±3 282±61 0.08±0.02III (n = 5) 7.33±0.03 26±2 367±11 0.08±0.01 7.23±0.04 28±4 256±43 0.14±0.03

Initial and final measurements were made of pH, Pco, Po, (FI" = 1.0) and shunt (Qs/Qt) for control (Group I), oleic acid and unilateralantisympathetic treatment (Group II), and oleic acid and bilateral stellate ganglion ablation and elevated left atrial pressure (Group III)groups of animals.

Pulmonary Venoconstriction Increases Lung Injury Edema

125

% 100INCREASE

INEVLW 75'

50

198:3

to histamine (21), norepinephrine (20, 21), and epi-nephrine (20) by the outflow occlusion technique mea-surement of vascular resistance changes. In addition,lymph flow studies have reflected increases in micro-vascular pressure due to constriction of "downstreamvessels" -presumably pulmonary veins, in response toendotoxin (7), norepinephrine (23), serotonin (35), ar-achidonate (36), cyclic endoperoxides (37), and his-tamine (38).

Responsiveness of the pulmonary veins to sympa-thetic stimuli seems well established. Anatomic studieshave demonstrated sympathetic innervation of the veins(32). Pulmonary veins have been shown to constrict toa variety of sympathetic stimuli. Kadowitz et al. (17)demonstrated constriction of intralobar pulmonary veins(2-3 mmdiam) to stellate ganglion stimulation by directpressure measurements. The constriction was preventedby alpha adrenergic blockade. Stern and Braun showedincreases in directly measured pulmonary vein pressurein response to ice-water immersion (18) and in responseto aortic chemoreceptor stimulation (19). Both theseresponses appeared to be sympathetically mediated.Maron and Dawson (20) and Peterson et al. (39) showedvenoconstriction in response to elevated intracranialpressure (20) and Sugg et al. (40) showed increases insmall pulmonary vein pressure in a hemorrhagic shockmodel. In addition, as already mentioned, pulmonaryveins respond to circulating catecholamines as well (17,20-23).

Sensitivity of the injured lung to changes in hydro-static pressure is shown by the correlation betweensmall vein pressure and extravascular lung water (Fig.5) and the steep relationship between excess lung water(i.e., edema) and vein pressure (Fig. 6). The sensitivityof the injured lung to hydrostatic pressure changes hasbeen demonstrated previously in sheep treated withPseudomonas (6), endotoxin (7), and intravenous airemboli (8); and in dogs treated with oleic acid (9, 26),alpha napthyl thiourea (7), or acid aspiration (5). Foyet al. (24) showed decreases in lymph flow in sheepwith Pseudomonas bacteremia with small vasodilator-induced decreases in microvascular pressure. Ali et al.(25) used furosemide and Prewitt et al. (26) infusednitroprusside to show similar dramatic beneficial effectsof small decreases in microvascular pressure on oleicacid edema in dogs.

Wemeasured small pulmonary vein pressure directly.Wedid not use the pulmonary artery wedge pressurebecause small postcapillary pressure changes might notbe detected by the use of a wedge arterial catheter.The wedged catheter would likely stop flow in the smallpulmonary veins downstream to it and therefore pre-clude the measurement of changes in small vein pres-sure. Indeed, on several occasions when the pulmonaryartery catheter and the small vein catheter were in thesame lung segment, wedging of the arterial catheter

reduced the measured small vein pressure to the levelof the wedge pressure. The larger the artery that isoccluded during the wedge pressure measurement, theless likely it is that the wedge pressure will reflectchanges in small vein pressure.

It seems probable that the increases in small veinpressure that we observed reflect increases in venousresistance. Sympathetic nerve stimulation has beenshown to increase small vein pressure by increasingresistance when measured in isolated perfused lobeswith constant flow (17). In our experiments, cardiacoutput decreased in the oleic acid-treated animals.Therefore, we expect that any pressure increases re-flected true resistance increases. Wedid not measureblood flow to each lung. Our pressure measurementsmight have been influenced by redistribution of bloodflow between the lungs. However, pulmonary bloodflow is typically diverted away from severely edematouslung regions (41, 42) which would tend to lower thepressure gradients, whereas we observed pressure gra-dient increases in the more edematous lungs. Therefore,it seems unlikely that the increase in small vein pressurewe observed in the more edematous lungs was due toan increase in flow. In fact, the pressure increases prob-ably underestimate the actual resistance change in theintact, and therefore, more edematous lungs whichprobably have less blood flow. Similarly, the resistancechange in the antisympathetically treated, less edem-atous lungs would, if anything, be overestimated.

While antisympathetic treatment appears to preventthe small vein pressure increase, it also appears thatblockade need not be complete. Unilateral stellate gan-glion ablation is not a total autonomic denervation ofthe lungs-there is remaining ipsilateral as well as con-tralateral innervation and our criteria for successfulunilateral alpha adrenergic blockade allowed for up to25% residual response to stellate ganglion stimulation.However, both of these interventions were effective inpreventing the increase in pulmonary vein pressure asdemonstrated by this study. More complete sympa-thectomy is also effective as shown by Sugg et al. (40)who prevented hemorrhagic shock induced pulmonaryvenoconstriction by autotransplantation of one lung andby Kabins et al. (43) who significantly reduced starch-embolism-induced pulmonary edema by bilateral tho-racic sympathectomy. Interestingly, unilateral thoracicsympathectomy appeared to have prevented the de-velopment of edema in one lung of a patient with theadult respiratory distress syndrome (44).

Our findings suggest that stellate ganglion ablationand alpha blockade decreased edema by lowering mi-crovascular hydrostatic pressure. However, a gradedrelationship between small pulmonary vein pressureand the amount of edema was not present within theintervention group itself but only for the oleic acid-treated groups as a whole. This lack of a graded re-

1984 I. M. Dauber and J. V. Weil

lationship may be due to the narrow range of extra-vascular lung water resulting from antisympathetictreatment. It might also reflect a non-pressure-mediatedmechanism by which antisympathetic treatment re-duces edema. Unfortunately, due to the nature of theantisympathetic interventions we used, establishing agraded range of pulmonary vein pressure responseswas not possible.

Hakim et al. (45) have shown that prolonged stellateganglion stimulation increases the flow of protein-richlymph in sheep, suggesting an increase in vascular per-meability that can be prevented by alpha adrenergicblockade. Alpha blockade has been shown to preventhistaminergic pulmonary vascular effects (46) andtherefore might prevent the edemogenic effects of his-tamine as well. It is possible that the beneficial effectof antisympathetic treatment was due to one or bothof these mechanisms or other non-pressure-mediatedeffects. The resultant decrease in edema could thenproduce the observed decrease in pulmonary vein pres-sure. The experiments in which we mechanically el-evated left atrial pressure after stellate ganglion ablationsuggest that the hemodynamic effects of the antisym-pathetic interventions (stellate ganglion ablation andalpha blockade) could account for most of the observeddecrease in the edema. Wefound that raising the veinpressure reversed the beneficial effect of bilateral stel-late ganglion ablation.

In conclusion, pulmonary edema due to lung injurywith oleic acid caused sympathetic, alpha adrenergi-cally mediated pulmonary venoconstriction in smallpulmonary veins. The resulting microvascular hydro-static pressure increase, although small, significantlycontributed to the amount of edema (Fig. 7) due to theenhanced sensitivity of the injured lung to edema for-mation. Antisympathetic treatment (either stellate gan-glion ablation or alpha adrenergic blockade with phen-oxybenzamine) decreased the edema produced by oleicacid. The decrease in edema was associated with the

1001

INCREASE

IN

EVLW

* ControlOIntact Lungs+ Oleic Acidt SGA+ Oleic Acid

Hemodynamic * Alpha - Blockade + Oleic Acideffect ofVenoconstriction

X ~ i30%Direct 100%permeability 70% O/effect of *oleic acid

O 8 10 I12- 14PULMONARYVEIN PRESSURE(mmHg)

FIGURE 7 The increase in lung water after oleic acid lunginjury is determined by both permeability and hemodynamiceffects of lung injury. Direct effect of oleic acid on perme-ability accounts for 70% of the resulting edema (extravascularlung water, EVLW). The remaining 30% is due to the he-modynamic effect of pulmonary venoconstriction.

decrease in small pulmonary vein pressure but a cor-relation within the antisympathetic intervention groupwas not present. Vasodilator interventions aimed atdecreasing small pulmonary vein pressure might havetherapeutic usefulness in patients with lung injuryedema. Since pulmonary artery wedge pressures maynot fully reflect increases in small vein pressure, re-duction of microvascular pressure might be useful intreating pulmonary edema even when wedge pressuresare normal or only slightly elevated. These results sug-gest that adrenergically mediated increases in pul-monary microvascular pressure contribute significantlyto the pathogenesis of pulmonary edema due to lunginjury and that interventions that decrease this responsemight have therapeutic utility.

ACKNOWLEDGMENTS

These experiments would not have been possible to performwithout the expert technical assistance of Stephen Hofmeisterand Rosann McCullough. The paper would not be possiblewithout the secretarial talents of Michele Jones and SharonSchear and the artistry of Eva Toyos.

This work was supported by National Institutes of Healthgrants HL 14985 and HL 07171.

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1986 I. M. Dauber and J. V. Weil