Effect of Furosemide in

Canine Low-Pressure Pulmonary Edema

J. ALI, W. CHERNICKI, and L. D. H. WOOD,Departments of Surgery and Medicine,University of Manitoba, Faculty of Medicine, Winnipeg, Manitoba, Canada

A B S T R A C T Westudied the effect of furosemide onpulmonary oxygen exchange, lung liquid, and centralhemodynamics in dogs with pulmonary capillary leakinduced by intravenous oleic acid (OA). 2 h after OA,triple indicator-dilution lung liquid volume and pulmo-nary shunt (Qs/Qt) doubled despite normal pulmonarycapillary wedge pressure in 16 dogs compared withdogs not given OAin which no variable change duringthe same time. Six edematous dogs were then treatedwith furosemide (1 mg/kg), and 2 h later they showedsignificant reductions in Qs/Qt and lung liquid. Incontrast, six other edematous dogs not given furosemideincreased Qs/Qt and lung liquid during the same time.The changes in edema after furosemide could not beattributed to altered wedge or colloid osmotic pres-sures, and similar changes in Qs/Qt and lung liquidwith furosemide were observed in four nephrectomizeddogs. We conclude that pulmonary vasoactive effectsof furosemide account for reduced shunt and edema incanine pulmonary capillary leak. These effects offurosemide differ from those in cardiogenic pulmonaryedema, and suggest a different rationale for diuretictherapy in low-pressure pulmonary edema. Analysis ofcount rates from 5'Cr-labeled erythrocytes and 1251_labeled albumin in lungs excised from 12 dogs indicatedthat the composition of excess lung liquid did notchange with furosemide, and was 50% plasma, 25%blood, and 25% crystalloid.

INTRODUCTION

Diuretics have long been used to treat pulmonaryedema secondary to left heart failure. Their effective-ness is attributable to the reduced filling pressure ofthe left heart and pulmonary capillaries, which resultswhen central blood volume is reduced by diuresis andby the diuretic enhanced capacitance of the systemicvenous bed (1-6). Conceivably, such other mecha-

Received for publication 11 May 1979 and in revised form29 June 1979.

1494

nisms as increased plasma oncotic pressure or increasedpulmonary lymph flow also reduce the pulmonaryedema. Another form of pulmonary edema in whichthere is no evidence of left heart failure and the pul-monary capillary pressure is normal or low is now fre-quently recognized (7, 8). Increased permeability ofthe pulmonary capillary to plasma constituents hasbeen proposed to explain this disorder, and severalanimal models have been developed which simulateaspects of it. After the intravenous injection of oleicacid in dogs, hemorrhagic pulmonary edema andsevere hypoxemia secondary to true intrapulmonaryshunt develop in the absence of elevated pulmonaryartery wedge pressure (9). The histopathologic changesand the hypoxemia seen in this model closely resemblethe findings in human subjects dying from posttraumaticpulmonary insufficiency (9). This study was designedto determine whether furosemide alters the course oflow-pressure pulmonary edema by studying the canineoleic acid model, and to determine if this alterationis related to diuresis.

GLOSSARYOF SYMBOLSGroups of dogs

OA Oleic acid onlyOA + NE + F Oleic acid, nephrectomy, and furosemideOA + F Oleic acid, furosemide, intact kidneysF Furosemide only

Pulmonary gas exchangePEO2 Partial pressure of oxygen in mixed expired gasPECO2 Partial pressure of carbon dioxide in mixed

expired gasPAO2 Alveolar partial pressure of oxygenPaO2 Arterial partial pressure of oxygenPaCO2 Arterial partial pressure of carbon dioxideCaO2 Oxygen content in arterial bloodCvO2 Oxygen content in mixed venous bloodCc'02 Oxygen content of pulmonary capillary blood

Indicator dilution techniquesQs/Qt Pulmonary shunt fractionCBV Central blood volume(s)Vw Pulmonary extravascular lung waterHTO Tritiated watert Mean transit time

J. Clin. Invest. (D The American Society for Clinical Investigation, Inc. 0021-9738/79/11/1494/11 $1.00Volume 64 November 1979 1494 -1504

Q Blood flowfB Water content of blood at central hematocrit

Assessment of lung liquid compositionWW Wet weight of lungVH Homogenate volumeCB Counts per minute per milliliter in a 0.5-ml

aliquot of bloodCH Counts per minute per milliliter in a 2-ml

aliquot of lung homogenateVB Volume of blood in the excised lungVp Difference in VB between 5'Cr and 1251 repre-

senting lung plasma in excess of lung bloodDW Dry weight of lungVwa Actual extravascular water contentW/D Wet:dry weight ratio(s)

Hemodynamics and lung liquid fluxQE Net flow of lung liquidQ lymph Pulmonary lymphatic flowKf Pulmonary microvascular permeability coef-

ficientReflection coefficient of the capillary membrane

Pmv Pulmonary microvascular hydrostatic pressurePis Pulmonary interstitial hydrostatic pressure(s)irmv Pulmonary microvascular colloid osmotic

pressureiris Pulmonary interstitial colloid osmotic pressurePLa Left atrial pressure(s)Ppa Mean pulmonary artery pressurePpw Pulmonary artery wedge pressureQt Cardiac outputPVR Pulmonary vascular resistancePalv Alveolar pressure

METHODS

20 healthy mongrel dogs weighing between 14 and 29 kgwere studied. Each was anesthetized with pentobarbital(29 mg/kg), and ventilated with oxygen and halothane (0.5%)with a tidal volume of 20 cm3/kg and a respiratory rate of15/min. Each animal was heparinized with 200 IU of sodiumheparin/kg body wt. Polyethylene catheters were placed inthe femoral artery and vein, and a thermal dilution Swan-Ganz catheter (Edwards Laboratories, Inc., Santa Ana, Calif.)was positioned in the pulmonary artery. A French Foleycatheter (No. 14, Edwards Laboratories, Inc.) was inserted inthe bladder by cystostomy. All animals had a midline ab-dominal incision through which both kidneys were mobilized.In a group of four dogs (group OA+ NE + F), the renalpedicles were completely ligated causing effective nephrec-tomy whereas in the others the kidneys were not altered otherthan the mobilization procedure.

After control measurements, OA (0.06 ml/kg) was injectedintravenously in three groups of dogs (group OA, groupOA+ NE + F, and group OA+ F). Measurements weremade after 2 h, and then furosemide (1 mg/kg) was injectedintravenously in group OA+ NE + F, group OA+ F andgroup F. Group OAanimals received no furosemide. GroupOAand group OA+ F consisted of six animals each, and thefourth group (group F), which consisted of four animals,received furosemide only. The measurements were repeatedat 4 h (i.e., 2 h postfurosemide). This design allowed assess-ment of the effect of furosemide on OApulmonary edema bycomparing 2- and 4-h measurements in intact dogs (group OAvs. group OA+ F) and nephrectomized dogs (group OA vs.group OA+ NE + F).

Pulmonary artery (Ppa), pulmonary wedge (Ppv), andsystemic blood pressure were measured with Statham vascular

pressure transducers (P23 DB and BB, Statham Instruments,Inc., Oxnard, Calif.) coupled to a multichannel BeckmanOscillographic recorder (Beckman Instruments, Inc., Fullerton,Calif.). Cardiac output (Qt) was measured by thermodilution(Columbus Instruments, Columbus, Ohio), and pulmonaryvascular resistance (PVR) was calculated: PVR= (Ppa - Ppw)/Qt. Arterial and mixed venous blood samples were collected inheparinized syringes and analyzed immediately for pH, Pco2,and Po2 on a Corning 165-2 blood gas analyzer (Corning GlassWorks, Corning, N. Y.), and for hemoglobin concentration(Hb, grams per 100 milliliters). Mixed expired gases werecollected and analyzed for PEO2 and PECO2 using the sameelectrodes, and these values were used to estimate pulmonarycapillary and alveolar 02 tension (PAO2 = PEO2 + PEC02- PaCO2). Blood gas tensions were corrected to blood tem-perature, and oxygen saturations were calculated using thenomogram of Rossing and Cain (10). Oxygen contents inarterial (CaO2), mixed venous (CvO2), and pulmonary capillary(Cc'02) blood were calcuilated as: percent saturation x (Hb,g/100 ml x 1.34) + Po2 x 0.003. These were used to estimateshunt (Qs/Qt). QsIQt = (Cc'02 - CaO2)/(Cc'02 - CvO2). Serumalbumin, globulin, and total proteins were also measured inarterial blood by the Biuret and bromo-cresol green techniques.

Estimates of central blood volume (CBV) and pulmonaryextravascular lung water (Vw) were made at control, 2, and 4 hin four animals from each group according to indicator-dilutiontechniques described in detail by Kirk (11). Briefly, a solutionof 5'Cr-labeled erythrocytes (30 mCi), '251-labeled humanserum albumin (8 mCi), and tritiated water (HTO) (25 mCi)was injected into the right ventricle and sampled at 1-s intervalsfrom the root of the aorta. 5'Cr- and '251-gamma activities ofan ethanol precipitate were determined in a 400-channelanalyzer with corrections for background and spillover, andHTO activity was determined in an ethanol extract by aNuclear-Chicago MKI liquid scintillation counter (Nuclear-Chicago Corp., Des Plaines, Ill). Assuming that erythrocytesdo not leave the circulation in a single pass, we calculatedblood flow (Q) from the dilution curves for 5'Cr. CBV wascalculated by the product of Q and the mean transit time (i)of cells, and represents the volume of blood from the rightventricle to the root of the aorta. Vw was calculated as sug-gested by Chinard et al. (12) where Vw = (Q t HTO) - CBVfB, and fB is the water content of blood at the central hematocrit.

The liquid composition of excised lungs was determined(11). 20 min after the final dilution curve in each animal,blood samples were drawn for final blood activity of 5'Cr and125I. The thorax was opened rapidly through a mediansternotomy. Clamps were placed on the lung hilae, and thelungs that contained blood were excised and weighed wet(WW). They were then homogenized in a Waring blender(Waring Products Div., New Hartford, Conn.) with 20 ml ofdistilled water. The homogenate volume (VH) was measuredafter overnight settling. Duplicate 2-ml aliquots of lunghomogenate and 0.5-ml aliquots of blood were counted for5'Cr and 125I, expressed as counts per minute per milliliterof each (CB, CH). The volume of blood (VB) in the excised lungswas then calculated for each isotope. VB = (CH-VH)/CB. Weassumed that differences in VBbetween 5'Cr and 125I representa different volume of distribution of cells and plasma withinthe lung, and expressed this difference as lung plasma inexcess of lung blood (Vp).

The remaining homogenate was dried to a constant weightin a vacuum oven at 60°C and 400 torr of absolute pressureto obtain dry weight (DW). To normalize for variations inlung size, all estimates of lung liquid components in gramsor milliliters (WW, DW,VB, Vwa, CBV, and Vw) were expressedas a ratio of body weight in kilograms.

Furosemide in Lowv-Pressure Pulmonary Edema 1495

OA+NE+F

-20 500S

400--15

-10

PaO2QS/QT 1%) (mmHg) 300

200-

S5 100-

I LO0 2 4

TIME (hr.)0 2 4

OA+F

I

0 2 4

TIME (br.)

600-

500-

400-

OS/QT 1%) P.O2 300-(mmHg)

200'

100

F

0 2 4

TIME (hrs)

FIGURE 1 Effects of OA and furosemide on PaO2 (left ordinate) and Qs/Qt (right ordinate) infour experimental groups. Solid lines (individual values) and interrupted lines (group mean values)connect base-line measurements (0 h) and measurements repeated at 2 and 4 h. Group OAreceivedOA only. Group OA+ NE + F was nephrectomized and received OAand furosemide 2 h afterOA. Group OA+ F with intact kidneys received furosemide 2 h after OA. Group F had furosemideand no OA. For discussion, see text.

RESULTS

Fig. 1 shows the effect of OAand furosemide in PaO2.The mean values of PaO2 (mmHg) at the start of thestudy (time 0) were 524 ± 19 (group OA),494 ±20 (groupOA+ NE + F), 533±51 (group OA+ F), and 439±37(group F). These values were not significantly differentamong groups by analysis of variance. In all groups

receiving OA, PaO2 decreased significantly by 2 h (P<0.01), but it did not change in group F (no OA) (Fig. 1).2 h after furosemide, all group OA+ F animals showedan increase in PaO2, and the mean values increasedfrom 215±45 to 327±47 (P < 0.01). In contrast, allanimals in group OA (no furosemide) had decreasedPaO2 during the same period, and the mean PaO2 de-creased from 308±41 to 211±39 (P < 0.05). In groupOA+ NE + F (nephrectomy), PaO2 did not changeafter furosemide (339±97) from the value 2 h afterOA (335±48). There were no obvious trends in PaO2in group F between time 0 and 2 h, and furosemidecaused no change in PaO2. No significant changes inPaCO2 or pH were observed in any group throughout

the study, and these averaged 35+3 and 7.34+0.04,respectively.

These changes in PaO2 were associated with changesin Qs/Qt (Fig. 1), which increased in all animals receiv-ing OA. After furosemide, five of six dogs in group

OA+ F had reduced Qs/Qt, and the mean value de-creased from 0.17+0.12 to 0.10+0.04 (0.05 <P < 0.1).All dogs in group OA increased their shunt during thesame time, and mean Qs/Qt increased from 0.11±0.04to 0.14+0.04 (P <0.05).

Table I summarizes the effects of OAand furosemideon the central hemodynamics. During the 2 h after OAinjection, Qt and Ppw tended to decrease in all groups

including the control group (F), and PVR tended toincrease. A continuation of these trends was observedin all groups after furosemide.' Note the statistically

The spontaneous changes in Qt at 4 h and Ppw at 2 hin group F were not associated with alteration in gas exchange.In group OA, deterioration in gas exchange at 2 h was notassociated with a significant fall in Qt, whereas in group

1496 J. Ali, W. Chernicki, and L. D. H. Wood

500-

400-

P002 300-(mmHg)

200-

100-

0-

-20

~13

0 2 4

0s/QT (%)-10

600-

5001

4001

96 i .4

.5

TIME (hrs)

PtOt(mmHg)

300'

200-

100-

OS/QT (%)

OA 600600-

-0

--e-

TABLE IEffect of OA and Furosemide on Central Hemodynamics*

Qt Ppw PVR

Group Control 2 h 4 h Control 2 h 4 h Control 2 h 4 h

liters/mimi nmmn Hg mmHg/liter/min

OA 2.14+0.82 2.05+1.45 1.66+0.94 7.3+2.0 6.0+2.1 4.5t±1.4 3.2+1.3 5.0+3.0 6.1+2.6OA+ NE + F 1.26±0.19 0.89±+0.02 0.76+0.12 8.3±1.3 6.8+±1.5 6.5+1.3 4.3+1.1 7.3t+1.2 11.04±0.9

OA + F 3.16±1.30 1.87t±0.73 1.59t±0.63 9.3±3.1 8.2±2.9 7.5±3.6 2.6±1.2 4.6±2.6 7.44±6.4F 1.71±0.27 1.30±0.18 1.04±+0.17 8.5±1.0 6.0t±0.8 5.5±1.0 3.2±0.52 4.6±1.04 6.24±1.0

* Mean±SD.4 Denotes significance (P < 0.05) from the preceding measurement.

significant reduction in Ppw between 2 and 4 h ingroup OA(no furosemide) compared with a smaller andinsignificant fall in group OA+ F. Both groups showedsimilar mean reduction in Qt, although this trend ingroup OA was not statistically significant (0.05 < P< 0.1). PVRincreased in all groups receiving furosemide,but the mean increase in group OA (no furosemide)was smaller and not statistically significant.

Urine output was similar in all nonnephrectomizedgroups before and after OA, and increased considerablyafter furosemide (Table II). Compared with group OA,there was a 300-ml greater urine output in group OA+ F during the 2 h after furosemide. This was associatedwith reduced mean Qs/Qt and increased mean PaO2without lowering mean Ppw as much as in group OA.Furthermore, even with no urine output after furosemide,the nephrectomized dogs (group OA+ NE + F) did notincrease their shunt or decrease their PaO2 as did thedogs in group OA.

Table III summarizes the results of serum albuminand globulin measurements and analysis. There wereno differences among groups at time 0 (control), andboth proteins tended to decrease slightly by 2 and 4 h.These trends were not significant in any group, andthere were no differences among groups after OA orafter furosemide.

WWand DWfrom the four dogs not given OA(group

F) did not vary much (Table IV). All of these valuesare within the normal range, and the mean wet:dryweight ratio (W/D) was 3.85. As calculated from the51Cr-labeled erythrocyte activity in the excised lunghomogenate, about one-third (3.2 ml/kg) of the WW(9.4 g/kg) was blood (VB). The lung blood was alsocalculated from '251-labeled albumin in the lung homog-enate. These values are expressed in Table IV (Vp,ml/kg) as the lung blood calculated from 1251 less the[51Cr]VB. The small difference between these twoestimates of lung blood volume in each normal dogaveraged zero, which indicates that lung blood andplasma were in the same proportion as in the vascularspace. Blood-free extravascular lung water averaged6.2 ml/kg body wt (Table IV, H20 ml/kg). In these fourdogs the hematocrit at the end of the experiment rangedfrom 46 to 60%, and gave blood W/D values from 3.9to 2.9, and the blood-free lung W/D values ranged from3.5 to 4.5 (mean 4.07).

The excised lungs of 12 dogs given OAhad doubledWWand a small increase in DW(Table IV) comparedwith group F. The W/D were larger in all dogs receiv-ing furosemide after OA (group OA+ F) than in alldogs receiving only OA. In the nine OA treated dogsin which estimates of lung blood were obtained withboth 5'Cr-labeled erythrocytes and '251-labeled albumin,the mean WWwas 20.9+±2.7 (Table IV). The difference

OA+ NE + F and group OA+ F, there was significant depres-sion of Qt in association with the deteriorating Qs/Qt at 2 h.A fall in Qs/Qt in OApulmonary edema is known to accompanya decrease in Qt (13), and, because there was no such decreasein shunt with the decreased Qt in these groups, there mustbe other factors responsible for the change in shunt. Thefurther fall in Qt at 4 h in group OA+ F is, therefore, notentirely responsible for the decreased shunt. Overall examina-tion of the hemodynamic data shows that the trends werethe same in all the measured parameters for all groups, yetthe changes in shunt did not follow this pattern. It wouldappear, therefore, that these hemodynamic changes, thoughimportant, are not crucial to the understanding of the actionof furosemide in this study of low-pressure pulmonary edema.

TABLE IIUrine Output

Group I h* 2 h 3 h 4 h

ml

OA 43±134 38±+10 37±+12 34±+18OA+NE+F 0 0 0 0

OA+ F 29±10 33±15 177±68 201+48F 29±+10 43+21 128+62 155±21

* Hourly collections at times after OA injection.4 Mean±SD.

Furosemide in Low-Pressure Pulmonary Edema 1497

TABLE IIISerum Protein Concentrations in All Four Groups of Animals*

Control 2 h 4 h

Groups Albumin Globulin Albumin Globulin Albumin Globulin

gmldl

OA 2.1±0.1 3.5±0.6 1.9±0.2 3.5±0.1 1.7±0.2 3.4±0.4OA+ NE + F 2.0±0.2 3.4±0.4 1.7±0.3 3.1±0.4 1.7±0.3 3.0±0.3

OA+ F 2.2±0.2 3.4±0.3 2.0±0.2 3.4±0.3 1.9±0.2 3.3±0.1F 1.8±0.2 3.8±0.4 1.7±0.1 3.6±0.3 1.6±0.2 3.7±0.3

* Mean±SD.

between this mean and the corresponding mean WWin group F indicates that OA caused -11.5 ml/kg ofexcess lung liquid. Blood accounted for 6.2±2.4 ml/kgof the WWin those nine OA-treated dogs, which in-dicates an average increase in lung blood after OAof3.0 ml/kg compared with group F. This blood may beinterstitial or intravascular and accounted for aboutone-quarter of the excess of lung liquid. There was noobvious difference in the amount of excess blood amongOA, OA+ NE + F, and OA+ F.

In each of these dogs, the lung blood calculated from125I exceeded that calculated from 5'Cr (Table IV). Weassumed that this indicated greater plasma than bloodleak, and we tabulated the difference between thesevalues as the plasma leak in excess of blood leak (Vp).This averaged 5.3 ml/kg after OAand 0 ml/kg in groupF, which indicates that OAcaused a leak of cell-freeplasma accounting for about one-half of the excess lungliquid. Again, there was no obvious difference in plasmaleak among the other groups. The remaining 28%of the

TABLE IVWeights and Composition of Excised Lungs

Lung weights Lung composition

W/D DW WW Blood V. H,0

ml/kg body wt ml/kg ml/kgbody wt body wt

Group F 4.15 2.0 8.3 2.4 -0.1 6.03.91 2.2 8.6 2.9 0.2 5.53.65 2.6 9.5 3.3 0.1 6.13.67 3.0 11.0 4.0 -0.3 7.3

Mean (+SD) 3.85±0.24 2.4±0.4 9.4±1.2 3.2±0.7 0±0.22 6.2±0.8

OAgroupsGroup OA 5.29 4.8 25.4 6.6 5.6 13.4

5.24 3.8 20.1 6.1 6.0 8.05.58 3.3 18.4 6.65.69 4.3 24.6 6.4 6.4 11.8

Group 4.58 3.1 14.2 - -OA+ NE + F 5.22 3.6 18.8 3.7 5.3 9.9

8.44 2.5 21.1 8.5 2.4 10.35.32 3.7 19.7 7.9 2.7 9.1

Group OA+ F 6.32 3.1 19.66.35 2.6 16.5 1.9 8.7 5.97.67 2.7 20.7 5.2 7.0 8.57.57 2.8 21.2 9.9 4.0 7.4

Mean (±SD) 6.31 3.5 20.9 6.2 5.3 9.4(n = 9)* (1.26) (0.8) (2.7) (2.4) (2.0) (2.3)

* Mean and SD of the nine experiments in thewere measured.

OA group in which all variables in this table

1498 J. Ali, W. Chernicki, and L. D. H. Wood

weight gain after OA was attributed to blood-free,plasma-free lung water excess. Lung water averaged9.4±2.3 ml/kg in the nine OA-treated dogs in whichit could be calculated, and this value exceeds correspond-ing means in group F by 3.2 ml/kg.

In summary, the excess lung liquid in OApulmonaryedema was composed of about one-quarter wholeblood, one-half cell-free plasma, and about one-quarterblood- and plasma-free crystalloid. With the mean W/Dvalues measured for blood (4.0) and plasma (16.0) inthese nine dogs, we calculated the DWof the excessliquid to be 1.1 g/kg. This value closely approximatedthe difference in DWbetween OAand group F dogs,and gives a W/D of the excess lung liquid of 10.5. Thesedata indicate that OA caused a similar amount andcomposition of excess lung liquid in all three groups,with the possible exception that W/D of furosemide-treated group OA+ F dogs tended to exceed W/D ofgroup OAdogs (no furosemide).

The results of the indicator-dilution studies are il-lustrated in Fig. 2. CBV (upper panels, milliliters perkilogram) was similar in control conditions for allgroups and averaged 15.1+2.2 ml/kg. It decreasedprogressively with time to 12.1+2.0 at 2 h and to 10.2+ 1.8 at 4 h. The reduction in CBVbetween 0 and 2 hwas quite similar in the group not receiving OAas inthe other three groups.2 Between 2 and 4 h, there wereno obvious differences in CBVbetween group F andthe groups given OA. Furthermore, the upper panelsof Fig. 2 indicate that groups OA+ NE + F and OA+ Fhad a similar reduction in CBV during the 2 h afterfurosemide, as did group OA (no furosemide). Notethat the CBV were (juite similar in groups OA andOA+ F just before the lungs were excised at the end ofthe experiment.

Values of Vw (lower panels, milliliters per kilogram)were quite similar in all groups in control conditions,

2 CBVchanges in the individual groups were compared byanalysis of variance. At 0, 2, and 4 h, respectively, the meanand SD for the CBV in the four groups were: 15.2±+1.6,12.4+0.3, and 11.0±+1.3 for group OA; 13.8+1.3, 10.1+0.7,and 8.7±1.3 for group OA+ NE + F (nephrectomy); 16.3±3.0,13.7±2.8, and 11.1±2.3 for group OA+ F; and 14.9±2.7,12.1± 1.5, and 10.1+ 1.5 for group F. The F (statistical) valuefor 0-, 2-, and 4-h comparisons were, respectively: 0.797, 3.24,and 1.77, all of which were not significant. Analysis of variancefor the difference between 0 and 2 h and 2-4 h was conductedwith the following results: the mean+SDof the difference from0 to 2 h was 2.9+ 1.5 for group OA, 3.7±1.8 for group OA+ NE + F, 2.6 +0.8 for group OA+F, and 2.8 +2.6 for group F.The F valtie was 0.300, which was not significant. The mean+SD of the differences from 2 to 4 h was 1.4+1.6 for groupOA, 1.4±0.9 for grouip OA + NE + F, 2.6±0.9 for group OA+ F, and 2.2±0.5 for grouip F. The F value was 1.298, whichwas again not statistically significant. These statistical compari-sons of the individual groups, therefore, show that they allbehaved in aI similar mnanner as fhr as CBV changes wereconcerned.

10C

VW

(ml/kg) S

5

0n2 4

OA+NE+F OA+F

s Z\. <

0 2 40 2 4

TIME (Hours)

10

Vw(ml/kg)

.- 5

0 2 4

FIGURE 2 Effects of OA and fuirosemide on CBV (upperordinate) and indicator-dilution lung liquid (Vw, lower ordinate)in the same four experimental groups. Solid lines (individualvalues) and interrupted lines (group mean values) connectbase-line measurements (0 h) and measurements repeated at2 and 4 h. Note the similar reduction in CBV with time inall groups, and the increase in Vwin groups given OA(groupsOA, OA+ NE + F, and OA+ F). Vw tends to decrease in the2 h after furosemide in groups OA+ NE + F and OA+ F,but tends to increase during the same time in group OA (nofurosemide). For discussion, see text.

and averaged 3.37+±0.56. There was no obvious changein Vw in group F during the next 4 h (lower right).In contrast, each of the 12 dogs studied 2 h after OAincreased Vw, and the mean (± SD) value approximatelydoubled to 5.35±2.0 (P < 0.01). The mean value of Vwwas less in group OA (5.36) than in group OA+ NE+ F (6.79) or group OA+ F (6.94). During the next2 h, three of four group OAdogs increased Vw further(Fig. 2, left lower) and mean Vwin group OAincreasedto 6.94. During that same time, five of the eight animalsin group OA+ NE + F and group OA + F decreasedVwafter furosemide, and the mean values of these eightexperiments tended to decrease from 6.86±2.29 at 2 hto 6.32±0.97 at 4 h. Conse(quently, values of Vw werequite similar in groups OAand OA + F just before thelungs were excised at 4 h.

To assess the accuracy of in vivo estimates of extra-vascular lung water by indicator dilution in this study,we plotted Vw against actuial extravascular water con-tent (Vwa) of the excised lungs (Fig. 3). Vwa was cal-culated by subtracting the blood volume of lung fromthe W/D differeince. This underestimates Vwa by thewater content of extravascular lung blood. Group Fvalues cluster about the identity line, and the averageVw/Vwa value was 0.95. In contrast, Vwa was under-estimated by indicator dilution in all dogs treated withOA. There was Ino obvious difference in the amountof underestimiiation in the dogs given furosemide afterOA(mean±SD, Vw/Vwa = 0.59±0.08, n = 6) from thegroup OA dogs (mean±SD, Vw/Vwa = 0.61±0.14,n = 4). We concluide that ouir indicator-dilution tech-

Furosemide in Lotv-Pressure Pulm)onary Edema 1499

Yw /A

(mi/kg)5-

0.

5 10 15

Vwa (ml/kg)

FIGURE 3 Relationship between actual lung liquid (Vwa,abscissa) and indicator-dilution lung liquid at 4 h (Vw, ordinate).Solid circles from group F (no OA) cluster about the con-tinuous line of identity, but Vw values from each of theedematous groups (OA, *; OA+ NE + F, 0; OA+ F, A) are-0.6 Vwa. The interrupted regression line for these edemtousvalues is shown (r = 0.63, n = 10). For discussion, see text.

niques underestimated OApulmonary edema by _40%,and this error was not influenced in a major way byfurosemide. This underestimate of in vivo lung watermay be a reflection of known limitations of indicator-dilution methodology. Because the indicators are alladministered intravenously, only perfused areas wouldbe assessed. Edema itself may, however, decreaseperfusion by extravascular mechanical compression.Furthermore, with increased capillary permeability inOAhemorrhagic pulmonary edema there is no guaranteethat so-called intravascular markers would remainintravascular.

DISCUSSION

Furosemide unequivocally reduced intrapulmonaryshunt in dogs with OA pulmonary edema. Even innephrectomized animals, it prevented the increase inQs/Qt between 2 and 4 h after OAobserved in groupOA dogs not given furosemide. By definition, thereduced shunt observed 2 h after furosemide in groupOA+ F indicates that a smaller fraction of the pulmo-nary blood flow perfused nonventilated regions. In ourmodel, the most likely cause of nonventilated air spaceafter OA is alveolar flooding with excess lung liquidas demonstrated by the lung liquid in Table IV andFig. 2. One surprising finding in this study was thatthe improvement in gas exchange was not obviouslyassociated with reduced pulmonary edema. In fact, theW/D of the excised lungs suggest that edema may beworse in the furosemide-treated group OA+ F than

in group OA. However, confident assessment of therelative amount of excess lung liquid from our datawas more difficult than we anticipated. In the followingdiscussion, we consider several interpretations of theresults of excess lung liquid and its composition derivedfrom our in vivo indicator-dilution techniques and ourexcised lung measurements. Wealso attempt to relatethese considerations to our measurements of factorsgoverning lung liquid in OApulmonary edema. Finally,we attempt to use the possible conclusions concerninglung liquid balance and central hemodynamic effectsof furosemide to explain how furosemide decreasedpulmonary shunt.

Amount and composition of excess lung liquid. Ofseveral methods to determine the amount of extra-vascular lung water, the most direct is to subtract DWand lung blood volume (VB) from the WWof excisedlungs (14). This approach was partially confounded inour study because about one-fourth of the excess lungliquid was blood, which could be intravascular orextravascular. Based on the gross appearance of theexcised lung, on the reported histology of canine OApulmonary edema demonstrating interstitial and alve-olar erythrocytes (9), and on the similarity of our CBVestimates in all groups in this study, we think that mostof the excess blood is extravascular. Nevertheless, theamount of lung liquid was not obviously differentamong groups OA+ NE + F and OA+ F (furosemide)and group OA(no furosemide) when it was estimated(Table IV) as either WW-DW(viz., no intravascularblood) or WW-DW-VB(viz., all the blood is intra-vascular). All three OAgroups had more than twice thelung liquid content of group F. Accordingly, OAcaused hemorrhagic pulmonary edema, and it seemsunlikely that there was less lung liquid in excisedlungs of the furosemide-treated groups.

An alternative index quantitating pulmonary edemais the W/D. W/Dhas the potential advantage of normaliz-ing lung liquid volume to an index of lung mass (DW).This was also partially confounded in our study becausethe total excess extravascular lung liquid containedsubstantial nonevaporable substance in the form of 25%blood (mean W/D -3.5) and a further 50% excessplasma (mean W/D -16.0). In the nine OA-treatedexcised lungs in which blood and plasma content weredetermined, there were no obvious differences inamount of excess blood or plasma between furosemide-treated groups and group OA(Table IV). Furthermore,furosemide did not influence CBV estimates (Fig. 2).These arguments suggest that the strong trend towardhigher W/D in group OA+ F than in group OA is nota result of artifacts introduced by variable W/D ofedema liquid between the groups, but, rather, indicatesthat the furosemide groups had more pulmonary edema.

Regardless of whether group OA+ F dogs had similaror greater edema than group OA, the in vivo indicator

1500 J. Ali, W. Chernicki, and L. D. H. Wood

IF ._

estimates of Vwsuggest that furosemide reduced edemaaccumulation after OA. Our values of Vw were notaecurate in OAedema because the 4-h measurementsaveraged =60% of the actual water content of excisedlungs (Fig. 3). Assuming the same relationship (Vw/Vcwax 0.6) at 2 h, mean Vwa would be less in group OA(9.0 ml/kg) than group OA+ F (11.5 ml/kg) or groupOA+ NE + F (11.3 ml/kg). Although the scatter is wideamong these 12 dogs, these data suggest the possibilitythat group OA + F animals received, by chance, alarger OA lesion and developed greater pulmonaryedema by 2 h than did group OAanimals. Furthermiiore,during the next 2 h, three of four group OA animalsincreased Vwa, and the mean value increased to 11.5ml/kg. In contrast, furosemide treatment was associatedwith reduced Vwa between 2 and 4 h in five of eightanimals in groups OA+ NE + F and OA+ F, and meanVwa at 4 h tended to decrease after fuirosemide. Wewondered whether these results might be a result ofgreater underestimation of VwNa by indicator dilutionafter furosemide, but the results in Fig. 3 do not supportan obviously different Vw/Vw"a among the OAgroups.Accordingly, our data do not exclude the possibilitythat furosemide treatmiient decreased lung water eventhough the actual water content and W/D of excisedlungs wvas as large or larger in group OA+ F thanin group OA.

Weconclude that our indicator-dilution and excised-lung studies did not clearly demonstrate an effect offurosemide on canine OApulmonary edema. This short-fall was in part because of the complex compositionof OApulmonary edema, which this study quantitatedfor the first time. The excess lung liquid measured4 h after 0.06 ml/kg OAwas administered intravenouslyconsisted of -50% cell-free plasma, -25% whole blood,and -25% crystalloid. These findings are consistentwith the notion that intravenous OAcauses a range oflesions increasing pulmonary vascular permeability towater, plasma proteins, and erythrocytes. One conse-quence of the observed vascular permeability to plasmaproteins is a marked reduction in potential therapeuticeffectiveness of raising vascular colloid oncotic pres-suire in low-pressure pulmonary edema (15).

Effect offurosemide on factors governing lung liquidbalance. The major factors governing the net flow oflung liquid (QE) from pulmonary microvessels (mv) tolung interstitium (is) may be expressed in the e(quation:QE = Kf[(Pmv - Pis) - (7rmv - ris)of] - Q lymph,where P and IT represent hydrostatic and colloidoncotic pressures, respectively, Kf is the pulmonarymicrovascular permeability coefficient, a- is the reflec-tion coefficient of the capillary membrane, and Q lymphrepresents pulmonary lymphatic flow and any otherfactors removing liquid from the lung interstitium (14).Because OA did not raise Pmv as deduced from thepulmonary vascular pressures (Table I) or lower 7rmv

as deduced from protein concentrations (Table II), thepulmonary edema is likely a result of a substantialincrease in Kf, to a lesser extent to reduced 0a, andremotely to altered Pis, vris, or Q lymph. Once Kf isincreased and a is reduced, the amount of edema flowis very sensitive to altered PIm1v and (quite insensitiveto altered 7rmv (15).

After receiving furosemide, dogs in group OA+ Ftended to inerease their mean Ppa (16.7-19.2 mmitHg)and to decrease their Ppwx (Table I). During the sametime, group OA dogs had a larger and statisticallysignificant reduction in Ppw and tended to decreasePpa (16.3-14.5 mmHg). To the extent that the ratioof vascular resistance upstream and downstream fromthe site of major leak is not substantially altered byfurosemide, these hemodynamic measurements indi-cate that Pmv increased in group OA+ F comparedwith group OA during the 2 h after furosemide (16).Beca'use 7Tmv was not different between groups afterfurosemide (Table II), edema should increase in groupOA+ F. These consideratioins are consistent with thestrong tendency of WV/D of excised group OA + F lungsto exceed WV/D of group OA lIIIugs.

On the other hand, increased PIm1v after fUirosemidegoes couinter to the expected chanige if furosemnidereduced the rate of edema formation as suiggested bythe indicator-dilution data in Fig. 2 discussed above.Reduced edema formation might occur despite increasedPmv if furosemide reduced Kf or increased Q lymph.We are aware of Ino evidence concerning furosemideeffects on pulmonary microvascular Kf, but the pos-sibility is not inconsistent with effects of diuretics onwater transport in other organs. Furosemide has complexeffects on thoracic duct lymph flow (17, 18), but theavailable evidence suggests that lymph flow changesin accord with factors governing QE, as if furosemidewere having no direct effect on lymphatic mobility (19,20).One explanation of reduced shunt, reduced edema,

and increased Ppa after furosemide is enhanced pul-monarv vasoconstriction in edemiatous lung regions.Such an effect of furosemide would reduce the fractionof total pulmonary blood flow going to nonventilatedlung units. To the extent that such vasoconstrictionwas upstream from the major site of liquid leak, hydro-static pressure there (Pmv) would tend to decreaseafter furosemide (21). In turn, QE might decreaseconsiderably for a small reduction in Pmv because Kfis high (15). In our study, Ppa tended to increaseafter furosemide, and PVR, calculated as (Ppa - Ppw)/Q(t, increased considerably. These hemodynamic meas-urements were made at end-expiration when alveolarpressure (Palv) was 0, so Ppw exceeded Palv in alllung regions in groups OAand OA + F. Accordingly,this calculation of PVR indicates narrowing of pulmo-nary vessels in group OA+ F compared with groupOA, and underestimates the narrowing to the extent

Furosenl ide itn Lotw-Pre.s.sure Pulmotnary Edenma 1501

that increased Ppa in group OA+ F recruits and dis-tends pulmonary vascular bed (22). Although reducedQt is associated with increased PVR, Qt decreased bya similar amount in groups OAand OA+ F between2 and 4 h. Furthermore, if furosemide is reducing edema,it seems likely that pulmonary vascular compressionby edema is decreasing in group OA+ F comparedwith group OA. These considerations suggest that PVRincreased after furosemide in part as a result of pulmo-nary vasoconstriction. This vasoconstriction could re-duce edema formation and shunt if it occurred pre-dominantly upstream from the major site of leak inedematous lung regions.

Weare unaware of conclusive studies of the effectsof furosemide on pulmonary vascular tone in vivo.Furosemide blocks adrenergic constriction of mesentericvessels (23), and a brief communication suggests asimilar action on intralobar pulmonary veins (24).Recent studies in our laboratory demonstrated that thefraction of pulmonary blood flow perfusing a singleedematous lobe in otherwise normal lungs of anaes-thetized dogs increased 30 min after furosemide whenthe lobar edema had not changed and the lobar shuntdecreased (unpublished observations). These resultsdo not support pulmonary vasoconstriction in edematousregions as an explanation of reduced shunt after edema,but offer an alternative consistent with most of ourdata. Conceivably, pulmonary vascular tone is increasedin lungs made edematous by OA, furosemide reducesvascular tone, and fractional perfusion increases to lungunits in which alveolar flooding and vascular compres-sion by edema is not the limiting impedance to flow.Consequent redistribution of pulmonary blood flowaway from edematous lung units is associated withreduced Qs/Qt and reduced Ppa. The latter is associatedwith derecruitment of vessels having closing pressures,as might be imagined to occur preferentially in edema-tous regions where extravascular pressures (Pis) areelevated. This secondary effect would further reduceshunt and increase PVR.

Comparison of furosemide effects in high- vs. low-pressure pulmonary edema. Pulmonary edema second-ary to left ventricular failure is quite responsive tofurosemide. The reductions in symptoms, intrapulmo-nary shunt, and radiologic edema have been attributedto diuresis and the diuretic enhanced capacitance ofthe systemic veins. Both mechanisms reduce CBV,which in turn reduces Pmv in inverse proportion tothe compliance of the pulmonary circulation. Considera-tion of our data in low-pressure edema focused ourattention on the left ventricular diastolic complianceas the major determinant of APmv. Because the leftventricular diastolic volume-pressure characteristicsare nonlinear (Fig. 4), a reduction in CBV and leftventricular diastolic volume after furosemide causesa large fall in Pmv in cardiogenic pulmonary edema,

50

LEFTVENTRICULAR

ENDDIASTOLICPRESSURE(mmHg)

20

10- I!Hg25m1

50 100 150LEFT VENTRICULARVOLUME(ml)

200

FIGURE 4 Schematic diastolic volume (abscissa) -pressure(ordinate) relationship of the left ventricle. When furosemidereduces left ventricular end diastolic volume by 25 ml, leftventricular end diastolic pressure decreased by 20 mmHgincardiogenic edema and by 5 mmHgin low-pressure edema.For discussion, see text.

but the same reduction in ventricular volume in low-pressure pulmonary edema causes a much smaller re-duction in ventricular diastolic pressure and Pmv.

Kiely et al. (5) studied the central hemodynamiceffects of 40 mg of intravenous furosemide in 15 pa-tients with acute myocardial infarction. In the nine pa-tients who had a large diuresis, Ppw decreased from20±4 to 12±3. In 27 patients with elevated left atrialpressures (PLa), furosemide or ethacrynic acid loweredmean left atrial pressure from 22 to 15 mmHgdespitea small reduction in mean pulmonary blood volumefrom 341 to 321 ml (6). In contrast, seven patientswith normal central hemodynamics during the con-valescent period of high altitude pulmonary edema hada small and insignificant reduction in mean atrialpressure from 5.0 to 3.5 mmHgwhen furosemide causeda much larger reduction in mean pulmonary bloodvolume from 327 to 252 ml (3). In normal adult sheep,80 mgof furosemide caused mean PL, to decrease from2.5 to 1.2 mmHg(20). This small reduction in hydro-static pressure was statistically significant and wasassociated with a 30% reduction in pulmonary lymphflow, which the investigators attributed to reducedsteady-state edema formation. Similarly, Bland et al.(19) observed in eight normal lambs that PLa decreasedfrom 2 to 1 mmHg(P < 0.05) associated with a 27%reduction in lymph flow. In five lambs given largesaline loads in the same study, PLa increased to 9 mmHg.After furosemide, PLa decreased from 9 to 1 mmHg,and lymph flow was reduced to one-half of the controlvalue. These data support the concept that furosemidehas a much greater effect on Pmv in cardiogenic orhigh-pressure pulmonary edema than in pulmonaryedema associated with low or normal vascular pres-sures, presumably because the left ventricular diastolicvolume-pressure relationship is quite curvilinear.

Although the reduction in left ventricular diastolicpressure is much less in low-pressure edema, such

1502 J. Ali, W. Chernicki, and L. D. H. Wood

small reductions may effectively reduce the edemaformation rate because Kf is so high. In this setting,Pmvand its effects on edema may be affected as muchby small changes in pulmonary vascular muscle toneas by altered ventricular diastolic volume. Pulmonaryvenous dilatation or pulmonary arteriolar constrictionby furosemide could lower the hydrostatic pressureat the leak site by several millimeters of Mercury with-out detectable changes in Ppa or Ppw (16). Similarly,pulmonary venous constriction or arteriolar dilationwould increase Pmvand edema. These considerationssuggest that even limited vasoactive effects of furosemideeasily overlooked in cardiogenic edema might signifi-cantly alter low-pressure edema formation rate. Thisrationale applies to other pulmonary vasoactive drugscommonly used in acutely ill patients for other reasons;viz., nitroprusside, isoproterenol, and dopamine.Finally, the effects of these drugs on ventricular func-tion and diastolic volume-pressure curves may signifi-cantly alter Pmv and edema. Apparently, furosemidehas no such effects on canine left ventricular function (25).

In summary, out attempt to determine the mechanismof action of furosemide in a canine model of low-pres-sure pulmonary edema revealed several surprising dif-ferences from cardiogenic edema. First, pulmonaryoxygen exchange was considerably improved 2 h afterfurosemide with only equivocal reductions in theamount of edema. Second, if the edema were reducedby furosemide, this effect could not be attributed tomeasured reductions in Ppw or Ppa. Accordingly, boththe improved gas exchange and the reduced edema areas likely a result of the pulmonary vasoactive effectsof furosemide redistributing pulmonary blood flow awayfrom edematous areas and the lowering the hydrostaticpressure in pulmonary microvessels. Such effects areless important and unreported in cardiogenic edema,where furosemide-induced reduction in CBVcauses alarge reduction in Pmv, edema, and shunt because ofthe low diastolic compliance of the distended ischemicleft ventricle.

Although furosemide produces smaller reductions inPmv in low-pressure edema, it seems reasonable toemploy this therapy because even minor reductions inPmv markedly reduce the rate of edema formationwhen pulmonary capillary permeability is increased.Such an approach requires careful monitoring of someestimate of Pmv and the awareness that altered pul-monary vascular tone might confound estimates basedon measured Ppa and Ppw. One approach is to usediuretics and fluid restriction to seek the lowest Ppwconsistent with adequate cardiac output. An acknowl-edged pulmonary risk of induced circulatory hypo-volemia is that it may increase the permeability per se(26). Another potential problem is that potent loopdiuretics obscure the early detection of renal hypo-perfusion by prerenal oliguria. Conceivably, reduced

Qt and renal blood flow during circulatory hypovolemiacan be prevented by vasoactive agents such as dopamineused in the dopaminergic range (3-5 ug/kg per min).Finally, when further reduction in Pmv and edema issought after circulating blood volume and Qt are re-duced to acceptable limits, agents which alter leftventricular diastolic compliance or systolic pumpingfunction may be effective. Because each vasoactiveagent employed may have significant and independenteffects on pulmonary shunt and pulmonary edemaformation, measured changes in Qs/Qt are only looseand indirect indicators of edema rate in pulmonarycapillary leak. Further attempts to test these complicatedtherapeutic considerations seem warranted becausecurrent therapy of pulmonary capillary leak is associ-ated with high mortality (27).

REFERENCES

1. Biagi, R. W., and B. N. Bapat. 1967. Furosemide in acutepulmonary edema. Lancet. I: 849-852.

2. Lal, S., J. G. Murtagh, A. M. Pollock, E. Fletcher, andP. F. Ginnion. 1969. Acute haemodynamic effects offurosemide in patients with normal and raised left atrialpressures. Br. Heart J. 31: 711-717.

3. Bhatia, M. L., I. Singh, S. C. Manchanda, P. K. Kanna,and S. B. Roy. 1969. Effect of furosemide on pulmonaryvolume. Br. Med. J. 2: 551-552.

4. Dikshit, K., J. K. Vyden, J. S. Forrester, K. Chatterjee,R. Parkash, and H. J. C. Swan. 1973. Renal and extra-renalhemodynamic effects on furosemide in congestive heartfailure after acute myocardial infarction. N. Engl. J. Med.288: 1087-1090.

5. Kiely, J., D. T. Kelly, D. R. Taylor, and B. Pitt. 1973.The role of furosemide in the treatment of left ventriculardysfunction associated with acute myocardial infarction.Circulation. 48: 581-587.

6. Austin, S. M., F. B. Schreiner, D. H. Kramer, P. M. Shah,and P. N. Yu. 1976. The acute hemodynamic effects ofethacrynic acid and furosemide in patients with chronicpostcapillary pulmonary hypertension. Circulation. 53:364-369.

7. Robin, E. D., L. C. Carey, A. Grenvik, F. Glouser, andR. Gaudio. 1972. Capillary leak syndrome with pulmonaryedema. Arch. Intern. Med. 130: 66-71.

8. Gelb, A. F., and E. Klein. 1976. Hemodynamic andalveolar protein studies in non-cardiac pulmonary edema.Am. Rev. Respir. Dis. 114: 831-835.

9. Ashbaugh, D. G., and T. Uzawa. 1968. Respiratory andhemodynamic changes after injection of free fatty acids.

J. Surg. Res. 18: 417-421.10. Rossing, R. G., and S. M. Cain. 1966. A nomogram relating

PO2, pH, temperature and hemoglobin saturation in thedog. J. Appl. Physiol. 21: 794-798.

11. Kirk, B. W. 1969. Effect of alterations in pulmonary bloodflow on lung exchangeable water in the dog. J. Appl.Physiol. 27: 607-612.

12. Chinard, F. P., R. M. Effros, W. Perl, and M. Silverman.1967. Organ vascular and extravascular compartment invivo. In Compartments, Pools and Spaces in MedicalPhysiology. P. E. E. Bergner and C. C. Lushbaugh,editors. U. S. Dept. of Commerce Clearing House, Conf.661010, Springfield, Va. 381-422.

13. Lynch, J. P., J. G. Mhyre, and D. R. Dantzker. 1979.

Furosemide in Low-Pressure Pulmonary Edema 1503

Influence of cardiac output on intrapulmonary shunt.J. Appl. Physiol. 46(2): 315-321.

14. Staub, N. C. 1974. Pulmonary edema. Physiol. Rev. 54:678-721.

15. McCarthy, J., R. M. Prewitt, and L. D. H. Wood. 1978.Relative importance of vascular hydrostatic and oncoticpressures in testing low pressure pulmonary edema. Am.Rev. Respir. Dis. 117: 211. (Abstr.)

16. Gaar, K. A., and A. E. Taylor. 1967. Pulmonary capillarypressure and filtration coefficient in the isolated perfusedlung. Am. J. Physiol. 213: 910-914.

17. Szwed, J. J., S. A. Lkeit, and R. J. Hamberger. 1972. Effectof furosemide and chlorothiazide on the thoracic ductlymph flow in the dog. J. Lab. Clin. Med. 79: 693-698.

18. Stowe, N. T., and J. B. Hook. 1976. Effect of furosemideon renal hilar lymph flow. Arch. Int. Pharmacodyn. Ther.224: 229-309.

19. Bland, R. D., D. D. McMillan, and M. A. Bressack. 1978.Decreased pulmonary transvascular fluid filtration inawake newborn lambs after intravenous furosemide. J.Clin. Invest. 61: 601-609.

20. Demling, R. H., and J. A. Will. 1978. The effect of furosemideon the pulmonary transvascular fluid filtration rate. Crit.Care Med. 6: 317-319.

21. Jeanneret-Grosjean, J., R. M. Prewitt, and L. D. H. Wood.1979. Effect of alveolar hypoxic vasoconstriction on rate

of edema formation in pulmonary capillary leak (PCL).Fed. Proc. 38: 1379. (Abstr.)

22. Permutt, S., P. Caldini, A. Maseri, W. H. Palmer, T.Sasamori, and K. Zierler. 1969. Recruitment versus dis-tensibility in the pulmonary vascular bed. In The Pulmo-nary Circulation and Interstitial Space. A. P. Fishmanand H. H. Hecht, editors. University of Chicago Press,Chicago, Ill. 375-390.

23. Mtabaji, J. P., M. S. Naker, and D. F. Horrobin. 1976.Vascular actions of furosemide and brimetanide on ratsuperior mesenteric vascular bed: interactions withprolactin and prostaglandins. Can. J. Physiol. Pharmacol.54: 357-366.

24. McGowan, C. S., Greenberg, and R. D. Wilkerson. 1978.Effect of furosemide and morphine on canine pulmonaryintralobar arteries and veins and splenic arteries andveins. Fed. Proc. 37: 917. (Abstr.)

25. Mierzwiak, D. S. 1975. Acute effects of furosemide onleft ventricular contractility in dogs. Arch. Int. Pharma-codyn. Ther. 213: 180-185.

26. Michel, R., S. Inoue, and J. C. Hogg. 1979. Pulmonarycapillary permeability in dogs. A physiological study usinghorseradish peroxidase. J. Appl. Physiol. 42: 13-2 1.

27. Murray, J. F. 1977. Mechanisms of acute respiratoryfailure. Conference Report. Am. Rev. Respir. Dis. 115:1071-1079.

1504 J. Ali, W. Chernicki, and L. D. H. Wood