ventilation-perfusion abnormalities in pulmonary...

Journal of Clinical InvestigationVol. 44, No. 10, 1965

Ventilation-Perfusion Abnormalities in ExperimentalPulmonary Embolism *

STEVENE. LEVY,t MYRONSTEIN, ROBERTS. TOTTEN, ISREAL BRUDERMAN,STANFORDWESSLER,ANDEUGENED. ROBIN t

(From the Departments of Medicine, University of Pittsburgh School of Medicine, Pittsburgh,Pa., and the Harvard Medical School and Beth Israel Hospital, Boston, Mass.)

The changes in pulmonary function that occuras a result of experimental pulmonary vascular oc-clusion have been intensively investigated. Thetechniques employed for producing pulmonary vas-cular occlusion have included balloon occlusion(1-3) and the injection of particulate matter (4)into the pulmonary artery. The results of suchstudies are not directly comparable to clinical pul-monary thromboembolism, where vascular occlu-sion is produced by autogenous thrombi. It mightbe anticipated, a priori, that substantial differenceswould occur because of the different physicochem-ical nature of the embolic material and the differentpattern of embolization. In the present studies theeffects of autogenous thromboemboli on ventila-tion-perfusion relationships, pulmonary gas ex-change, pulmonary mechanics, and the ultrastruc-ture of the lung are described.

Two questions related to pulmonary thromboem-bolism are of particular interest. First is the prob-lem of redistribution of ventilation after emboliza-tion. Several investigators have described a shiftof pulmonary ventilation away from nonperfusedlung segments after balloon occlusion of a pulmo-nary artery (1, 5, 6). We have developed atechnique to evaluate whether redistribution ofventilation occurs after autogenous pulmonarythromboembolism. Second is the evaluation ofthe mechanisms resulting in arterial hypoxemiaafter autogenous pulmonary thromboembolism.

* Submitted for publication December 22, 1964; ac-cepted July 1, 1965.

This work was supported in part by grants HE-05059and HE-05317 from the National Institutes of Health andin part by a grant from the Tuberculosis League ofPittsburgh.

t Research fellow, Pennsylvania Thoracic Society.t Address requests for reprints to Dr. Eugene D. Robin,

Dept. of Medicine, University of Pittsburgh School ofMedicine, Pittsburgh, Pa. 15213.

MethodsSixty-five healthy, mongrel dogs ranging in weight

from 9 to 26 kg were studied. The animals were anes-thetized with either pentobarbital, thiopental sodium, orchloralose by intravenous administration and intubatedwith an endotracheal tube. Thirty-four dogs were stud-ied during spontaneous ventilation (spontaneous ventila-tion dogs, SVD), and in 31 dogs spontaneous ventilationwas abolished by either d-tubocurarine or succinylcholineadministered intravenously, and ventilation was thenmaintained with an Etsten bellows pump set to delivera constant tidal volume at a constant frequency (con-trolled ventilation dogs, CVD). The total amount ofbarbiturate administered was such as previously ob-served to maintain adequate anesthesia in nonparalyzedanimals. Autogenous thrombi were produced and re-leased into the pulmonary circulation as previously de-scribed (7).

The following measurements were made before andwithin 30 minutes after embolization in the SVD andCVD while they were breathing room air. Minute ven-tilation (VE) was measured by standard techniques.Femoral arterial blood was analyzed for oxygen contentand capacity, and C02 content by the technique of VanSlyke and Neill (8). Arterial pH was measured with aglass electrode at 37° C. Plasma C02 content was de-rived with the correction factors of Van Slyke and Send-roy from the whole blood CO2 content, the arterial he-matocrit, and arterial pH (9). Arterial Pco% (Paco,)was calculated from the Henderson-Hasselbalch expres-sion of the mass law or measured directly with a Pco2electrode. Arterial Po2 (Pao2) was measured with amodified Clark electrode in the CVDonly. End-tidal C02tension (PAco2) was monitored continuously with an in-frared CO2 analyzer. The peak values of end-tidal Pco2in each respiratory cycle were used to approximate "al-veolar" Pco2. Previous studies in this laboratory haveshown that in the normal anesthetized dog studied withinan hour of anesthesia the mean difference between PAco,and Paco, averages 1.5 ± SD 1.9 mmHg (3). ExpiredCO2 (FEco2) and oxygen (FEO2) concentrations weremeasured by analyses of expired gas by the micro-Scholander method (10). PaO2 was measured after 30minutes of 99.6%o oxygen inhalation in the SVD and af-ter 20 minutes in the CVD. In the latter, the postembolicmeasurement was made during the third hour after em-bolization, and in the former, during the first 2 hours.

1699

LEVY, STEIN, TOTTEN, BRUDERMAN,WESSLER,ANDROBIN

10% helium in air

FIG. 1. DIAGRAM OF SYSTEM USED FOR MEASUREMENT

OF SINGLE BREATH CARBONMONOXIDEDIFFUSING CAPACITY

IN CONSTANTVENTILATION DOGS.

In the SVD the effect of intermittent positive pressure

breathing (IPPB), nebulized isoproterenol, and paren-

teral aminophylline on the a-A Pco, difference before andafter embolization was observed. In addition, in theSVD functional residual capacity (FRC) was measuredby a closed circuit helium technique and nitrogen washoutby the technique of Darling, Cournand, and Richards be-fore and after embolization (11). Total lung resistance(RL) and lung compliance (CL) were measured in theSVD before and after embolization by the techniques de-scribed by Mead and Whittenberger (12), and Marshalland DuBois (13). Thirteen of the SVD were allowed tosurvive for 4 days after embolization so that the timecourse of the observed changes could be studied.

In the CVD diffusing capacity for carbon monoxide(DLco) 1 was measured before and after embolization bya modification of the single breath technique of Ogilvie,Forster, Blakemore, and Morton (14) as follows: A bel-lows pump was set to deliver a fixed volume rangingfrom 700 to 800 ml (Figure 1). The anesthesia bag usedto collect alveolar air was evacuated. The system was

then flushed with a mixture of 0.3% COand 10%o heliumin air from a second anesthesia bag. The apneic dog was

attached to the system at point C in the Figure. Thefixed volume of test gas mixture was rapidly pumped as

a single inspiration into the dog's lungs and held therefor 10 seconds. Then with an assistant compressing thedog's thorax, 200 ml of end-expired (alveolar) air was

collected in the anesthesia bag by transferring the clampat position A to position B. The dog was then ventilatedwith room air for 1 minute and the measurement of dif-

fusing capacity repeated. Helium concentrations of theinspired gas and alveolar air were measured with a catha-

1 Measurements of the DLco by the steady-state tech-nique proved unsatisfactory presumably because of smallerrors in the determination of Paco,. This parametersignificantly affects the calculation of physiologic dead

space, and with the proportionately large dead spaces en-

countered in these experiments, there were significant er-

rors in calculation of PAco and hence, DLco.

rometer, and the carbon monoxide concentration of therespective gases was measured with an infrared carbonmonoxide analyzer, after passing the gas through a dry-ing agent. The FRC used to calculate DLco had beenmeasured by the nitrogen washout technique before em-bolization and was not remeasured after embolization,since as will be shown, it was not found to be significantlychanged after embolization of the type produced in theseexperiments.

Five minutes before sacrifice of each animal with in-travenous barbiturate, heparin was administered intra-venously to prevent post-mortem clotting. After sacri-fice the lungs were examined for evidence of infarctionand atelectasis. An estimate of the degree of pulmonaryarterial occlusion was made in all animals. In the SVDan arbitrary scale of degree of embolism ranging from 1to 4+ was used (15). In the CVD the degree of em-bolization was expressed as a percentage of the number ofpulmonary arteries containing thromboemboli. In nine ofthe CVDan india ink infusion technique (see below) wasused to quantitate more accurately the amount of embo-lized and nonperfused lung. In all of the CVD, sectionsof embolized and nonembolized lung selected at randomwere studied by light and electron microscopy. Indiaink injection was used to quantitate the degree of em-bolized and nonperfused lung in nine CVD as follows:The right ventricle was catheterized immediately beforesacrificing the animal. Twenty ml of 50% india ink wasrapidly infused through the catheter, followed by 20 mlof saturated potassium chloride, which produced immedi-ate cardiac arrest. The lungs were rapidly removed andfixed in Bouin's solution. Forty-eight hours later thelungs were dissected and carbon stained and noncarbonstained lung segments separated. There was usually aclear delineation between the areas of carbon stained andnoncarbon stained lung tissue. The weight and volume(as determined by water displacement) of carbon stainedand noncarbon stained lung segments were measured, andthe relation of carbon staining to gross embolic occlusionof pulmonary arteries was noted.

Calculations. Standard formulae were used to calcu-late alveolar oxygen tension (PAo2), respiratory exchangeratio (RER), FRC, RL, CL, DLco, and the arterial-alveo-lar CO2 tension difference (a-A Pco2 difference).

The following equation (see Appendix) was used tocalculate alveolar dead space (VDaiv) as a percentage ofthe tidal volume entering the alveoli with each breath:

VDaiv=

Paco2 - PAC02 X 1 00(VT - VDanat) Paco2 - PACo2 + PEC02

where VT = tidal volume in milliliters, VDanat = anatomicdead space in milliliters, Paco2 = arterial C02 tension inmillimeters Hg, PACo, = alveolar CO2 tension in milli-meters Hg, and PEco, = CO2 tension in expired air inmillimeters Hg.

The per cent decrease in effective alveolar ventilation(VAeff) in the CVDafter embolization was calculated bythe following formula: Since VE before = VE after, andassuming a value of 100% to VAeff before embolization,

1700

VENTILATION-PERFUSION ABNORMALITIES IN EXPERIMENTALPULMONARYEMBOLISM 1701

TABLE I

Mean values for pulmonary ventilation and gas exchange before and after embolization*

Decrease a-A Pco2 Pao2 afterDogs VE in VAeff Paco2 difference Sao2 Pao, 100% oxygen PAO2 DLco

L/min % mmHg mmHg % mmHg mmHg mmHg ml/min/mm HgSVD3to4+ B 7.1 (243 (1) 5 (1 90 (1)533 4

(21) A 12:3 (21) (19) 19 (19) 84 (19) 333().01 >p >.001 .05 >p >.025 p .01 >p >.001 .05 >p >.025

1to2+ B 55 (10) 41 (13) 2 (13) 92 (13) 566 (7)(13) A 13:0 (1)35 12 92 446.02 >p >.01 .025 >p >.01 p .6 >p >.5 .1 >p >.0s

CVDGroup 1 B 2.4 (18) (18) 3318) 3 (17) 94 (18) 95( 1) 466 (13) 105 (18) 12.8 ( )(19)t A 2.3 19 42 (1) 11(7 88 78 460 94 1 1.5

.2 >p >.1 p <.001 p <.001 .025 >p >.01 p <.001 p >.9 p <.001 .05 >p >.025

Group2 B 2.4 (6) (6) 33 (6) 1 (4) 92 (4) 78 (1) 433 (3) 109 (4) 13.1 (3)(6) 2.5 4 34 0 92 81 461812.5

.7 >p >.6 .7 >p >.6 .4 >p >.3 .6 >p >.5 .2 >p >.1 .6 >p >.5 .5 >p >.4

*Abbreviations: SVD, spontaneous ventilation dogs; CVD, controlled ventilation dogs; B, before embolization; A, after embolization; VE,total ventilation; VAff, effective alveolar ventilation; Paco,2 arterial carbon dioxide tension; a-A Pco2 difference, arterial-alveolar carbon dioxidetension difference; Sao2, arterial oxygen saturation; Pao2, arterial oxygen tension; PAO2, alveolar oxygen tension; DLoo, diffusing capacity (singlebreath) for carbon monoxide. Figures in parentheses indicate number of animals studied. p values represent the statistical significance of thedifference between the mean values.

t One animal died immediately after release of thromboemboli.

then the per cent decrease in VAeff =

PacO2 before PECo0 after) 100

PacO2 after- PECo2 before

where Paco2 before = arterial CO2 tension in millimetersHg before embolization, Paco, after = arterial CO2 tensionin millimeters Hg after embolization, PEco, before = CO2tension in expired air in millimeters Hg before emboliza-tion, and PEco, after = CO2 tension in expired air in mil-limeters Hg after embolization.

A fall of 10% or more was accepted as significant, sincechanges of 9%o or less could result from errors in themeasurement of Paco.

Unperfused lung = per cent of noncarbon stained lung= [weight (grams) or volume (milliliters) noncarbonstained lung]/[total weight (grams) or volume (milli-liters) of lungs]. The values for weight and volumewere averaged together.

The per cent of apparent air shift = (per cent unperfusedlung - per cent decrease in VAeff) /per cent unperfusedlung.

Results

The SVDconsisted of two groups: 21 dogs with3 to 4 + emboli and 13 dogs with 1 to 2 + emboli.The CVD consisted of three groups: group 1included 19 dogs in which there was a significantfall in 'VAegf after embolization, i.e., 10% or more,

or a decrease in Pao2 disproportionately great forthe decrease produced by the fall in VAetf, or both.There were 6 dogs in group 2 in which the fall in'VAeff was less than 10%o and without a dispro-

portionate fall in Pao2. In the 6 dogs in group 3no pulmonary emboli were found at autopsy.

Ventilation and blood gases. The effect of em-

bolization on these parameters is summarized inTables I and II, which contain mean values foreach group. In the SVD after the release of em-

boli, there was an increase in VE. This was pro-

duced for the most part by increases in the fre-quency of respiration. VAeff increased in all theSVD. In the CVDobviously no essential changeof VE occurred after embolization, and in the ab-sence of compensatory hyperventilation, there was

a mean decrease in calculated VAeff of 19% in the

Mean values for

TABLE II

a-A Pco2 difference after embolizationin SVD*

Beforeembo- After embolization

liza-tion Day 1 Day 2 Day3 Day 4

mmHgt mmHgt mmHgmmHgmmHgVentilation

with room air 4 (13) 14 (13) 9 (13) 7 (13) 6 (13)

Ventilationwith IPPB, B 2 16 12 7isoproterenol, (7) (5) (1) (1)or aminophylline A 6 18 14 11

* Abbreviations: IPPB, intermittent positive pressure breathing;B and A before and after IPPB, isoproterenol, or aminophylline.Figures in parentheses indicate number of animals studied.

t Measurement made within 30 minutes of release of thrombi.

LEVY, STEIN, TOTTEN, BRUDERMAN,WESSLER, AND ROBIN

group 1 dogs and 4% in the group 2 dogs. InSVDand the group 1 CVDthere was an increasein alveolar dead space and in the a-A Pco2 differ-ence. In the group 2 CVDthe change in alveolardead space and a-A Pco2 difference fell within therange of experimental error. It is well knownthat there are changes in VA/Qc (capillary bloodflow) ratios in the lung of anesthetized dogs notsubject to any other experimental procedure. Theeffect of this factor on calculated \VAeif was elimi-nated by using each dog as his own control. Alsoin the 6 dogs (group 3) in which no pulmonaryemboli were found there was no significant changein calculated VAeff after the experimental proce-

dure. Thus, the changes found in the group 1 dogsclearly occurred as a result of pulmonary vascularocclusion. As shown in Table II, in the SVDthe a-A Pco2 difference decreased with each suc-

cessive day after embolization, and by the fourthpostembolic day was usually near control levels.Bronchodilators and IPPB caused the a-A Pco2difference to increase both before and after the re-

lease of emboli. In the SVD with the 3 to 4 +emboli and the group 1 CVD, the arterial bloodoxygen saturation (Sao2) and the Pao2 fell sub-stantially. In the former group the decrease in

Sao2 apparent during inhalation of ambient airpersisted for 3 to 36 hours and could not be re-

stored to normal with room air administered byIPPB. In the 1 to 2 + SVD and the group 2CVD the Sao2 did not change significantly.

In 6 of 11 group 1 CVD the fall in Pao2 couldnot be explained entirely on the basis of the fall inVAeff. In 4 dogs the fall in Pao2 could be ex-

plained on this basis, and in 1 dog there was no

postembolic change in Sao2 or Pao2.In the 3 to 4 + SVD the Pao2 after 99.6% oxy-

gen inhalation was significantly reduced after em-

bolization as compared with changes in Pao2 be-fore embolism, whereas in the CVD there was no

significant change.In the CVD the RERwas greater than 1.0 be-

fore embolization in most of the dogs, indicatingthe presence of an unsteady state. This was pre-sumably related to the decreased metabolic rate andCO2 production after induction of anesthesia andmuscle paralysis with maintenance of ventilationat a preanesthesia level. By the time the post-embolic studies had been carried out, the majorityof the dogs showed an RERof less than 1.

Nitrogen washout curves before and after em-bolization showed no significant change.

Diffusing capacity. There was a mean fall ofborderline significance of 1.3 ml per minute permmHg of the Dtco in 11 of the group 1 CVD(Table I). There were wide variations in the pre-embolization values with a range from 3.8 to 21.2ml per minute per mmHg. Of the 6 group 1 CVDwith a disproportionate fall in Pao2, the DLC0 wasmeasured in 4; in 3 there was a fall ranging from0.8 to 2.9 ml per minute per mmHg, whereas in 1there was a 1.2 ml per minute per mmHg rise.DLCo did not change significantly in 3 of the group2 CVD.

Pulmonary mechanics. Immediately after em-bolization in the SVDthere were large increases inRL and large decreases in CL (Table III). Al-though changes in lung mechanics occurred in thepresence of a single embolus, these abnormalitiestended to be greater in the 3 to 4 + SVD. Fourto 30 minutes after embolization, RL and CL re-turned to normal. At the time of the majorchanges in RL, the a-A Pco2 difference was large,and although it gradually fell, was still abnormalwhen the mechanical abnormality was no longerdetectable (Figure 2).

The FRCwhen measured by helium dilution inthe SVD did not change significantly within 30minutes after embolization.

India ink studies. In the group 1 CVDthe ana-tomical estimate of the degree of pulmonary ar-

TABLE III

Mean values for lung mechanics before and after embolizationin SVD*

Before Afteremboliza- emboliza-

tion tion

RL, cm/L/sec 3.2 6.0 p < .001(19)

CL, L/cm 0.09 0.06 p < .001

(19)a-A PCO2

difference, mmHg 17 p < .001(19)

FRC, ml3 to 4+ 1,170 1,320 p >0.5

(9)1 to 2+ 1,060 1,190 p>0.5

(3)

* Abbreviations: RL, total lung resistance; CL, lung compliance;a-A Pco2 difference, arterial-alveolar carbon dioxide tension difference;FRC, functional residual capacity. Figures in parentheses indicatenumber of animals studied. p values represent the statistical differ-ence between the mean values.

1702


terial occlusion judged by the number of throm-boemboli in the pulmonary arterial tree averaged64%. In approximately a third of this group theentire pulmonary arterial tree contained thrombo-emboli, i.e., 100% occlusion. In the group 2 CVDthe anatomical estimate of pulmonary arterial oc-clusion averaged 40%'. India ink infusion in 3group 3 CVD in which no emboli were found inthe pulmonary arteries showed that all lung tis-sue became darkly carbon stained. Noncarbonstained lung, which was clearly discernible, was in-variably associated with an embolus in the regionalpulmonary artery. However, when carbon stainedlung was found, it was not uncommonly associatedwith an embolus in the regional pulmonary artery.Thus, not all emboli effectively prevented perfusionof the involved lung segments by dye, and presum-ably emboli may be present without a total cessa-tion of blood flow. It should be emphasized thatthese dogs were sacrificed by inducing asystolewithin seconds after the infusion of the india ink.Assuming that noncarbon stained lung representstotally nonperfused lung, then the amount of non-perfusion ranged from 11 to 48% in 5 of the group1 CVD so studied (Figure 3). On the basis ofthis assumption, the apparent degree of air shiftranged from 0 to 69% in these 5 animals (Figure3).

Necropsy studies. In none of the 65 dogs wasgross or microscopic evidence of pulmonary in-

9

-J8

awI7

e,5C04

E

03z

-J

4wI-j

0CONTROL

FIG. 2. TOTAL LUNG

LAR CARBON DIOXIDE T

BEFORE AND AFTER EMVENTILATION DOG.

80 l l I

70 0(15)

. 60 _(18)zw

50

40 -

30*0(20)X 30

20 ( ) INDICATES THE PER-42 0 CENTAGE DECREASE IN-

EFFECTIVE ALVEOLAR

10-_VENTILATION FOLLOW-_ING EMBOLIZATION

0 -yl'4) 1(44)0 10 20 30 40 50 60 70 80 90 100

NON- PERFUSED LUNG TISSUE(PERCENT)

FIG. 3. RELATIONSHIP BETWEEN NONPERFUSEDLUNG

TISSUE, DECREASE IN EFFECTIVE ALVEOLAR VENTILATION,ANDAIR SHIFT IN 5 GROUP1 CONSTANTVENTILATION DOGS

AFTEREMBOLIZATION.

farction or pulmonary edema found. Scatteredareas of atelectasis were observed in most dogs,but were unrelated to the degree or location of em-boli. The only anatomical difference between the3 to 4 + SVDand group 1 CVDand in the 1 to2 + SVD and group 2 CVD was the volume ofthromboemboli in the pulmonary arteries. In theSVD th'at were allowed to survive 96 hours, largeamounts of thromboemboli were still present. Inthe 6 group 3 CVDno thromboemboli were found.Each of these dogs had severe metabolic acidosispossibly related to the barbiturate anesthesia andthe experimental procedure.

Electron microscopy showed no essential differ-ence in the appearance of alveolar walls, blood ves-sels, or subcellular structures in the affected versusnonaffected areas of the lung. The appearancewas identical to that found in control dogs withoutpulmonary emboli.

Discussion(23mm) The changes in pulmonary function that take

_l place after pulmonary thromboembolism are com-

1jplex and involve interrelated alterations in ventila-tion-perfusion relations, pulmonary mechanics, andpulmonary gas exchange.

2MINN POST 10 MIN POST Redistribution of ventilation. Effective occlu-EMBOLIZATION EMBOUZATIONsion of a pulmonary artery by an embolus should

RESISTANCE AND ARTERIAL-ALVEO- arteryENSION (a-A PCO2) DIFFERENCE result in a segment of lung that is ventilated, butIBOLIZATION IN A SPONTANEOUS not perfused. Such areas are referred to as alveo-

lar or parallel dead space. Severinghaus and

LEVY, STEIN, TOTTEN, BRUDERMAN,WESSLER, AND ROBIN

Stupfel ( 16) and Julian, Travis, Robin, andCrump (3) have demonstrated an increase inalveolar dead space after pulmonary arterial oc-clusion due to air embolism and balloon occlusionof the pulmonary artery, respectively, in the dog.In the absence of any change in the proportion ofthe ventilation delivered to the embolized, nonper-fused lung segments, the relative increase in al-veolar dead space theoretically could be used toquantitate the amount of embolized, nonperfusedlung tissue. This has been the basis for the clini-cal use of the a-A Pco2 difference to determine thepresence of pulmonary emboli and to quantitate theamount of involved lung (3, 16). Recent workby Severinghaus and others (1) indicates that theassumption of a change in perfusion alone afterpulmonary arterial occlusion may be incorrect.In the dog, they demonstrated that after balloonocclusion of the pulmonary artery to one lung,there was a relative decrease in ventilation to thislung. It was postulated that hypocapnea subse-quent to the loss of perfusion resulted in bronchi-olar constriction, and in some areas complete air-way closure with atelectasis, and that these me-chanical changes were responsible for the shift inventilation away from the nonperfused lung. Re-cent data have suggested that the bronchoconstric-tion subsequent to experimental pulmonary throm-boembolism produced by autogenous thromboem-boli is related to the release of humoral agents fromthe platelets coating the thromboembolus (17).Moore, Humphreys, and Cochran, in dogs, alsofound that ventilation to a nonperfused lung de-creased (5). On the other hand, Julian and asso-ciates (3) and Lategola and Rahn (18) in the dog,and Folkow and Pappenheimer (19) in the cat,found no significant shift in ventilation after lossof perfusion to one lung. Marshall and his associ-ates (20) were unable to demonstrate any shiftin ventilation after release of an aged autogenousthromboembolus to one lung in dogs. They didnot, however, exclude the possibility that a shifthad occurred only within the involved lung, andnot from one lung to the other.

In the absence of compensatory hyperventilationafter thromboembolism a shift in ventilation fromnonperfused to perfused lung segments would de-crease the predicted change in VAeff. The indiaink technique has permitted a study of the relation-ship between the degree of nonperfusion and the

decrease in VAeff in the CVD after embolization.An air shift was considered to have occurred whenthe per cent decrease in VAeff was less than therelative amount of nonperfused lung. In 3 of the5 group 1 CVDsubjected to dye infusion, the de-crease in VAeff was substantially less than the rela-tive amount of nonperfused lung, indicating that anair shift had taken place. In the remaining 2 dogs,no air shift could be demonstrated (Figure 3).There are alternative explanations for the resultsof these 5 experiments. 1) If there was an in-crease in excretion of CO2 by the bronchial cir-culation after thromboembolism, the calculated de-crease in VAeff would have been underestimated.This possibility seems unlikely since it has beenshown that, acutely, after pulmonary arterial ob-struction there is insignificant carbon dioxide ex-cretion by the bronchial circulation (21). 2) Ifsome of the noncarbon stained lung segments wereactually perfused, with the carbon not grossly ap-parent, the degree of nonperfusion would havebeen overestimated.

Figure 3 shows the relation between the rela-tive amount of nonperfused lung and the degreeof apparent air shift. Although the number of ob-servations is too few to permit statistical evalua-tion, it would appear that as more lung is embo-lized and nonperfused, the degree of air shift in-creases in a more or less linear fashion. Eventhough varying degrees of air shift may occur inautogenous pulmonary thromboembolism, its mag-nitude is insufficient to prevent significant in-creases in the a-A Pco, difference. Thus, thea-A Pco2 difference may be used to detect thepresence of massive thromboemboli.

Mechanical alterations related to air shift. Anattempt was made in the present studies to relatethe apparent air shift observed to the mechanicalalterations that took place after embolization.There were increases in total pulmonary resistancewithin 20 seconds after release of the thromboem-boli, lasting 4 to 30 minutes. The a-A Pco, dif-ference, however, persisted for periods up to 4days and did not increase as RL returned towardnormal, as would have been expected if the in-creased resistance reflected regional bronchiolarnarrowing in the embolized, nonperfused lung seg-ments. Although there was an increase in the a-APco2 difference with the administration of bron-chodilator drugs, a similar increase was observed

1704


after bronchodilator drugs before embolization.It seems likely that the increase in RL was due togeneralized and not regional airway narrowing,and could not be equated with the apparent airshift. Furthermore, the apparent air shift was cal-culated on the basis of perfusion measurementsmade 2 to 3 hours after mechanical alterations hadreturned toward normal. Although it is reason-able to assume that there were changes in the me-chanical properties of the lung after embolizationthat were responsible for the apparent air shift,they were either masked by the generalizedchanges that did occur or they were too small tobe measured by present techniques.

Arterial hypoxemia. Another aspect of thisstudy was concerned with the mechanisms respon-sible for arterial hypoxemia, a common finding inexperimental as well as clinical pulmonary throm-boembolization. Various mechanisms have beenproposed to explain this finding: alveolar hypoven-tilation, a decrease in lung diffusing capacity (22),abnormally rapid passage of blood through a pul-monary capillary bed decreased in volume, venti-lation-perfusion abnormalities, localized right-to-left shunts, and atelectasis.

Alveolar hypoventilation was certainly a con-tributory factor to the fall in Pao2 in the group 1CVD. However, in 6 of 11 of these animals, thepostembolic drop in Pao2 was disproportionate tothe degree of hypoventilation, indicating that anadditional mechanism was responsible. The de-velopment of arterial hypoxemia after emboliza-tion in the SVD was not associated with alveolarhypoventilation.

Lung diffusing capacities were measured onlyin the CVD. It is unlikely that the observed de-creases in Pao2 could be accounted for quantita-tively by the small changes in DLCO. Further-more, anatomically the alveolar-capillary membranein the embolized and nonembolized lung seg-ments showed no ultrastructural abnormality. Ithas been noted that balloon occlusion of a pulmo-nary artery will result in a fall in DLCo (23) withno change in Sao2 (24). The small decreases inDLCo may reflect decreased pulmonary capillaryblood volume, while gas exchange across nonembo-lized segments continues unchanged.

Abnormally rapid passage of blood seems un-likely, as the occurrence of arterial hypoxemia inpulmonary embolism is associated with a marked

decrease rather than increase in cardiac output(25-27).

A ventilation-perfusion abnormality such as re-gional hypoventilation is an unlikely cause of thepostembolic arterial hypoxemia, as the nitrogenwashout curves after embolization were normal.Furthermore, the abnormal postembolic responseto 100% oxygen in many of the SVD indicatedthat regional hypoventilation could not be the onlycause of the arterial hypoxemia, unless there waswidespread atelectasis, and this was not observed.

The majority of the SVD developed a right-to-left shunt after massive embolization. Since theexperimental model was the same in the SVDandCVD, the right-to-left shunting would have beenexpected to develop in CVD. Possible explana-tions as to why it did not are 1) the anatomic de-gree of embolization may have been substantiallygreater in the SVD, and 2) the shunts were shownto be transient in many of the SVD, lasting only afew hours. Since the measurements were made inthe CVDduring the third hour after embolization,the shunting may no longer have been present.The anatomic pathway of the right-to-left shuntis unknown. Although perfusion of atelectaticlung may be important, it is probably not the onlypathway, as the post-mortem observation of atelec-tasis was related neither to the location nor thequantity of emboli.

It seems likely that the arterial hypoxemia afterpulmonary thromboembolism is related to morethan one mechanism.

Lung ultrastructure. The preservation of a nor-mal ultrastructural appearance of the lung in theCVD suggests that pulmonary arterial perfusionis not of prime importance in the nourishment ofthe pulmonary tissue up to periods of 3 hours.Whether this function is subserved by the bron-chial circulation or by the inspired air cannot bedetermined from the present studies. This findingcorrelates well with the relative rarity of pulmo-nary infarction after clinical pulmonary embolism.

General comments. The occurrence of air shiftaway from nonperfused lung segments is of gen-eral interest. There are data that demonstrate areverse process, namely a shunting of blood awayfrom nonventilated lung segments (28, 29). Thissuggests an autoregulatory system within the lungthat maintains optimal ventilation-perfusion rela-tions.

LEVY, STEIN, TOTTEN, BRUDERMAN,WESSLER,AND ROBIN

Another point of interest was the fact thatbranches of the pulmonary artery may containthromboemboli but still permit blood flow. Thisis indicated by several lines of evidence. The ap-parent maintenance of cardiac output and survivalof dogs with 100%o involvement of the mainstempulmonary artery indicate that blood must haveflowed around the thromboemboli. Carbon stain-ing of lung segments containing thrombi in somedogs likewise indicates maintenance of blood flowthrough these segments. Marshall has also shownthat reduced but continued perfusion of pulmo-nary arteries containing large thromboemboli mayoccur (20). The fact that after 4 days the a-APco2 difference returned to control levels despitethe anatomic presence of thromboemboli in thepulmonary arteries indicates that perfusion mayhave been re-established. In the present study,total exclusion of blood flow was most effectivelyproduced by relatively small emboli firmly im-pacted in regional branches of the pulmonary ar-tery. It is reasonable to conclude that under ap-propriate circumstances, clinical pulmonary throm-boembolism may produce increases in pulmonaryflow resistance without completely interruptingregional pulmonary blood flow.

Summary

1. After experimental pulmonary thromboem-bolism due to autogenous thrombi there is a redis-tribution of ventilation away from nonperfused toperfused lung segments.

2. This air shift is not of sufficient magnitudeto prevent an increase in alveolar dead space andsignificant arterial-alveolar carbon dioxide tensiondifference.

3. The air shift cannot be explained on the basisof the measured mechanical changes that follow au-togenous thromboembolism.

4. Arterial hypoxemia was observed only in thepresence of massive thromboembolism. One im-portant mechanism is right-to-left shunting.

5. A small decrease in diffusing capacity forcarbon monoxide was observed after thromboem-bolism, which did not account for the degree of hy-poxemia observed.

6. Not all pulmonary thromboemboli result incomplete cessation of blood flow to the involvedlung segment.

7. Acute thromboembolism as produced in thesestudies does not lead to any ultrastructural changein the lung for periods up to 3 hours.

AppendixVE = volume of expired air in liters body temperature

and pressure, saturated (BTPS).VA = total volume of alveolar air (perfused and unper-

fused calculated from PACo2) in liters BTPS.VD = volume of series dead space calculated from

PAcO2.FECO2 = fraction of CO2 in expired air; PECO2tension of

CO2 in expired air.FacO2 = fraction of CO2 in perfused alveoli; Paco2

tension of CO2 in perfused alveoli.FACo2 = fraction of CO2 in perfused and unperfused

alveoli; PACo2 tension of CO2 in perfused and unperfusedalveoli.

FA.CO2 = fraction of CO2 in unperfused alveoli.fp = fraction of total alveoli perfused by pulmonary

arterial blood.1 - fp = fraction of total alveoli unperfused by pul-

monary arterial blood.Volume of expired CO2 = volume CO2 from perfused

alveoli + volume of CO2from unperfused alveoli:

VEXFEc02=VAXFacO2Xfp+VAXFAucO2X(l-fp). [1]

Volume of CO2 leaving unperfused alveoli = volume ofCO2entering unperfused alveoli from dead space:

FAuCO2 X VE (1 - fp) = FACo2 X VD (1 - fp), [2]or

FACo2 X VD VD FACo2 - FECo2FAUCO2 - VE but, VE FACo2so that

FAuCO2 = FACo2 - FECO2- [3]

If Equation 3 is substituted in Equation 1, then,

VE X FECo2 = Faco2 X fp + FACo2VA- FECo2 X fp + FECo2 X fP.

If one solves for fp and substitutes for (VE/VA) X FECO2,its equal, (FACo2/FECo2) X FECO2,

fp = Faco2 - FECo2FaCO2-FACo2 + FECO2

(1-fp) = Faco2 - FAcO2(1-f)=Faco2 - FACo2 + FECo2'

Percentage of alveoli unperfused,

VDaiv Faco2 - FAco2 X(VT - VDanat) Faco2 - FACo2 + FEcO2

and as gas tensions equals,

PacO2 - PACo2+ 100.Paco2 - PAC02 + PEC02 X10

1706


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ventilation-perfusion abnormalities in pulmonary...

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