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Hypoxemia in Pulmonary Embolism, a Clinical Study

JAMESE. WILSONIII, ALANK. PIERcE, ROBERTL. JOHNSON,JR.,EDWARDR. WINGA, W. Ross HARREL, GEORGEC. CumRY, andCHARESB. MULuNS

From the Pauline and Adolph Weinberger Laboratory for CardiopulmonaryResearch, Department of Internal Medicine, University of Texas (Southwestern)Medical School at Dallas, Dallas, Texas 75235

A B S T RA C T The cause of hypoxemia was studied in21 patients with no previous heart or lung disease shortlyafter an episode of acute pulmonary embolism. The diag-nosis was based on pulmonary angiography demonstratingdistinct vascular filling defects or "cutoffs." It was foundthat virtually all of the hypoxemia in patients with previ-ously normal heart and lungs could be accounted for onthe basis of shunt-like effect. The magnitude of theshunting did not correlate with the percent of the pul-monary vascular bed occluded nor with the mean pulmo-nary artery pressure. The shunts tended to gradually re-cede over about a month after embolism. Patients with-out pulmonary infarction were able to inspire 80-111%of their predicted inspiratory capacities, and this maneu-ver temporarily diminished the observed shunt. Patientswith pulmonary infarcts were able to inhale only to 60-69% of predicted inspiratory capacity, and this did notreverse shunting. These data suggest that the cause ofright-to-left shunting in patients with pulmonary emboliis predominantly atelectasis.

When the elevation of mean pulmonary artery pres-sure was compared to cardiac index per unit of unoc-cluded lung, it fell within the range of pulmonary hyper-tension predicted from published data obtained inpatients with exercise in all except one case. This obser-vation suggests that pulmonary vasoconstriction follow-ing embolism is not important in humans, although thesedata are applicable only during the time interval inwhich our patients were studied and in patients receivingheparin.

This study was presented in part at the 1969 meeting ofthe American Society for Clinical Investigation.

Dr. Wilson was a U. S. Public Health Service SpecialResearch Fellow (HE 35, 818). Dr. Winga was a Traineesupported by U. S. Public Health Service Training GrantHE05812.

Received for publication 17 June 1970 and in reiAsed form16 November 1970.

INTRODUCTIONHypoxemia usually accompanies pulmonary embolism inman (1), but its causes are ill understood, and its naturalcourse is poorly documented. Attempts to determine thecause of the hypoxemia have been made in laboratoryanimals, but results are contradictory. Moreover, animalstudies may not be satisfactory for describing the physio-logic events after pulmonary embolism in man for thefollowing reasons. (a) Since animals must be anesthe-tized, they are studied either under conditions of bluntedrespiratory response or artificial ventilation. (b) Ani-mals usually are studied immediately after embolizationwithout extended observations. (c) The response toforeign body or autologous blood clot emboli may differfrom the response to emboli that have existed as thrombiin peripheral veins. (d) There are considerable speciesdifferences in the responses to emboli (2-5).

Interpretation of previous studies in man concerningthe cause of hypoxemia after pulmonary embolism isimpaired by the following factors. (a) The interval fromthe first symptom of embolization to the study is fre-quently over a month (6-8). (b) Patients may havecongestive heart failure (9-11) or unrelated pulmonarydisease (12) as a cause for hypoxemia. (c) Patientswith recurrent emboli are not separated from those witha single episode of embolization (7). (d) Postoperativepatients, who may have other causes for hypoxemia, areincluded (13). (e) The diagnosis frequently is madeonly on clinical grounds, and the extent of embolic oc-clusion is seldom assessed. (f) Serial studies on thesame patients are not available.

The purposes of the present study were to determinein patients without other heart or lung disease themechanisms and course of the hypoxemia associatedwith proven pulmonary emboli and the relationship ofhypoxemia to the extent of embolic occlusion.

The Journal of Clinical Investigation Volume 50 1971 481

METHODSStudy plan. Patients had a right heart catheterization in

the supine position as soon as possible after pulmonaryembolism was suspected. Cardio-green dye was inj ectedfrom the superior vena cava and pulmonary artery in orderto estimate cardiac output and to detect intracardiac right-to-left shunts. Pressures were recorded in the right atrium,ventricle, and pulmonary artery; wedge pressures were ob-tained when possible. Expired gas was collected for measure-ments of oxygen consumption and carbon dioxide produc-tion while the patient breathed room air; simultaneously,samples of arterial and mixed venous blood were collectedfor measurement of pH and blood gases. Blood collectionwas repeated after breathing 100% oxygen for 15 min inorder to estimate venous admixture due to true right-to-leftshunting. Next, pulmonary angiograms were obtainedthrough a No. 8 catheter with the tip in the main pulmonaryartery, injecting 1 mg per kg of Renografin 761 up to amaximum of 70 ml.

On one to three occasions during the next 4 wk, expiredgas was collected and arterial blood gases were measuredwhile the patient breathed room air and then 100%o oxygenin the supine position for 15 min. During 100% oxygenbreathing, completeness of nitrogen (N2) wash out wasdetermined by continuously monitoring the exhalate with anitrogen analyzer. The effect of deep breathing (voluntaryor induced by intermittent positive pressure at 20-40 cmH20) on the arterial oxygen tension (Pao2) was noted; themaximum tidal volume during deep breathing was recorded.Spirometry was performed serially after each patient wasfree of pleuritic chest pain. Eight patients had repeat rightheart catheterizations and pulmonary angiograms 13-35(average 22) days after the first study. An additional pa-tient had repeat angiograms at 3 and 13 months.

To further elucidate the cause of hypoxemia, the follow-ing studies were performed in selected patients: (a) slowspace determination by Briscoe's two balloon-collecting sys-tem measuring expired nitrogen concentration at 1-min in-tervals while breathing 100% oxygen (14-16) ; (b) airwayresistance by the method of DuBois, Botelho, and Comroe

(17); and (c) dynamic compliance by the method of vonNeergaard, and Wirz (18).

Analytical methods. Blood oxygen saturation was mea-sured with a reflection oximeter, and blood pH, carbondioxide tension (Paco2), and Pao, were measured, respec-tively, by a glass pH electrode, Severinghaus Pco2 electrode,and modified Clark Po2 electrode. Each instrument was cali-brated just prior to each analysis with standard gases ofknown composition. Expired gas analysis was performed byinfrared and paramagnetic gas analyzers or Scholandermicroanalysis. These methods have equal accuracy in ourlaboratory (19). Volumes were determined with a Tissotspirometer.

Blood obtained while the patient breathed 100% oxygenwas injected into the cuvette of the Po2 electrode within 2min after withdrawal from the patient. When the Pao2 was300-600 mmHg the Po2 measured in shed blood maintainedat 370C decreased on average 2.5 mmHg per min; thiscorrection factor agrees with that suggested by Kelmanand Nunn (20), and it was added to the determined Pao,.Oxygen is consumed by the Clark Po2 electrode as well asby leukocytes during analysis (20). Therefore, a strip re-cording of oxygen tension with respect to time was ob-tained, and the slope was back extrapolated to the time ofinjection of blood into the cuvette for a more accurateestimate of oxygen tension.

Calculations. Arteriovenous oxygen difference (A-V 02)'in ml/100 ml of blood was determined from the product ofthe arteriovenous oxygen saturation difference in per cent, theblood hemoglobin concentration in g/100 ml, and the normaloxygen capacity of hemoglobin (1.34 ml/g); the additionalcontribution of dissolved oxygen was determined by multiply-ing the Bunsen solubility coefficient (0.003 ml per mmHg/100ml) times the difference between arterial and mixed venousP02. Alveolar-arterial oxygen tension differences (A-a D02)were calculated from the determined Pao2 and the meanalveolar oxygen tension (PAo2) determined from the alveolarair equation (21).

The fraction of true shunting was calculated from a modifica-tion of the Berggren formula (22, 23):

[(A-a Do2)(0.003) + 02 cap (1 - SaO2)] 100% 02Q5/QC = A-V 02 + [(A-a Do2)(0.003) + 02 cap (1 - SaO2)] 100% 02

where Qs/Qc = the fraction of the cardiac output shunted,02 cap = the oxygen capacity of hemoglobin/100 ml blood,and SaO2 = the fraction of hemoglobin saturated with oxygenwhen the patient breathes 100% oxygen. When Pao2 isgreater than 150 mmHg, the term 02 cap (1-Sao2) is neglected.It is apparent that maneuvers which reduce the A-a D02breathing 100% oxygen might do so either by reducing A-V02 difference (i.e., by increasing cardiac output) or by re-

ducing the shunt (24). However, in three of the patients A-V02 differences were measured both during spontaneous andassisted respiration, and the A-V 02 difference increasedslightly during assisted ventilation indicating that any de-crease in A-a D02 was caused by change in the shunt flowrather than change in cardiac output.

A calculation was made of the A-a Do2 breathing room airwhich could be explained by the shunt measured while thesubject breathed 100% oxygen. These calculations were madeassuming that the shunt caused the same oxygen deficit in

'Made by E. R. Squibb & Sons, New York.

arterial blood while breathing room air as while breathing100% oxygen. Thus,

(PAO2 -PaO2) air

(numerator of eq 1) - 02 cap (Sc'o2 - SaO2) (2)0.003

where (PAO2- PaO2) air = A-a D02 breathing air. Knowingthe alveolar oxygen tension breathing air (PAo2) and assumingthat the end-capillary 02 saturation (Sc'o2) is in equilibriumwith the PAO2 at arterial pH, the unique values of arterial 02

tension (Pao2) and O2 saturation (SaO2) are located on theoxyhemoglobin dissociation curve (25) which will satisfyequation 2.

RESULTS

37 patients suspected of having acute pulmonary em-

bolism had right heart catheterizations and pulmonary

482 Wilson, Pierce, Johnson, Winga, Harrell, Curry, and Mullins

(1)

angiograms 0-19 (average 6) days after the first symp-

toms of the present episode of embolism. 21 of the 37 pa-

tients had positive angiograms and no other heart or

lung disease, and form the basis of this report. Cardiaccatheterization data of the patients are listed in Table Iand arterial blood gas results in Table II.

Shunt-like effect. Each patient had one to four ar-

terial blood gas determinations obtained 0-33 days afterthe first symptom of embolism. The measurements ofA-a Do2 breathing 21% 02 have been plotted against theA-a Do2 which could be accounted for entirely by theshunt measured while breathing 100% 02 (Fig. 1); thepoints fall randomly around a line near the line of identity(r = 0.80); P < 0.005). The mean A-a Do2 measuredwith the patient breathing air exceeded the mean pre-

dicted A-a Do2 by only 5.5 mmHg. Thus, true shuntingaccounted for most of the hypoxemia associated withacute pulmonary embolism in these patients with previ-ously normal heart and lungs.

Shunting usually receded gradually over about a monthfollowing embolism (Fig. 2). However, hypoxemia thatwas severe persisted for only 2 hr in one patient who,2 days after the acute episode, showed 21% pulmonaryvascular occlusion by angiography. The mean A-a Do2

breathing 100% 02 the 1st wk after diagnosis was notsignificantly different from the mean A-a Do2 the 2ndwk but was significantly different from the mean A-aDo2 3 wk-6 months after the diagnosis (P < 0.05). 12patients had at least one repeat measurement, and pairedt test analysis of the first with the last A-a Do2 breathing100% 02 showed a statistically significant reduction(P < 0.005).

13 patients had serial observations of A-a Do2 breath-

ing room air and no recent surgical procedures. In seven

of these, the A-a Do2 breathing room air increased at a

later time when A-a Do2 breathing 100% 02 had de-creased. In one of the seven, the cause of the increasingA-a Do2 breathing room air was undoubtedly due to ven-

tilation-perfusion mismatching. However, in the othersix, the increased A-a Do2 breathing room air was as-

sociated with some combination of increased pH, in-creased RQ, or decreased Paco2-all of which exag-

gerate an A-a Do2 breathing room air that is due to a

shunt-and the shunt could still explain the A-a Do2 ob-served breathing room air.

The magnitude of the shunt did not correlate sig-nificantly with the per cent of vascular bed occluded(r = 0.07; P> 0.30) nor with mean pulmonary arterypressure (r = 0.12; P > 0.30).

When 100% oxygen was administered to these pa-

tients by intermittent positive pressure (IPPB )2 at pres-

2 Abbreviations used in this paper: IPPB, intermittentpositive pressure; FEV, forced expiratory volume; FVC,forced vital capacity.

50

Caa

K

:a0

a

(0

w

40

30

20

10

l0 20 30 40 50A-a DO2 ON ROOMAIR

CALCULATED FROM SHUNT

60

FIGURE 1 Alveolar-arterial oxygen tension differences dur-ing room air breathing are compared with the A-a D02 that

can be accounted for solely by the right-to-left shunt mea-sured during 100% oxygen breathing. These data are from18 of the patients before any surgical procedures and in-clude one-four (average two) studies on each patient. Thesolid line is a line of identity, and the dashed line is theorthogonal regression line of best fit for the data. The opencircles refer to measurements in three patients obtainedbefore heparin administration.

sures of 20-40 cm H20 causing tidal volumes of 1500-4000 ml, two types of response were observed (Fig. 3).Patients with pulmonary infarction had a relativelysmall A-a Do2 breathing 100% 02 at normal tidal vol-umes, indicating a small shunt, and deep breathingcaused little change. However, the maximum tidal vol-umes of these patients were only 60-69% (average65%) of their predicted inspiratory capacities. Patientswith emboli but no infarction had larger levels of A-aDo2 breathing 100% 02 at normal tidal volumes, and theA-a Do2 was decreased significantly by IPPB; in thesepatients tidal volumes achieved on IPPB were 80-111%(average 88%) of the predicted inspiratory capacity.Five patients whose A-a Do2 breathing 100% 02 de-creased during deep breathing continued to breathe 100%oxygen for 15 additional min after deep breathing, andthe A-a Do2 returned to the level observed before deepbreathing. One patient performed voluntary inspiratorycapacities while breathing room air. The A-a Do2 breath-ing 21%O02 was reduced from 29-20 mmHg and re-

turned to 26 mmHg within 15 min. Paired t test analysisshowed that deep breathing caused no significant changein A-a Do2 breathing 100% 02 in patients with infarction(P > 0.3) but caused a significant reduction in patientswithout infarction (P < 0.02).

10 of the 21 patients with positive pulmonary angio-grams showed discoid atelectasis on roentgenograms ofthe chest. Only 1 of 10 patients with negative angiogramsdemonstrated discoid atelectasis, but no association be-

Hypoxemia in Pulmonary Embolism 483

0~

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TABLE I

Right Heart

Mean Rightpulmonary ventricular

Angiogram artery Wedge end-diastolicPatient Age Sex ocdusion pressure pressure pressure Cardiac index

% mmHg mmHg mmHg liters/minim'D. C. 35 F 70 11 5 7 2.7*S. M. 31 F 3 11 6 5 4.0

M.S. 59 F 6§ 18 9 6 3.0H.Mc. 27 F 35j 25L. M. 59 M 52 25 1.311 (2.4)

39 20 11 2.53 13 5 2.4

N. S. 20 F 8§ 11 6 6 4.30 9 3.7*

B.T. 29 F 61§ 27 12 9 4.30 15

J.V. 65 M 35 22 5 5 2.83 16 8 8 2.6

L. T. 56 F 80§ 24 7 15 2.311 15 6 8 3.4*

W.W. 68 M 18§ 20 4 8 2.30 12

J. P. 44 F 14D. M. 25 F 22§ 15 9 3 2.5*

18 15 8 8 2.323 12

I. R. 59 F 5§ 10 3 4 2.6*C. L. 42 F 29§ 23 5 2 3.7M. B. 48 F 6 14 6 5 3.2

0 14 5 3 3.3B. L. 43 M 81§ 28 10 11 1.6

9 16 10 8 3.5K. M. 34 F 26§ 14 5 5 3.3L. H. 43 F 8 15 7F. B. 31 F 17 12 4 3 6.0A. R. 53 F 54 16 4 6 5.8E. T. 60 M 21 14 6 5 3.4

* Fick cardiac output.Interval of time since the first symptom of the first episode of embolism studied.

§ Pulmonary infarcts present on chest roentgenogram.II This Fick cardiac output is probably falsely low because of a technical error givinga Vo, of 147 ml/min. On six subsequent occasions Vo, was 275 4-23 ml/min. Using aVo, of 275 ml/min gives the cardiac index indicated in parentheses.

tween a positive pulmonary angiogram, and the presenceof discoid atelectasis could be demonstrated by chisquare analysis (P> 0.1). Although there was a highincidence of pleuritic chest pain (81%), there was notgood correspondence between the severity of pain andthe extent of shunting; some patients with severe painhad small shunts. In addition, the A-a Do2 breathing100% 02 was not significantly different in patients re-quiring no more than one dose of narcotics for pain com-pared with those requiring two or more doses of nar-

cotics for the pain. The patients received on average 2.4doses of narcotics (range 0-10 doses) before the firstset of blood gases. After the first set of blood gases theyreceived an average of 2.7 doses of narcotics (range0-25 doses) over the next 2-3 wk.

Lung compliance. Specific dynamic compliance wasperformed on three patients with A-a Do2 breathing100% O of 200-122 mmHg. In two patients the A-aDo, breathing 100% O. was reduced (61 and 79%) andspecific dynamic compliance increased (17 and 30%) by


Catheterization Data

Arteriovenousoxygen Time since

Pulmonary difference Time most recent Recurrent Recurrentvascular since first exacerbation emboli at emboli since

resistance Air/100% 02 symptom: of symptoms first study last study

dyne-cm/sec-8 cc/100 cc days hr

100 3.3 3.4 2 2491 3.7 3.7 19 96

160 4.7 14 16814 24

5.1 1 24 X126 4.5 3.6 95114 436 X

61 3.9 3.5 14 723.4 4.1 33

148 3.7 3.6 15 2439

278 5.0 0 6 X139 4.4 4.3 32252 6.4 6.0 5 120

99 3.8 4.0 29305 6.0 6.3 11 72

31 192

117 3.8 3.8 7 96 X151 4.0 3.3 43 X

3.6 163 X84 3.4 3.6 5 120

169 3.9 3.4 19 48105 3.8 4.2 5 24174 3.6 3.7 18480 S.1 3.8 1 6

75 4.0 4.2 19 120106 5.8 5

2 2465 3.1 4.1 5 72 X96 3.3 3.6 8 9689 5.5 5.3 3 24

deep breathing. In the third patient the A-a Do2 breath-ing 100% Os decreased less (27%) during deep breath-ing than in the other two patients, and her specific dy-namic compliance was not changed by deep breathing.The right-to-left shunt in this latter patient was at theatrial level as was demonstrated by a superior vena cavadye dilution curve.

Extrapulmonary shunts. In only 1 of 10 patients inwhom superior vena cava (SVC) dye dilution curveswere performed was right-to-left shunting demonstrated

at the atrial level. In this patient (F. B.) pulmonaryartery pressure was normal; mean right atrial pressureand mean pulmonary wedge pressure were both 4 mmHg, and the angiogram showed 17% occlusion of the pul-monary vascular bed.

Ventilation-perfusion-diffusing capacity mismatching.The average discrepancy between the measured A-a Do.breathing air and that predicted from the shunt calcu-lated with the A-a Do2 measured on 100% oxygen wasonly 5.5 mmHg, a value easily explained by normal


TABLE I IArterial Blood Gas Studies during Hospitalization

Pao2 Respi- PAo2-Pao2 Oxygen Respi- DaysHemo- - - ratory Tidal breathing consump- ratory since

Patient globin PAo2 Meas Pred Paco2 pH rate volume VD/VT 100% 02 tion quotient embolism

gm% mmHgD. C. 7.6 107S. M. 10.8 102

M. S. 10.6H. Mc.L. M. 14.2 113

12.6 11412.3 108

N. S. 10.3 11910.9 95

B. T. 11.6 9611.2 10811.7 101

J.(V. 13.4 9710.4 1129.4 110

10.2 106L. T. 11.6 99

9.8 95W. W. 17.0 83

15.4 9115.3 84

J. P. 7.8 977.6 94

D. M. 9.2 1029.3 101

I. R. 6.6 985.9 118

C.L. 10.7 9910.7 9310.7 106

M. B. 13.0 10313.0 9411.4 9810.4 127

B. L. 15.2 9912.9 11213.2 7812.8 117

K. M. 13.6 9813.5 11711.4 123

L. H. 14.6 110F. B. 12.9 107A. R. 12.6 117E. T. 11.1 125

10.0 123

mmHg mmHg liters ml/min74 75 32 7.53 17 0.282 0.22

35 7.47 1735 7.4035 7.40

64 32 7.45 2266 32 7.47 2171 33 7.46 1887 23 7.52 1487 41 7.39 12

36 7.46 2585 36 7.44 1791 40 7.44 1478 44 7.40 14

28 7.54 2832 7.50 19

85 35 7.52 1779 32 7.44 17

35 7.45 1572 42 7.39 2076 37 7.44 1973 44 7.44 21

43 7.44 779 35 7.41 983 34 7.46 1589 37 7.46 1266 33 7.49 1676 27 7.54 1658 34 7.48 1371 39 7.44 1292 32 7.46 1369 39 7.44 2065 35 7.48 2370 36 7.44 2385 24 7.58 2289 38 7.43 4290 30 7.48 2374 42 7.42 11

34 7.48 2181 38 7.48 2384 32 7.54 1995 28 7.55 1584 31 7.46 1286 36 7.47 1784 25 7.60 18

107 19 7.63 1494 22 7.63 18

0.398 0.41

0.450.350.450.210.340.420.310.320.510.520.430.400.420.340.600.550.530.380.380.320.470.380.290.370.410.220.470.430.570.340.650.320.400.390.360.360.210.290.380.320.250.32

0.3160.5310.5980.6180.4050.3440.4780.4830.4960.6610.7070.6780.2720.5620.2300.4410.4690.4760.6340.3160.6490.2600.5830.6130.5930.5660.37 10.3030.2890.6290.2 140.4720.5240.2830.3850.6020.8630.6380.5650.8311.1230.990

677480705764798675818369607276676268807775838080587262708863666682647375

10260718178729595

103

120200140

43231824011248

14058

144

19696

13484

140127103

629160

153113311147

7021324819611294

12244

139144

79159122934349

158148

147310277223188273249237194351327271139301119235257118218155218140215290255278181241149214155283275106305222267224268345299341

0.74 20.86 19*

1414

0.83 10.76 40.75 100.75 140.73 330.66 150.85 180.81 220.82 00.76 3*0.82 8*0.83 320.61 50.69 12*0.60 110.61 150.65 220.80 80.77 150.72 70.75 120.58 50.89 110.64 190.69 230.75 300.85 50.58 90.68 181.10 320.72 10.82 40.56 131.14 190.72 51.13 81.15 130.81 40.86 50.81 80.83 30.86 5

* Blood gases may have been affected by complications of therapy in these studies. S. M. had had an iatrogenic pneumothorax requiring a chest tube onday 18, J. V. a vena caval ligation on day 1, and L. T. an embolectomy on day 7.

degrees of uneven ventilation-perfusion-diffusing ca- A-a Do2 breathing air in two of the patients but ex-pacity relationships. plained only 75% of the A-a Do2 breathing air in the

11 patients had spirometry tracings during the 1st wk patient with the most severe obstructive ventilatoryafter diagnosis at a time when increased A-a Do2 breath- defect.ing 100% 02 was still present. Eight had FEV2.o less Two patients with moderate hypoxemia due to pulmo-than 85% of predicted, but seven of these also had nary embolism had determinations of slow space ventila-restrictive ventilatory defects (FVC less than 85% of tion. One study was 5 days and another 32 days afterpredicted). Only three of these eight had FEV1.o less the first symptom of embolism. Both patients demon-than 80% of FVC (57, 78, and 72%). In these three strated normal nitrogen clearance rates and a slowlythe A-a Do2 breathing 100% 02 accounted for all of the ventilated compartment could not be clearly defined.


DISCUSSIONExtent of embolic occlusion and reliability of its

estimate. The estimated extent of embolic vascular oc-clusion varied from 3-81% of the pulmonary vascularbed and showed a good correlation with the reesting meanpulmonary artery pressure (r = 0.66; P <0.01). Thusthe study encompasses a wide range of severity. As pul-monary vascular bed becomes progressively occluded byemboli, the remaining fraction of the vascular bed mustaccept a progressively higher blood flow in order to sus-tain the normal cardiac output. It is a reasonable ap-proximation to assume that if reflex pulmonary vaso-constriction does not occur after a pulmonary embolusthe mean pulmonary artery pressure will rise no higherin response to the increment of blood flow through theremaining vascular bed than would be expected for a

( A-a DO2)

MEASUREDDURING

100% OXYGENBREATHING

(mmHg)

similar increment of pulmonary blood flow in a normalperson from rest to exercise. Based upon this assump-tion the solid lines in Fig. 4 reflect the normal range ofmean pulmonary artery pressures expected in our pa-tients from the increments in resting flow through theremaining normal lung after taking into account theextent of occlusion. These ranges were obtained fromcomposite data relating mean pulmonary artery pressureand cardiac output in normal persons at rest and exercise(26-35).

In only one instance was the pulmonary artery pres-sure higher than could be explained by simple mechanicalobstruction; thus the data provide no support to thecontention that generalized pulmonary vasoconstrictionoccurs after an embolus. In those instances where cardiaccatheterization was repeated the fall of mean pulmonary

DAYS j0-2 3-6 7-14 15-28 1-6

DAYS MONTHS

FIGURE 2 Duration of right-to-left shunting. The solid vertical lineindicates the time of angiographic diagnosis of pulmonary embolism.The dashed lines to the left indicate the duration of symptoms beforeangiography, and the solid lines to the right indicate the A-a Do2while breathing 100% oxygen as an estimate of shunting.


( A-a DO2 )

MEASUREDDURING

100% OXYGENBREATHING

(mmHg)

320

30028026024022020018016014012010080604020

Ag

KINFARCTION NO INFARCTIONPRESENT PRESENT

FIGURE 3 Changes in A-a Do, during 100% oxygen breathingare shown before and after deep breathing. The open circlesindicate measurements during normal tidal volumes, and thetriangles indicate those during large tidal volumes. Tidal vol-umes of 60-69% of predicted inspiratory capacity were achievedin patients with pulmonary infarction, and tidal volumes of 80-111% of predicted inspiratory capacity were possible in patientswithout lung infarction.

artery pressure seemed to accurately reflect the amountof angiographic clearing. This internal consistency ofthe results lends credence to the accuracy of the angio-graphic assessment of the extent of vascular occlusion.In only one instance was there a marked discrepancy be-tween the estimated extent of occlusion and the level ofresting mean pulmonary artery pressure (patient D. C.).The angiogram in this instance showed filling defects inboth major pulmonary arteries without any sharp cut-offs; peripheral vasculature filled well and the scintilla-tion scan showed no perfusion defect. The hemodynamicimportance of the filling defects in this instance wasobviously less than our arbitrary assessment of theangiogram indicated.

Shunts as the cause of hypoxemia. Among these pa-tients who denied any prior lung disease, some degreeof arterial hypoxia was almost always present within thefirst 3 wk after a pulmonary embolus, although in no in-stance was the hypoxia profound. The lowest arterialPo2 breathing air was 57 mmHg. The average A-aDo2 was 29.8 mmHg and 24.3 mmHg on average couldbe accounted for by the shunt measured while breathing100% oxygen. Only 5.5 mmHg remain to be explainedby mechanisms other than shunt. Since the unexplained5.5 mmHg are no more than the normal A-a Do2 at-tributable to uneven ventilation-perfusion or unevenperfusion-diffusing capacity relationships in the lung,we must conclude that the major mechanism of thehypoxemia among our patients was right-to-left shunt-ing of a fraction of the cardiac output. These results

are in contrast to the findings of Kafer (8) who at-tributed most of the hypoxemia in pulmonary thrombo-embolic disease to ventilation-perfusion (V/Q) mis-matching. However, most of his cases were studied inthe subacute or chronic stage with a mean duration ofsymptoms of 29 months prior to study while our pa-tients were studied within 19 days of the acute episode.

Most of our patients were receiving heparin by thetime the first measurements were made. Consideringonly the measurements in which the A-a Do, breathingair was above 20 mmHg, there were 7 patients outof 16 in whom the shunt explains less than 70% of themeasured A-a Do, (J. V., L. T., D. M., B. L., K. M.,F. B., and E. T.). Three of these patients (J V., B. L.,and E. T. noted as open circles in Fig. 1) were theonly patients studied prior to heparin administration.In these three patients an average of 15 mmHg of theA-a Do2 remained unexplained by the shunt (approxi-mately 50% of the total A-a Do2). Therefore, we havenot ruled out the possibility that early heparin therapyeliminated some ventilation-perfusion mismatching whichmight have existed before heparin therapy. The tendencyof heparin to relieve bronchospasm after pulmonaryembolism has been reported by others (36). Further-more, our data do not clearly exclude the possibilitythat much of the hypoxemia due to ventilation-perfusiondisturbances could have spontaneously receded withinhours after embolization before our initial measurementswere made.


There was mismatching of ventilation with perfusionin the form of wasted ventilation as indicated by anincreased VD/VT in 17 of 19 of our patients with theappropriate measurement. However, part of the explana-tion for increased VD/VT is related to shallow breathingwhich increases the relative importance of anatomicdead space. It is difficult to quantitate whether wastedventilation in one region leads to relative overperfusionin another region, but the rest of our data suggest thatsuch an effect was minor in our patients.

The calculation of the fraction of the alveolar-arterialoxygen tension difference while breathing air that isdue to true shunting is based on the assumption thatthe A-V 02 difference and the fraction of cardiac out-put shunted do not change from air to 100% oxygenbreathing. These assumptions may not be invariablycorrect, but they are reasonable approximations whichhave been made by others (24, 37, 38). We have ex-perimental evidence that the A-V 02 difference did notchange significantly from room air to 100% oxygenbreathing during the cardiac catheterization study (P> 0.6). We had no independent way of estimating thefraction of cardiac output shunted under the two condi-tions, but it seems an unlikely source of systematicerror since there were no other significant hemodynamicalterations between air and 100% oxygen breathingduring cardiac catheterization.

Cause of right-to-left shunts. The lack of correla-tion between the mean pulmonary artery pressure andthe per cent of the cardiac output shunted weighsagainst the opening of potential anatomical pathwaysfor shunting which, though normally present, are usuallynot patent; this is a mechanism proposed but not provenby animal experimentation (39-42) and human autopsystudies (43, 44). Furthermore, our data indicate thatintracardiac shunts occasionally do occur but were rela-tively infrequent among our subjects.

Both atelectasis (45) and temporary airway closuredue to pneumoconstriction (46) or pulmonary edema(47) can cause right-to-left shunting that can be tem-porarily reversed by deep breathing. Indeed pulmonaryedema has been suggested as one source of hypoxemiain animals following starch embolism (3, 48). In thepresent study the persistence of the shunting for severalweeks after the embolus makes pulmonary edema un-likely as a cause. Furthermore, a significant obstructiveventilatory defect was uncommon suggesting that bron-choconstriction was not a major cause. The considera-tions above, along with the high incidence of discoidatelectasis observed after embolization on routine chestroentgenograms, favor atelectasis as the cause of theshunting. The fact that the shunts reappear so promptlyafter deep breathing and the fact that IPPB treatmentdoes not seem to alter the natural, prolonged course of

401

MeanPulmonary

ArteryPressuremmHg

301-

0 0~ -

I~~~~.\L,, ,_4~~~

o80201

10-

,W0 5 10 15Cardiac Index per Unit of Unoccluded Lung

liter/min/m2unoccluded fraction of lung

FIGuRE 4 Mean pulmonary artery pressure is compared tocardiac index through unoccluded lung. The per cent of pul-monary vascular bed occluded was estimated from pulmonaryangiograms. The closed circles represent the initial measure-ment. The open circles indicate repeat studies and are con-nected by straight lines to the corresponding data on thesame patient obtained during earlier studies. In each instancea significant fall of mean pulmonary artery pressure occurredon the second study as the pulmonary arteries were re-canalized. The solid lines represent the limits of mean pul-monary artery pressure expected from the increment inpulmonary blood flow through the remaining normal vascu-lar bed; in only one instance was the pulmonary arterypressure greater than could be explained by the increase incardiac output through unoccluded lung.

disappearance of these shunts make it apparent that theshunts are not simply a consequence of an altered pat-tern of breathing. The lungs seem mechanically predis-posed to atelectasis. In order for the shunt-like effectto appear perfusion would have to be preserved or re-stored in the area of atelectasis. Possible explanationsare that pulmonary emboli that only partially occludeflow cause alteration in surface-active properties enoughto cause atelectasis, or that spontaneous fibrinolysis withclearing of some emboli occurs faster than restoration ofsurface active properties of the alveoli in that region. Asimilar process may explain shunting through infarctedareas that cannot be reversed by deep breathing-spon-taneous fibrinolysis with recanalization may occur inthe infarcted area where the alveoli cannot functioneither because of destruction or delayed clearance ofred cells and debris. The duration of shunts agrees wellwith the time over which most of the clot lysis and ar-terial recanalization occurs.

ACKNOWLEDGMENTSThe authors wish to express their appreciation to Pat Wellsfor assistance with the manuscript and tables, and to JimHarper, Brenda Beilby, and Janett Street for their technicalassistance. Doctors D. S. Mierzwiak, N. P. S. Chawla, B. A.Khero, R. Robin, L. S. Cohen, and W. Shapiro generouslyassisted in performing part of the cardiac catheterizationstudies.


This study was supported in part by a grant from theU. S. Public Health Service (HE 06296), and by a grantfrom the Dallas Heart Association.

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