C.\RDIORESPIRA'rORY EFFECTS OF EXPERIMIENTAI,LUNGEMBOLISM*

By D. F. J. HALMAGYIt AND H. J. H. COLEBATCHt(Front the Department of Mfedicine, University of Sydney, Sydney, N.S.W., Australia)

(Submitted for publication October 10, 1960; accepted May 18, 1961)

Respiratory embarrassment and pulmonary hy-pertension are important consequences of pulmo-nary embolism. Respiration is affected at severallevels. Changes in rate and depth have beensummarized by Whitteridge (1) as "rapid shal-low breathing" unaffected by the inhalation of100 per cent oxygen (2, 3). Sectioning or cool-ing of the vagi prevented this phenomenon whichwas therefore regarded as neurogenic, caused bythe excitation of (unspecified) lung receptors.

Embolism is usually followed by an increasedresistance to lung inflation in the artificially re-spired animal (4, 5) or a rise in the intrapleuralpressure swing in those breathing spontaneously(6). This was thought to be due to broncho-constriction.

A fall in arterial oxygen saturation has alsobeen reported to accompany pulmonary embolism;several mechanisms were suggested to explainthis change. An acceleration of blood flow throughthe non-occluded areas of the lung (= decreasedcontact time) was proposed by Binger, Brow andBranch (2). A fall in the pulmonary diffusingcapacity for oxygen was assumed by Williams(7) to be due to a reduction in the area of thealveolocapillary membrane. Venous admixturewas not abolished, however, by breathing 100 percent oxygen (8, 9), and it also occurred after theintravenous injection of oxygen itself (10). Thisprompted the conclusion that arterial hypoxia wascaused by the opening of pulmonary arteriovenousanastomoses (9).

These changes do not seem to account for theoften distressing dyspnea seen in clinical pul-

*This study was supported in part by grants fromthe National Health and Medical Research Council ofAustralia, The Postgraduate Foundation and the Con-solidated Medical Research Fund of the University ofSydney, and The Joint Coal Board.

t Adolph Basser Research Fellow of the Royal Aus-tralasian College of Physicians.

tJoint Coal Board Research Fellow.

monary embolism. It occurred to us that changesin lung mechanics-the most common causes ofdyspnea-have not yet been investigated in thiscondition, and we therefore decided to includelung mechanics in our study of experimental lungembolism.

The dose-response relationship in embolic pul-monary hypertension, as demonstrated by sev-eral investigators, suggests that the rise in pres-sure is related to the number of occluded vessels.This implies that pulmonary hypertension wouldoccur only in widespread embolization, since a50 per cent occlusion of the pulmonary circula-tion is followed by mild changes only (Table I).Two-thirds of the pulmonary vascular bed had tobe excluded in order to create a more markedpulmonary hypertension (14, 15).

These data are difficult to reconcile with someother observations. Repeated intravenous injec-tions of blood clots into rabbits resulted in amarked right ventricular hypertrophy, suggestingpulmonary hypertension. Yet postmortem angi-ography of the lung vessels failed to reveal ob-struction ( 16). This finding and numerousothers not mentioned here appeared to indicatethat reactive vasoconstriction contributes to thistype of pulmonary hypertension. Embolic con-striction of the systemic arteries was shown tobe neurogenic. It was expected that neuro-plegic procedures might also modify the pulmo-nary vascular response to embolism, but in themajority of technically acceptable experiments,spinal cord section, vagotomy, and chemical andsurgical sympathectomy were found ineffective(7, 17-19). Only Price, Hata and Smith (20)obtained a reduced response.

It was decided to study two aspects of thesechanges. By using two different doses of embolicmaterial (one 10 times larger than the other),an attempt was made to assess the quantitativenature of the response. By using different drugs,

1785

8D. V. 5. I4ALMAGYI AND H. J. 14. COLEBATCI4

TABLE I

CLhanges o] pulmtonary t:irtulation with pulmnonary vascular occlusioult *

Pulm. art. Pulm. art.mean press. Cardiac output Ventil. resist.

Subjects C 0 C 0 C 0 C 0 Ref.

mmHg L/min Llmin dynes-sec-cm-F5 men 16 23 7.9 8.2 162 224 (11)

15 men 13 15 9.3 8.4 8.6 8.3 112 143 (12)9 dogs 15 18 3.1 3.1 3.2 4.3 387 464 (12)6 men 21 30 5.8 5.5 290 435 (13)

* C = control; 0 = occlusion.

the possibility of a non-neurogenic pulmonary vaso-constriction was explored.

METHODS

Material. Forty-six sheep weighing 21 to 48 kg wereused in these experiments. The supine animals wereanesthetized with thiopentone and intubated. The femo-ral artery and vein were dissected free and a thermometerwas inserted into the rectum.

Circulation measurements. A cardiac catheter waspassed via the femoral vein into the pulmonary arteryand a cannula was introduced into the femoral artery.Oxygen saturation of the arterial (Sao.) and mixedvenous (Svo2) blood and hemoglobin content were meas-ured spectrophotometrically (21). In experiments inwhich 100 per cent oxygen was breathed instead of air,oxygen content and capacity were measured manometri-cally (22). Expired air was collected for 1.5 to 2.5minutes in Douglas bags; their content was measuredand analyzed by the Haldane method. In later experi-ments oxygen uptake, tidal volume (VT) and rate ofbreathing (f) were measured from the record obtainedwith a Pulmotest twin-spirometer.1 The animal breathedair from a closed-circuit system, oxygen being fed fromthe second bell at the rate at which it was removed fromthe first system. The same arrangement was used forexperiments performed with 100 per cent oxygen, bothsystems being washed out and filled with oxygen.

Blood samples were taken in the mid-period of ventila-tion measurements. The Fick principle was used to cal-culate pulmonary arterial blood flow (Q), the shunt-formula (Cco2 - Cao2/Cco2 - CvO2) to calculate venousadmixture (Qs) in per cent of Q. Oxygen content ofthe pulmonary capillary blood (Cco2) was estimated bysubtracting 0.60 vol per cent from the oxygen capacityof the arterial blood (23). In other experiments (24)this method gave good agreement with the more labori-ous procedure of calculating alveolar oxygen tension,measuring blood pH and obtaining the saturation ofpulmonary capillary blood from the oxygen dissociationcurve for sheep's blood.

Pulmonary (Pp.a.) and femoral (Pf...) arterial pres-sures were measured by Sanborn transducers (no. 267)

' Godart-Mijnhart, Utrecht, Holland.

and recorded on a 6-channel direct-writing Sanborn oscil-lograph and expressed in millimeters of mercury. Totalpulmonary (RpUim) and total systemic (R8.8t) resistanceswere calculated by the usual formulas and expressed indynes-sec-cm.

Blood flows, resistances and ventilated volumes wereexpressed on the basis of 1 m2 body surface area (BSA).The latter was calculated by the formula: 8.3 -4w2 whereW= body weight in grams (25). Details of the circula-tion measurements were described elsewhere (26).

Intrapleural pressure (Ppl) was measured via aspecially prepared 17 gage needle introduced into thethird or fourth interspace, 7 to 10 cm from the anteriorsurface of the chest. A pneumothorax of 60 to 80 mlwas induced. The needle was connected by 70 cm poly-ethylene tubing to a Sanborn transducer no. 267 B. Ppiwas recorded relative to atmosphere in centimeters ofwater.

Air flow rate and tidal volume were obtained with aGodart pneumotachometer and integrator.' The pneumo-tachometer is similar to that described by Silverman andWhittenberger (27) and the one used in these experimentscovered the range of flow from 0 to 100 L per minute.The integrator consists of a high stability D.C. amplifierwith an extremely effective time constant and a lowdrift rate so that the error of VT measurements fromthis source was not likely to exceed 1 per cent. The Ppi,airflow and volume changes were electrically amplifiedand recorded simultaneously on the oscillograph.

Method of analysis. Lung compliance (CL), expressedin milliliters per centimeter water per kilogram, wasobtained by dividing the VT by the simultaneously re-corded Ppi between points of zero flow; 6 to 10 breathswere measured from a recording made at 25 to 50 mmper second and the mean value taken. Mean frictional(= nonelastic) resistance was calculated at points ofequal volume (28). Differences in pressure and rateof airflow were read from the recording. Due allowancewas made for the resistance of the instrument. Fivebreaths were analyzed for each period.

Calibration. Pressure, volume and flow were all linearwithin 2 per cent. The coefficient of variation for a singlemeasurement of CL averaged 5.6 per cent and duplicatemeasurements invariably agreed within 10 per cent. De-tails of the lung mechanics measurements are describedelsewhere (24).

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CARDIORESPIRATORYEFFECTS OF EXPERIMENTALLUNGEMBOLISM

Volume-pressure relationship over an extended range.On three occasions in three animals the volume-pressurerelationship of the lung over an extended range wasstudied by a method similar to that described by Cookand co-workers (29). The measurements were per-formed after the injection of 0.20 ml per kg barium sulfatewhile the animals were paralyzed with succinylcholine.Increments of 150 ml were introduced in 1 second with5 seconds between each step. The transpulmonary pres-sure was measured with a Sanborn differential pressuretransducer 267 B. Inflation was continued until the trans-pulmonary pressure was approximately 30 mm Hg

greater than in the resting position. The gas was thenremoved in a stepwise fashion at the same time intervalsas for the inflation. An approximate correction forchange in gas volume from ATP to BTPS and for gasexchange was made by taking the volume increments as160 ml BTPS for both inflation and deflation. Statisticalmethods were used as recommended by Snedecor (30).Embolic material consisted of a 33 vol/vol emulsion ofbarium sulfate injected into the pulmonary artery.

Groups. The animals were divided into two maingroups. Group I (Table II), consisting of 19 animals,was given 0.20 ml per kg barium sulfate. Group -II

TABLE II

Cardiorespiratory effects of the administration of 0.20 ml per kg barium sulfate emulsion in sheep *

Group I t Intact Vagot. Atrop. Bretyl. Lysergic acid

No. of animals 6 3 4 2 4

Cardiac output(L/min/m2 BSA)

Femoral art. meanpressure (mmHg)

Syst. art. resistance(dynes-sec-cm5b/m2 BSA)

Pul. art. meanpressure (mmHg)

Pulm. art. resistance(dynes-sec-cmnr/m2 BSA)

Art. oxygen saturation(%)Venous admixture(% cardiac output)

0 3.125 3.12

30 2.87

0 1235 135

30 109

0 3,2895 4,014

30 3,169

0 135 32

30 24

0 3445 896

30 670

0 91.65 81.7

0 135 33

30 45

Ventilation(L/min/m2 BSA)

Breathing rate (min)

Tidal volume(ml/m2 BSA)

Lung compliance(ml/cm H20/kg)

Mean airway resistance(cm H20/L/sec)

0 6.45 11.7

30 8.9

0 305 48

30 50

0 2195 253

0 3.495 0.75[21]

30 1.06E33JI 1.51[43]

0 2.215 5.81

10.512.1

3133

338370

2.580.79[31]

1.10[43]1.824.60

8.212.2

4156

198216

16.519.6

6083

271248

3.330.83[25]

1.19[36]1.202.94

9.215.3

4357

226272

2.52 2.900.34[13] 0.99[34]

1.51 [52]

3.504.13

107111

2,4392,408

1530

357693

90.979.4

1639

3.293.42

118123

2,9992,950

1732

435776

77.168.8

3747

2.752.91

115120

3,4493,477

1425

432717

81.173.5

3039

3.193.06

125128

3,1793,392

1629

396753

78.076.4

3738

* Italicized figures = significant difference (p < 0.05). Numbers in brackets attached to compliance measurements= values in per cent of control.

t 0 = control period; 5 and 30 = 5 and 30 minutes after the injection of embolic material; I = after inflation of thelung.

1787

D. F. J. HALMAGYIAND H. J. H. COLEBATCH

(Table III), 28 animals, was given 0.02 ml per kg ofthe same substance, 0.1 of the previous dose.

After a control period (0) six animals of group I and5 of group II were injected with barium sulfate. Pres-sures were continuously measured; other parameters were

measured 5 minutes later. In some animals of group I,measurements were again repeated at 30 minutes. Afterthe last measurement the lungs were inflated to a pres-

sure of 30 mmHg and CL was again determined (I,Tables II and III). The remaining animals were sub-iected to various procedures prior to the control period.

Bilateral cervical vagotomy was carried out in 7 sheep;0.2 to 0.4 mg per kg atropine sulfate was administeredintravenously to 4 vagotomized and 4 intact animals.Ten mgper kg bretylium tosylate (Darenthin) was admin-istered intravenously to 2 animals 30 minutes prior to thecontrol period. N,N,N',N,-3-pentamethyl-N,N',-diethyl-3-aza-pentane-1-5-diammonium-dibromide (Pendiomid)was injected intravenously into 1 animal in a dose of 2mg per kg; 100 to 150 mg promethazine hydrochloride

(Phenergan, May and Baker) was intravenously admin-istered to 5 animals 30 minutes prior to the control pe-

riod; 0.5 mg per kg lysergic acid butanolamide (Deseril)was injected intravenously into 4 sheep 30 minutes priorto the control period.

In 3 animals control measurements of lung mechanicswere followed by continuous breathing of 100 per centoxygen. After an equilibration period of 10 minutes,circulation measurements were taken, barium sulfateadministered and at 5 minutes, circulation measurementswere repeated while the animals were still breathingoxygen. Oxygen breathing was then discontinued andmeasurement of lung mechanics repeated.

A continuous infusion of adrenalin (0.4 ,g per kg perminute) was administered to 4 animals; a continuous infu-sion of isoproterenol hydrochloride (Isuprel; 0.03 Imgper kg per minute) to 6 others. Control measurementsand embolization were performed during the infusion.2

2 Darenthin was supplied by Burroughs Wellcome &Co. (Aust.) Ltd.; Pendiomid by Ciba Co., Pty. Ltd.;

TABLE III

Cardiorespiratory effects of the administration of 0.02 ml per kg 33% barium sulfate emulsion in sheep *

Vagot. + OxygenGroup II Intact atrop. Pendiomidt 100% Promethazine Adren. Isoproterenol

No. of animals 5 4 1 3 5 4 6

Cardiac output 0 3.93 2.91 5.31 3.27 3.64 5.16 5.00(L/min/m2) 5 4.09 3.73 4.93 3.80 4.37 5.84 5.09

Femoral art. mean 0 120 107 115 131 102 133 76pressure (mm Hg) 5 117 111 127 136 107 145 71Syst. art. resist. 0 2,468 2,970 1,732 3,218 2,497 2,172 1,216(dynes-sec-cmn5/m2) 5 2,489 2,433 2,062 2,912 2,057 2,001 1,148Pulm. art. mean 0 15 16 16 15 19 17 9pressure (mmHg) 5 20 23 30 25 22 20 10Pulm. art. resist. 0 302 440 241 381 446 271 153(dynes-sec-cm56/m2) 5 384 506 487 514 414 280 169

Art. oxygen sat. 0 90.4 84.2 86.9 105.9 81.3 88.8 93.8(%) 5 86.8 81.0 69.7 105.5 72.0 88.0 94.0

Venous admixture 0 16 26 27 18 33 29 8(% cardiac output) 5 22 30 50 19 45 32 8

Ventilation 0 8.7 10.8 16.9 8.0 14.5 10.6 11.0(L/min/m2) 5 12.3 11.8 23.8 10.2 19.0 13.5 11.0

Breathing rate 0 35 26 58 31 48 33 35(min) 5 44 26 71 41 53 39 34

Tidal volume 0 253 415 288 250 304 317 302(ml/m2) 5 284 447 334 243 359 338 293

Lung compliance 0 3.13 3.24 4.10 4.41 3.01 4.14 4.02(ml/cm H20/kg) 5 1.46[47] 1.78[55] 0.67[16] 1.96[44] 1.91[63] 2.94[71] 4.22[105]

I 3.16[1013 2.66[82] 3.69[90] 3.24[73] 4.38E106]Mean airway res. 0 2.15(cm H20/L/sec) 5 3.06

* See footnote to Table II.t Ciba; see formula in Methods.

1788

CARDIORESPIRATORYEFFECTS OF EXPERIMENTALLUNGEMBOLISM

At the end of the experiments the lungs were in somecases removed and macroscopically assessed for edema.

RESULTS

Results are summarized in Tables II and III.

A. Intact animals

1. Effects on circulation. Q remained practi-cally unchanged in both groups. The slight in-crease in Pf.a. and RYst at 5 minutes in group Iwas significantly different (0.02 < p < 0.05) fromthe slight decrease in group II. The injection ofthe embolic material was followed by a rapid risein Pp.a.. The peak value was reached within 30to 60 seconds (Figure 1). At this stage the dif-ference between the average peak values obtainedafter the injection of 0.20 ml per kg (= 52 mmHg) and 0.02 ml per kg (= 44 mmHg) was notstatistically significant (p 0.30). From then onPp.a. gradually declined and at 5 minutes the dif-ference between the two groups was statisticallysignificant (p < 0.01).

2. Effect on arterial oxygen saturation andventilation. Sao2 decreased significantly in groupI only. There was a significant rise in VE in both

Deseril by Sandoz (Aust.) Pty. Ltd.; and Isuprel byWinthrop Labs. Their courtesy is gratefully acknowledged.

EXP 129 1

0 20ml/ Kg. 0.02 ml/Kg.Ba S04.

6050- 0

40~~~~~~~30 I20

1 00

I I0 2 4 6 0 2 4 6

Time,min following embolism.( o = control.)

-60

-50

-40

-30

-20-10

FIG. 1. AVERAGEVALUES OF THE MEAN PULMONARYARTERIAL PRESSUREBEFORE (o), 1 MINUTE AND 5 MIN-

UTES AFTER THE INJECTION OF 0.20 AND 0.02 ML/KGBARIUM SULFATE IN UNTREATED (SOLID LINES) AND ISO-PROTERENOL-TREATED(DOTTED LINE) ANIMALS. Pressuresin mmHg.

groups; the values were higher in group I. Theincrease in f was significant in group I only. VTincreased in both groups, significantly in groupII only.

3. Effect on mean frictional resistance. A sta-tistically significant rise, which averaged 250 percent, occurred in group I only. The administra-

II miP 30 - ',-

mm.Hq .0,Id_,,0 4, i; j . , TDJ

Pf~~~~oi~2"iI1Emfftq100

t./Sec °o 0g t A

cm. 1120 - b_ P iFa 4/Qs -k4I

FIG. 2. INSTANTANEOUSEFFECTS OF EXPERIMENTAL PULMONARYEMBOLISM. I. Control measurement. II. Em-bolism. Note the instantaneous increase in the negativity of intrapleural pressure. III. Three minutes after embo-lization. PP.a. = pulmonary arterial pressure. Pf.a. = femoral arterial pressure. V = integrated volume. V = airflow (pneumotachygraph) .

1789

D. F. J. HALMAGYIAND H. J. H. COLEBATCH

5.

101LUNG

COMPLIANCE20MLI CM H2O

4Q60.

100.

200.

300 -

200 -

x 100-

Lu

N. 60 -

> 40

z3 20-0.

0u 10 -

zm

0

0 00 0 0

0

0 000

00

0 . % -

0, 0

,00

go 0

100 200 400 OO 5000

PULMONARY ARTERIAL RESISTANCEDYNES SEC CMW5

FIG. 3. RELATIONSHIP OF LUNGCOMPLIANCEAND PUL-MONARYARTERIAL RESISTANCE IN LUNGEMBOLISM. Blackdots represent sheep subjected to barium sulfate emboliza-tion. Open circles indicate measurements taken in spon-taneous pulmonary embolism due to blood clots.

tion of the smaller dose resulted in a lesser risenot statistically significant.

4. Effect on lung compliance. Embolism wasfollowed by a gross fall in CL, as illustrated byFigure 2 and Tables II and III. The fall wasmore severe after the large dose and increased onlyslightly throughout the first 30 minutes. Inflationto 30 mmHg produced a variable improvementin group I but restored CL in group II.

A definite correlation was obtained betweenRpulm and CL (Figure 3). A decrease in CL wasassociated with an increase in Rpulm.

A further correlation was established betweenCL and mean frictional resistance (Figure 4). Asizable rise in the latter occurred only with agross fall in CL.

Effective capillary blood flow (QE = 100 - QS)was plotted against values of CL between the rangeof 10 to 60 ml per cm HO (Figure 5). Theregression coefficient (+ 0.47) would have oc-curred by chance less frequently than 1 in 100times (p < 0.01).

5. Effect on lung volume. During the first 20seconds after the injection of the embolic material,

0 .

..

. 0 .

1112 1-41-6F82 3 4 5 6 7 B 9 1 15 20

Mean airway resistance CMH20/LT/SEC.

FIG. 4. RELATIONSHIP OF LUNGCOMPLIANCEANDMEANFRICTIONAL ("AIRWAY") RESISTANCE IN EXPERIMENTAL

PULMONARYEMBOLISM.

air was expelled from the lungs, as illustrated bythe volume trace on Figure 2. This was alsoconfirmed by spirometer records not shown here.Parallel to this change there was an increase inend-expiratory transpulmonary pressure-i.e., thePx,1 became more negative, as shown by the rise

90 I

s0 1

0% 7o

60

50

10 20 30 40

CL ml/cm H2050 60

FIG. 5. RELATIONSHIP OF EFFECTIVE PULMONARYCAPII-

LARY BLOODFLOW (QE) IN PER CENTOF TOTAL PULMONARY

ARTERIAL BLOOD FLOW AND LUNG COMPLIANCE (CL) IN

EXPERIMENTAL PULMONARYEMBOLISM 5 MINUTES AFTER

INJECTION OF THE EMBOLIC MATERIAL. Only animals witha compliance value of less than 60 ml/cm H20 were

included.

*/

1790

CARDIORESPIRATORYEFFECTS OF EXPERIMENTALLUNGEMBOLISM

800-

.600

-0

200 a

o 10 20 30 40 50 60PRESSURE. CM. H20.

--- I sec values. 5 sec values.

......0.. 5sec values after repeated inflations.

FIG. 6. VOLUME-PRESSURECURVE OVER AN EXTENDED

RANGEIN AN EMBOLIZED LUNG (0.20 ML/KG BARIUM SUL-

FATE). For explanation see text.

in the expiratory level of the Pp, trace (bottomline) on Figure 2. The amount of air expelledwas 150 to 200 ml. The end-expiratory trans-pulmonary pressure gradually returned toward thecontrol level.

6. Volume-pressure relationship over an ex-

tended range. The result of a typical experimentis shown in Figure 6. The solid-line loop in themiddle represents the volume-pressure curve meas-

ured at 5 seconds corresponding to the intervalbetween successive volume steps. The curve forthe pressure at 1 second lies to the right. Therewas a small fall in pressure between 1 and 5 sec-

onds for each volume step in the tidal range. Athigher levels of inflation the fall in pressure be-tween 1 and 5 seconds increased to 10 to 15 cm

H2O. The total lung volume at 50 cm H2O in-flating pressure was still markedly reduced. Afterinflation the slope of the 5-second volume-pressurecurve increased somewhat, but the total lung vol-ume remained unchanged. Compliance, taking a

pressure value between 1 and 5 seconds, equaled13.4 ml per cm H2O. The compliance measuredduring spontaneous breathing was 15.2 ml per cm

H20.

7. Postmortem findings. Extensive lung edemawas found in only one animal in group I.

B. Animals subjected to neuroplegic procedures

In vagotomized animals, f was lower than in the

intact ones and failed to rise after embolism. VT

was higher and the rise in VE was less than inthe controls. Mean airway resistance was lowerin the atropine-treated group. The postembolicrise, expressed as per cent of control value, was notdifferent from that of the untreated group. Withthese exceptions the embolic response in thesegroups was essentially similar to that seen in theintact animals.

C. Other procedures

Lysergic acid butanolamide. The only differ-ence in the response was a lesser rise in Qs.

Oxygen breathing. The response was un-changed.

Promethazine. This group had the highest in-itial Pp.a. and Rpulm. Embolism produced thesame initial rise in_Pp.a. as in the controls; at 5minutes, however, Pp.a. was only slightly elevated.Because of a simultaneous increase in Q, no risein Rpulm occurred. The rise in Q was not statisti-cally significant (0.05 < p < 0.10). The differ-ence between the change in Q in this group and inthe corresponding control group was not statisti-cally significant (p = 0.30).

Adrenalin. The adrenalin infusion resulted ina gross rise in Q and in some increase in Pt.a..Both increased further after embolism. The post-embolic rise in Pp.a, was considerably less than inthe corresponding control group and Rpulm re-mained unchanged. The fall in CL was less thanin the preceding groups.

Isoproterenol. Infusion with this substancecaused a gross rise in Q. a fall in systemic andpulmonary arterial pressure and resistance, and arise in Sao2. Embolism was followed by a mar-ginal rise in Pp.a. and virtually no change in Rpulm.The initial peak rise in Pp.a. was also largelyabolished (Figure 1). Changes in Qs, VE andCL were completely prevented.

DISCUSSION

1. Ventilation. These experiments have thrownsome doubt on the view that hypoxemia contrib-utes to the ventilatory response to embolism assuggested by previous workers (12); the responsewas not significantly affected by 100 per cent oxy-gen breathing. Contrary to the widely held belief,VT increased in both intact groups and decreasedonly after the repeated injection of large doses of

1791

D. F. J. HALMAGYIAND H. J. H. COLEBATCH

embolic material. Vagotomy or the administra-tion of atropine, or both, reduced but did notabolish the response, while bretylium, lysergic acidbutanolamide, promethazine, or adrenalin waswithout effect. Hyperventilation was completelyabolished by isoproterenol infusion.

2. Lung mechanics. The most surprisingchange was the gross fall in CL, the extent ofwhich appeared to be related to the amount ofembolic material injected. CL is the sum of com-pliances of all distensible units within the lungs.When part of the lung was removed CL showeda proportional fall (31). A reduction of the num-ber of distensible units due to surface tensionforces created by the alveolar transudate in lungedema was shown to be responsible for the fallin CL (29, 32). A gradual collapse of the ter-minal airways was suggested to account for a partof the spontaneous fall in CL in anesthetized dogs(33). This mechanism, the sudden exclusion ofa significant portion of the distensible units, ap-pears to be the only possible cause for a gross andrapid fall in CL; changes in lung blood volumewould account only for minor changes (34, 35).

Pulmonary edema has occurred under certainconditions (36) and after a variable latent period(37) in lung embolism. Postmortem inspectionof the lung revealed edema in only one of ouranimals. Further evidence against the presence ofedema is the effect of inflation. In the presenceof fluid in the airways, large inflations tend topromote its distribution, resulting in no improve-ment or a further drop in CL (24). Inflation ofthe lung had a variable effect in group I (intact)and restored CL in group II (intact). A normalCL, a few minutes after embolization, is incom-patible with lung edema.

The increase in mean frictional resistance wasremarkably -well correlated with the fall in CL.This may represent flow through a smaller num-ber of patent airways which in effect reduces themean diameter of the sum of airways throughwhich flow occurs. However, it is likely that partof the increase was due to bronchoconstriction.

Otis and colleagues (38) have demonstratedthat the distribution of ventilation is influenced bybreathing frequency if the time constants (prod-ucts of compliance and resistance) of the separateareas in the lung are different. The problem,therefore, is how much of the fall in CL is due to

the inclusion of a dynamic element, in the meas-urement after bronchoconstriction, that was notpresent before.

The dynamic element in vagotomized animals islargely abolished by the inspiratory pause; thefall in CL was, however, unchanged. The in-creased elastic resistance could also be demon-strated under semistatic conditions, as shown bythe volume-pressure curve. This inflation throughan extended range also indicates that the increaseis not restricted to the tidal range. The agree-ment between CL values taken under semistaticconditions and during spontaneous breathing indi-cates that the fall in CL after embolism has notbeen overestimated.

A gross fall in pressure in the interval be-tween inflations occurred only at higher levels ofinflation. This indicates three possible causes:1) surface hysteresis, 2) tissue relaxation, 3)opening of distensible units.

The behavior of the embolic lung differs fromthat of the edematous lung in which one observesan earlier increase in slope, and the volume at30 cm H20 pressure is not much different fromthe normal lung (29). This suggests that theincreased resistance to inflation is not due to sur-face forces and is consistent with a hypothesis thatthe alteration in lung mechanics is due to airwayclosure.

The airway musculature in man and animalsextends over both the proximal (supported) anddistal (unsupported) parts of the bronchial tree,with muscular rings surrounding the orifices ofthe atria (39), also referred to as "alveolar sphinc-ters" (40). Muscular contraction of the proximalpart of the airways, if unaccompanied by hyper-secretion or mucosal swelling, or both, can onlycause a narrowing of the lumen; the presence ofcartilagenous rings prevents complete occlusion.Muscular contraction in the distal unsupportedsegments would result in airway closure with ex-clusion of the more peripheral alveoli from ex-pansion. This suggested action might be facilitatedby the thickness of these muscular bands; they arerelatively five times thicker than the muscle ringsof the cartilagenous bronchi (39).

It is suggested that pulmonary embolism is fol-lowed by a contraction of the smooth muscles ofthe airways. In the proximal segments this con-traction causes some narrowing in the lumen, as

1792

CARDIORESPIRATORYEFFECTS OF EXPERIMENTALLUNGEMBOLISM

indicated by the moderate rise in mean frictionalresistance. In the distal segments the same con-traction would cause widespread closure of theterminal airways with a fall in ventilated lungvolume and CL. This appears to be the "unknownmechanism" (41) that produces a shift of venti-lation toward the unaffected parts of the lungs, asdemonstrated by fluoroscopy (42) and broncho-spirometry (43) and by means of a balloon-catheter (44, 45).

The fall in CL after embolization was accom-panied by a decrease in lung volume amounting to150 to 200 ml. If muscular contraction squeezedout air one would expect the end-expiratory Ppito become more negative. Since compliance ofthe chest wall in the sheep is on the average 150ml per cm H2O (24), the expected rise in end-expiratory transpulmonary pressure could not ex-ceed 1 to 2 cm H2O. This was the change actuallyobserved in the first half-minute following theembolus. Its subsequent return to normal can beaccounted for by a gradual further expansion ofthe ventilated areas of the lung. In other casesthe return to normal was apparent rather thanreal owing to active expiration, the Pp, at the endof expiration at the moment of zero flow remain-ing more negative than before embolism.

Robin (8) and Julian (44), and their associates,observed an increased alveolar dead space basedon a widened alveolar-arterial Pco2 difference inpulmonary embolism. In view of the gross me-chanical nonhomogeneity of the lung after em-bolism, alveolar sampling is invalid. This mayaccount for the gross variation in their results.

Because of the tendency of the anesthetized ani-mal to breathe at a fixed VT-i.e., constant trans-pulmonary pressure swing-CL is likely to remainreduced until a large inflation is performed. Theapparent duration of the stimulus responsible forthe fall in CL can therefore only be assessed bythe period of time that must elapse after emboliza-tion before CL can be restored by inflation. Thisperiod varied with the amount of embolic materialinjected. With larger doses, 30 minutes was notsufficient; with small doses, CL was successfullyrestored a few minutes after embolization.

The inability of vagotomy and atropine to pre-vent the embolism-induced rise in mean frictionalresistance is at variance with the findings of Binetand Burstein (5) and Boyer and Curry (6) and

confirms the observations reported by Singh (4).The parasympathetic nervous system is apparentlynot involved in this change.

The fall in CL remained unaffected by neuro-plegic procedures and by the administration ofantihistaminic and antiserotonin drugs. It seemssafe to conclude that the suggested constriction ofthe airway musculature is unrelated to neurogenicstimuli and to the release of histamine or sero-tonin. The fall following the small dose of em-bolic material was reduced by adrenalin and com-pletely abolished by isoproterenol. This provedthe functional nature of airway closure and ap-pears to suggest that some yet unidentified sub-stance, causing a constriction of the airway mus-culature, might be released as a response toembolism.

The severe fall in CL as demonstrated in theseexperiments is bound to increase the strain of therespiratory muscles already burdened by hyper-ventilation. We suggest that the resulting in-crease in the work of breathing could well beresponsible for the severe dyspnea seen in somecases of clinical pulmonary embolism. Since theadministration of isoproterenol abolished both hy-perventilation and the rise in elastic resistance,it is likely to be beneficial in patients.

3. Arterial hypoxemia. Closure of the terminalairways, if relatively more extensive than obstruc-tion of the vessels, may result in the perfusion ofnonventilated alveoli with consequent venous ad-mixture. This explanation is consistent with theinability of 100 per cent oxygen to abolish venousadmixture (8, 9), and appears to be supported bythe partial correlation between QE and CL (Fig-ure 5).

4. Pulmonary hypertension. The sudden steeprise in Pp.a. after the injection of embolic material(Figure 1) does not appear to be dependent onthe amount injected. The extraordinary rise in Qthat would be necessary of itself to cause such arise is unlikely to have occurred. It is more prob-able that the rise represents a time lag betweenthe embolism-induced obstruction and the openingof reserve capillaries. In this case one wouldexpect the rise to be reduced or largely absentafter repeated doses of emboli, but this is not thecase; an equal initial rise was regularly observedwith repeated injections. It is therefore suggested

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that this sudden steep rise represents pulmonaryvasoconstriction.

The argument most frequently used against theoccurrence of embolic pulmonary vasoconstrictionis mainly based on the absence of pulmonary hy-pertension following lobar emboli (18). Thisimplies that local embolism does not cause gen-eralized vasoconstriction in the lungs. The situa-tion is analogous in the systemic circuit wherelocalized emboli also fail to cause a generalizedvascoconstriction. Lobar emboli are, however, oflittle assistance in excluding the occurrence of a lo-cal response, i.e., constriction of vessels actuallycontaining the embolic particles. This mechanismis consistent with the dose-response relationshipand would also explain how a relatively small doseof particles, as in our group II, can cause pulmo-nary hypertension.

The lack of effect of neuroplegic procedures toprevent postembolic pulmonary hypertension hasbeen confirmed in these experiments. Even 100per cent oxygen, an otherwise potent pulmonaryvasodilator, proved ineffective. The lack of pro-tection by lysergic acid butanolamide suggests thatserotonin release is probably not involved in thismechanism.

The administration of promethazine failed toaffect the immediate pressure response but re-duced the 5-minute values considerably. Changesin lung mechanics were not influenced. This find-ing, therefore, does not provide evidence for therelease of histamine, which is known to producebronchoconstriction but no pulmonary hyperten-sion (46).

The effect of adrenalin and even more the effectof isoproterenol provide conclusive evidence thatpulmonary hypertension after the small dose ofbarium sulfate is predominantly functional. Iso-proterenol has been demonstrated to be a potentpulmonary vasodilator in animals (47). In pa-tients suffering from various types of heart dis-ease isoproterenol in considerably smaller dosesreduced Rpulm by increasing Q; Pp.a remainedunchanged (48). It is not clear whether thisdifference is due to the lower dose or to the dif-ferent mechanism of pulmonary hypertension inthose patients.

From these observations isoproterenol emergesas a substance which, if administered in high dosesand continuously, effectively prevents all major

consequences caused by the intravenous adminis-tration of 0.02 ml per kg barium sulfate. Noother substance is known to offer a similar protec-tion. It remains to be decided how effectively thisdrug can block the effects of larger doses of em-bolic material and what its action is if adminis-tered after embolism.

SUMMARY

Experimental pulmonary embolism was pro-duced in sheep, by means of graded amounts ofa barium sulfate emulsion. Ventilation, lung me-chanics and circulation were measured. The ef-fect of various neuroplegic procedures, oxygenbreathing, the administration of antihistaminic andantiserotonin drugs, and continuous adrenalinand isoproterenol infusions was assessed.

In addition to the already known consequencesof pulmonary embolism (hyperventilation, arterialhypoxemia, pulmonary hypertension and broncho-constriction), a gross fall in lung compliance wasshown to occur, unrelated to lung edema.

All but one of the procedures used in these ex-periments were ineffective in altering the onset orseverity of the above changes, but the effect ofthe smaller dose of embolic material was com-pletely prevented by the administration ofisoproterenol.

It is concluded that postembolic pulmonaryhypertension and compliance-fall after a smalldose of embolic matrial are predominantly func-tional and probably caused by the release of anunknown substance as a response to embolism.The physiological and clinical implications of thesefindings are discussed.

ACKNOWLEDGMENTS

We are indebted to Mr. P. Donnelly, Miss MaureenWoodward and Mr. T. Miller, members of our technicalstaff. Many parts of this work depended on their col-laboration. It was a privilege to enjoy Prof. C. R. B.Blackburn's constant interest and support.

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