A comparative analysis of pulmonary perfusion scans with pulmonary angiograms

A comparative analysis of pulmonary perfusion scans with pulmonary angiograms FROM A NATIONAL COOPERATIVE STUDY* W i l l i a m R. Bell** T o b y L. S i m o n * * * Baltimore and Bethesda, Md.

For more than a decade, lung perfusion scans have been employed to evaluate patients with suspected pulmonary emboli. When four views are obtained, a normal lung perfusion scan virtually excludes the diagnosis of pulmonary embolism. 1 Numerous pathologic processes can a l t e r p u l m o n a r y b l o o d flow a n d t h e r e f o r e a n a b n o r m a l s c a n is n o t d i a g n o s t i c . P u l m o n a r y angiography rarely yields false-positive results b u t m a y m i s s m i c r o e m b o l i in t h e p e r i p h e r a l p u l m o n a r y vessels. 2, ~ C o m p a r a t i v e s t u d i e s o f these techniques have stressed that they are c o m p l e m e n t a r y 2 -7 R e p o r t e d s t u d i e s w e r e c o m pleted, however, before the widespread use of l a t e r a l scans, w h i c h a r e s a i d t o i n c r e a s e d i a g n o s t i c From the Division of Hematology, Department of Medicine of the Johns HopkinsUniversitySchoolof Medicineand Hospital. Baltimore, Md., and the National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. Supported in part by Research Grant No. HL01601 and Contract No. PH43-68-1398 from the National Heart and Lung Institute. Receivedfor publication Aug. 15, 1975. Reprint requests: William R. Bell, M.D., Hematology Division. Blalock 1002, The Johns Hopkins Hospital, Baltimore, Md. 21205. *LIST OF PARTICIPANTS:Editorial Committee: William Bell. M.D., Chairman; Edward B. Black, M.D., David DeMets, Ph.D., Toby Simon, M.D. Principal Investigators: William Bell, M.D.. The Johns Hopkins MedicalInstitutions; John R. Blackmon,M.D., University of Washington; William de Groot, M.D., University of Texas Medical Branch; Edward Genton, M.D., University of ~Colorado Medical Center; Joseph V. Messer, M.D., Boston City Hospital; Arthur A. Sasahara, M.D., West Roxbury (Mass.) VA Hospital; Richard Sautter, M.D., MarshfieldClinic;Nanette K. Wenger,M.D., Emory University School of Medicine; Park W. Willis,III, M.D., and Joseph A. Walton, M.D., Universityof MichiganMedical Center; Frank J. Hildner, M.D., Mount Sinai Hospital of Greater Miami; Noble O. Fowler, M.D.. Cincinnati General Hospital. **Hubert E. and Anne E. Rogers Scholar in AcademicMedicine. ***Present address: Divisionof Hematology,Department of Medicine. University of Washington and Puget Sound Blood Center, Seattle, Wash. 98105.

accuracy. 4 A comparison of lung scans and pulmonary angiograms, performed almost simult a n e o u s l y in 162 p a t i e n t s w i t h s u s p e c t e d p u l m o nary emboli admitted to a therapeutic trial on the b a s i s o f a n g i o g r a p h i c e v i d e n c e of p u l m o n a r y embolism, forms the basis of this report.

Materials and methods A t o t a l o f 176 p a t i e n t s f r o m 11 m e d i c a l c e n t e r s were s t u d i e d in t h e p e r i o d f r o m 1970 t o 1973. s Study criteria. T h e p a t i e n t s in t h i s r e p o r t a l l had pulmonary embolism diagnosed by angiography. W h e r e possible, p u l m o n a r y l u n g p e r f u s i o n scans were also performed before entrance into the study. When done, pulmonary lung perfusion scans were performed within 1 to 2 hours, either before or after the pulmonary angiogram. In most instances, the angiogram and the lung scan were performed within minutes of each other. Verbal and written informed consent that was witnessed according to regulations of the Department of Health, Education and Welfare were obtained from each patient. Technique. T h e t e c h n i q u e s o f p u l m o n a r y angiography and lung perfusion scanning were p e r f o r m e d as p r e v i o u s l y d e s c r i b e d , s S p e c i f i c details of the properties of the radiopharmaceuticals, d o s e s c h e d u l e s , m e t h o d s o f c o l l i m a t o r c a l i b r a t i o n , a n d film d e n s i t y f o r t h i s s t u d y w e r e previously reported, s

Interpretation of angiograms and lung scans. The pulmonary angiograms were sent separately t o t h r e e r a d i o l o g i s t s w i t h e x p e r t i s e in t h i s a r e a , who independently interpreted the study, s Each expert was uninformed of the clinical history, patient identity, and institution where the study was performed. The experts interpreted the films

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by two approaches, one subjective and one objective. The subjective method was composed of two categories. Diagnostic evaluation. Massive pulmonary embolism: Presence of obstructions or significant filling defects involving two or more lobar pulmonary arteries or an equivalent number of defects in other vessels. Submassive pulmonary embolism: Presence of obstruction or filling defect in at least one segmental pulmonary artery with the sum of defects being less than t h a t for massive pulmonary embolism. Abnormal but not meeting, the criteria for pulmonary emboli. Normal pulmonary angiogram. Severity rating. The severity rating was based on the radiologist's visual estimate of severity, taking into account the amount, size, and locations of clots, blood flow, size of perfusion defects, cardiac size, and radiographic appearance of uninvolved vessels. This rating was subdivided as follows. Severe-awarded 3 points. Moderately severe-awarded 2 points. Minimally severe-awarded 1 point. Normal-awarded no points. The objective method to quantify perfusion defects assigned a numerical index of extent of pulmonary emboli present and has been previously reported in detail s For inclusion in the therapeutic trial at least two of the three panel members had to be in agreement on the presence of pulmonary emboli. The lung scans (anterior, posterior, right and left lateral views) accompanied by chest x-rays were independently read by five recognized experts. 8 Each expert was unaware of the clinical history, patient identity, and institution where scan was performed, They rated the quality of the study (excellent, satisfactory, unsatisfactory, or noninterpretable) and made a diagnostic evaluation as follows. H I G H P R O B A B I L I T Y OF P U L M O N A R Y E M B O L I S M .

(1) Chest x-ray: No consolidation or evidence of obstructive pulmonary disease. (2) Lung scan: Single or multiple characteristic perfusion defects which do not correspond to abnormalities seen on chest x-ray; a changing pattern of defects on serial scans.

American Heart Journal

Table I. Consistency among lung scan panel*

I

No.

Complete diagnostic a g r e e m e n t One panelist disagreement with difference of one diagnostic category One panelist d i s a g r e e m e n t w i t h difference of two diagnostic categories T w o panelists d i s a g r e e m e n t with difference of one diagnostic category T w o panelists disagreement with difference of two diagnostic categories T h r e e panelists disagreement w i t h difference of two or m o r e diagnostic categories T o t a l cases in which m o r e t h a n one p a n elist disagreed a n d t h e difference r a n g e d two or m o r e diagnostic categories

] Per cent

50 42

31.5 25.9

3

1.9

31

19.1

12

7.4

23

14.2

35

21.6

*Of 162 patients in whom the scan was interpreted as positive, 156 also had angiograms diagnostic of pulmonary emboli. There was no corre-

lation between the scan panel agreement and the likelihood of a positive angiogram.

M E D I U M P R O B A B I L I T Y OF P U L M O N A R Y E M B O L -

(1) Chest x-ray: No evidence of obstructive pulmonary disease. (2) Lung scan: Single or multiple areas of decreased perfusion which do not correspond to abnormalities seen on chest x-ray; however, the position and shape of the defects are not sufficiently characteristic of pulmonary embolism to allow a diagnosis of high probability of pulmonary embolism. ISM.

LOW P R O B A B I L I T Y OF P U L M O N A R Y

EMBOLISM.

Single or multiple perfusion defects are present on the lung scan, but either (i) the size or shape of these defects is not sufficiently characteristic of pulmonary embolism or (2) another explanation, e.g., obstructive pulmonary disease or roentgenographic abnormalities, accounts for these defects. NO E V I D E N C E OF P U L M O N A R Y E M B O L I S M . Either the lung scan is normal or the abnormalities present are accounted for by roentgenographic abnormalities not related to pulmonary embolism. The panelists expressed the degree of perfusion to both lungs (the right lung was considered to receive 55 per cent of the total perfusion, and the left lung 45 per cent). The perfusion defects in the anterior and posterior views were averaged to give the percentage perfusion defect for the scan set. To eliminate the problem of three angiogram readers vs. five scan readers the findings of one angiogram reader (index angiogram reader) and

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Table II. Diagnosis of p u l m o n a r y embolism

Lung scan panel High probability (1.0-1.49)*

Angiographic panel Classification Massive embolism Submassive embolism No pulmonary emboli (nondiagnostic) Total

No. of patients 99 56 7 162

Medium probability (1.50-2.49)*

Low probability (2.5-3.5)*

No.

%

No.

%

No.

72 26 2

72 46 28

24 21 4

24 37 57

3 9 1

I

% 3 17 15

*Score based on: 1 = h i g h probability of pulmonary embolism. 2 = medium probability of pulmonary embolism. 3 = low probability of pulmonary embolism. 4 = no evidence of pulmonary embolism. Note: This table compares the diagnostic categorization of patients by the five members of the lung scan panel with the number of patients classified according to clot(s) size by the three angiogram panelists. Each patient received a numerical score by each lung scan reader and the mean score of the five panelists was used to categorize the patients in the ranges indicated.

one scan reader (index scan reader) who m o s t frequently agreed with colleagues in their own panel were chosen for analysis.

Results: Reliability of diagnosis procedures A total of 176 patients were a d m i t t e d to the USPET (Urokinase-Streptokinase Pulmonary Embolism Trial) s t u d y by the investigators at the 11 participating medical centers. P u l m o n a r y perfusion scans, performed at t h e time of e n t r a n c e into the study, were available from 162 patients. Angiographic analysis. A total of 107 patients were defined as having massive p u l m o n a r y emboli and 60 patients as having submassive p u l m o n a r y emboli. Seventy-eight per cent of the p a t i e n t s had bilateral emboli identified on angiogram. Eleven of 176 patients, a d m i t t e d to the s t u d y on the basis of a positive angiogram for p u l m o n a r y emboli by investigators at their respective medical centers, failed to u n a n i m o u s l y meet the angiogram panel's criteria for the diagnosis of p u l m o n a r y embolism. In five p a t i e n t s none of the three panelists could identify abnormalities compatible with the diagnosis of pulmonary embolism. In four patients only one of the three panel members accepted the diagnosis. In seven patients two panel members r e p o r t e d t h a t the diagnosis of p u l m o n a r y embolism could be made. In 160 patients all three panel m e m b e r s agreed on the diagnosis of p u l m o n a r y embolism. T h u s there was panel disagreement on the diagnosis of p u l m o n a r y emboli in less t h a n 6 per cent of the patients.

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Lung perfusion scan analysis. D a t a from the lung scan panel were available on 162 patients. T h e diagnostic consistency of the lung scan panel for the total of 162 patients' scans is shown in Table I. Complete agreement with respect to the diagnosis of p u l m o n a r y embolism was reached in 31 per cent of the patients. In 26 per cent of the patients one of five panel members disagreed by one diagnostic category with the other panelists. In 2 per cent of the patients one panel m e m b e r differed by two diagnostic categories with the other panel members. In 19 per cent of the patients two panel members disagreed with the other three panelists by one diagnostic category. In 22 per cent of the patients there was disagreement by one or more panel members by two categories. In 32 of the 112 patients in w h o m t h e r e was a two diagnostic category difference disagreement was b y at least two panel members. There was a 3.9 per cent incidence of scans considered technically unsatisfactory by a majority of the scan panelists in the p a t i e n t group where there was complete agreement on the diagnosis. In those patients' lung scans where there was disagreement on the diagnosis or category placement there was an incidence of 14.3 per cent technically unsatisfactory scans. In 50 patients where there was complete a g r e e m e n t the incidence of massive embolism was 70 per cent. There was 112 patients in whom there was disagreement and the incidence of massive embolism was 49 per cent. In 48 of the 50 patients in w h o m there was complete lung scan panel a g r e e m e n t

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Table III. Diagnosis of pulmonary emboli* Angiographic index reader Lung scan index reader

I No.

Diagnostic evaluation Massive

No. ernboli

Severe

Moderately severe

29 14 10 1

85 8 7 0

3 4 1 0

60 3 2 0

44 11 9 0

9 9 6 1

5-'T

100

8

65

64

25

of patients

Submassive

117 26 18 1 162

High probability Medium probability Low probability Nondiagnostic Totals

l

Severity rating I

Not severe

*Note: This table compares the diagnostic evaluation and severity rating by the index angiographer with the number of patients placed in each of the scan diagnostic categories by the index lung scan reader. The eight angiograms read as nondiagnostic by the index reader were not given a severity reading.

the diagnostic evaluation was categorized as "high probability" of pulmonary embolism. The diagnostic evaluation of the angiogram panel is contrasted with the patient categorization by the lung scan panel in Table II. Patients with massive pulmonary emboli were more frequently categorized as "high probability" by scan than patients angiographically designated as submassive pulmonary emboli. The diagnostic categorization by the lung scan panel of those patients with a nondiagnostic angiogram showed that all but one patient had at least a "medium probability" classification by the lung scan panel. More than half of those patients with angiographically defined submassive embolism had a "medium-low probability" of the diagnosis of pulmonary emboli by the scan panel. Analysis of the distribution of lung scan classifications of the seven patients whose angiograms were nondiagnostic of pulmonary emboli revealed that two of seven were classified as having "high probability" of pulmonary embolism. Assessment according to diagnostic evaluation and severity rating by the index angiographer is compared with the diagnosis reported by the index lung scan reader in Table III. When the index lung scan reader interpreted "high probability" of pulmonary embolism, there was a corresponding agreement in the degree of severity and clot(s) size by the index angiographer. Eighteen patients were reported by scan analysis to have "low probability" of emboli but more than 50 per cent of these patients had an angiographic rating of severe or moderately severe. Only one of the 18 patients with a "low probability" of pulmonary emboli had a nondiagnostic angiogram.

American Heart Journal

A comparison was made between the defects seen on angiogram and those seen on lung perfusion scan. The majoz4ty of lesions were found in the lower lobes. The right lung was more frequently involved than the left. The two techniques were in agreement most often in patients in whom abnormalities were present in the lower lobe areas. Disagreement was most common in the middle lobes. Evaluation of the extent of perfusion defects by the index lung scan reader compared with the index angiogram was performed. In 43 per cent of the patients analyzed the estimate by the lung scan technique was within 10 per cent of the size of the defect demonstrated angiographically. There was a tendency for the scan reader to estimate a larger defect than t h a t reported by the angiogram reader. A relationship was present between more extensive emboli as estimated by angiography and the larger perfusion defects estimated by scan. Morbidity and mortality rates. The morbidity rate from angiograms was less than I per cent and the mortality rate was less than 0.5 per cent. The one death occurred in a patient with known cardiomyopathy. This patient died 3 days after the angiogram from probable tamponade resulting from myocardial perforation during the procedure. The morbidity rate associated with performance of the lung perfusion scan was less than 1 per cent and the mortality rate was zero. Death occurred in 16 patients 2 weeks after entrance into the trial. Ten additional patients died within 6 months after entrance into the trial. Two of the 16 patients who died in the first 2

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weeks had nondiagnostic angiograms. At postmortem one had emboli and one did not. Two of the 10 patients who died between 2 weeks and 6 months who had nondiagnostic angiograms were autopsied; one had emboli and one did not. Only one of the four patients with nondiagnostic angiograms also had a lung scan. This patient's lung scan was read as "medium" to "low probability" and at autopsy (within 6 months) no emboli were present. Fourteen patients with angiograms diagnostic of pulmonary emboli died by 2 weeks after entrance into the trial. Ten of the 14 were autopsied. Nine of these patients had emboli. The one patient without emboli at postmortem had massive emboli by angiogram and "high probability" by scan. Six of the nine patients with emboli at postmortem had lung scans. Four of the six patients had "high" to "medium probability" and two had "low probability" of emboli by scan. Eight of the 10 patients who died between 2 weeks and 6 months had diagnostic angiograms; four of the eight were autopsied. All four patients had emboli at the time of death. Three of these four patients had lung scans. On scan one had "high probability" and two had "low probability" of emboli. Discussion

This study compares pulmonary perfusion scan findings with angiograms in patients selected for a therapeutic trial. The angiogram was considered as the definitive basis for diagnosis. There is no available means for objectively evaluating the accuracy of the angiogram except by autopsy. Rigid criteria for the angiographic diagnosis were employed to ensure t h a t patients without pulmonary emboli were not subjected to experimental therapy. The question t h a t these data should answer is: what information will the clinician obtain from perfusion lung scans in patients who gnti,~fied rigid angingrnphic criteria for pulmonary emboli? Although it is recognized that angiography is the best available technique to objectively establish the presence of emboli in the pulmonary arterial vessels, it is not without error. In the four patients reported to have nondiagnostic anglograms who were autopsied, two had emboli grossly visible in the pulmonary arteries. The time interval between the initial angiogram and postmortem examination in four of the patients

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who had nondiagnostic angiograms prevents any firm conclusions about the accuracy of the interpretation of the initial angiogram. Because two of the four had recent emboli at postmortem, however, suspicions have been raised t h a t angiograms interpreted by the strict criteria of this protocol may result in misdiagnosis. In the one patient who was angiographically diagnosed as having massive emboli and who had no emboli at postmortem, there was a sufficient time interval (one month) following thrombolytic and heparin therapy to allow clot dissolution to occur. Thus there are no inconsistencies in the observations throughout this patient's course t h a t allow one to conclude that the initial angiogram reading was incorrect. In recent reports comparing lung perfusion scans and angiograms 12 validation of the accuracy of angiography was not available. In those reports of patient findings at postmortem examination performed in close proximity to the pulmonary angiogram, the angiographic reports were 100 per cent corrects 6 Sufficient autopsy data on the accuracy of pulmonary angiography are lacking. Of interest is the high mortality rate in the four* of the ~iine patients who were reported to have nondiagnostic angiograms in contrast to the over-all mortality rate in this study of 7 to 8 per cent. These four patients were severely ill with decompensated cardiopulmonary function and this may in part explain the problem in diagnostic interpretation of the angiogram. Since the introduction of the lung perfusion scan, its sensitivity has been universally recognized. Accurate information can be obtained of the blood flow in lung blood vessels as small as 50it in diameter with this technique. Equally well recognized is t h a t the lung scanning technique lacks specificity.TM 14 The lung scan image is the expression of blood flow in the pulmonary vessels. Anything that alters blood flow will give rise to an abnormal lung perfusion scan. Therefore, an abnormal lung scan is not necessarily indicative of pulmonary embolism. This is exemplified by the recent report of scan abnormalities seen in 88 per cent of 59 patients without angiographic demonstration of embolism. 11 The data in the present studies indicate t h a t interpretation of the lung scan to diagnose *The diagnoses in these four patients were acute myocardial infarction, congestive heart failure or pulmonary edema, carcinoma of the lung, and bacterial endocarditis.

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pulmonary, embolism is difficult. In more than two thirds of the lung scans reviewed by the expert panel, there was lack of agreement on the probability of pulmonary embolism. Disturbing was the observation t ha t all of seven patients without evidence of emboli on angiogram were reported to have a "high" or "medium probability" of having pulmonary emboli by lung scan. In 18 patients who were reported to have a "low probability" of having emboli by scan, 10 had massive and seven submassive emboli by angiography. In this report, some of the difficulty in interpretation may have resulted from poor technical scan quality. The incidence of technically unsatisfactory scans was 14.3 per cent in patients where there was panel disagreement as opposed to 3.9 per cent where there was complete agreement within the scan panel. T he exclusive use of the rectilinear scan in this study, as opposed to the camera scan, may raise some question, but superiority of one technique over the other, with respect to pulmonary embolism, has not been substantiated. The combination of ventilationperfusion scanning may lessen the problem of interpretation but reports demonstrating the value of these two techniques are without angiographic diagnosis. TM 1~ This study confirms t h a t the size of the lung perfusion defect was frequently estimated to be greater by scan than by angiogram. This is expected because of the sensitivity of the perfusion lung scan technique to changes in blood flow in vessels smaller in size t ha n can be assessed by angiogram. The agreement of the two techniques appears to be best in the lower lobes. This m a y be true because blood flow is normally less in the upper lobes, making interpretation in those areas difficult. In general, there was a greater degree of diagnositic agreement within the lung scan panel when the patients h a d massive, as opposed to submassive, emboli. It also was observed t h a t "high probability" lung scans were more likely to be "severe" or "massive" on angiogram. Discrepancies between the two techniques, however, were not statistically significantly different from the number of occasions t h a t were complementary. It should be noted t h a t despite the sensitivity of the perfusion scan there were several instances in which a report of low probability of emboli by scan correlated with a diagnostic angio-

American Heart Journal

gram often showing massive emboli present. In this series 22 per cent of the patients had multiple unilateral emboli by angiogram and this was more common on the right side. In this subgroup where unilateral defects were reported on angiogram, 70 per cent of these patients had bilateral defects on lung scan. In 30 per cent of this subgroup both scan and angiogram were in agreement that only unilateral emboli were present. In no patient was a single embolus described. Previous reports have indicated unilateral emboli to be very rare." In patients with pulmonary emboli, unilateral lung perfusion abnormalities are rare. In a series of 602 patients unilateral lung perfusion scan abnormalities were more common in bronchogenic carcinoma, congenital heart disease, and the hyperlucent lung syndrome t h a n pulmonary emboliY A unilateral scan abnormality does not exclude the diagnosis of pulmonary emboli. The clinician, who must decide when to t reat a patient for the presence of pulmonary emboli, frequently relies on the lung perfusion scan and often wonders if or when angiography should be performed. The data in this study support the accepted view that, if all four views of a technically satisfactory lung perfusion scan are normal, the diagnosis of pulmonary emboli is excluded. In this situation angiography is not indicated. If the lung perfusion scan is abnormal, should angiography be performed? This study has shown t h a t a lung scan interpreted as "low probability" m a y have a diagnostic angiogram. If the patient is at unusual risk if he were treated with conventional anticoagulants or considered a candidate for surgical intervention (embolectomy or vena caval interruption), angiography is advised. This study suggests t hat the quandary resulting from an abnormal lung scan may arise n o t only because of the lack of specificity of the technique but also because of the substantial problem of interpreting the results of the lung perfusion scan. The techniques of pulmonary angiography and lung perfusion scanning are not without error. Therefore, the clinician m u st thoughtfully combine all information about a given patient before i n s t i t u t i n g therapy for pulmonary thromboemboli.

Summary Pulmonary angiograms and pulmonary lung perfusion scans on 162 patients with pulmonary

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e m b o l i s m were c o m p a r a t i v e l y a n a l y z e d . A m o n g the expert angiographic panel m e m b e r s who independently evaluated the studies there was cons i s t e n t a g r e e m e n t o n t h e d i a g n o s i s , size of t h e e m b o l i , a n d severity. C o n s i s t e n c y of a g r e e m e n t a m o n g the expert p u l m o n a r y lung perfusion scan p a n e l i s t s was c o n s i d e r a b l y less. T h e s e d a t a d e m o n s t r a t e t h a t , i n a d d i t i o n to t h e l a c k of specificity of t h e l u n g p e r f u s i o n s c a n for t h e diagnosis of p u l m o n a r y t h r o m b o e m b o l i , t h e r e is a c o n s i d e r a b l e p r o b l e m of i n t e r p r e t a t i o n i n t h i s patient population. The authors express appreciation for the help provided by David DeMets, Ph.D. REFERENCES

1. Wagner, H. N.: Lung scanning in pulmonary embolism, Bull. Physiopathol. Respir. 6:65, 1970. 2. Szucs, M. M., Brooks, H. L., Grossman, W., et al.: Diagnostic sensitivity of laboratory findings in acute pulmonary embolism, Ann. Intern. Med. 74:161, 1971. 3. Dalen, J. E., Brooks, H. L., Johnson, L. W., et al.: Pulmonary angiography in acute pulmonary embolism: Indications, techniques and results in 367 patients, AM. HEART J. 81:175, 1971. 4. McIntyre, K. M., and Sasahara, A. A.: Angiography, scanning and hemodynamics i n pulmonary embolism: Critical review and correlations, CRC Crit. Rev. Radiol. Sci. 3:489, 1972. 5. Moser, K. M., Gennaro, M. T., Rhodes, G., et al.: Correlation of lung photoscans with pulmonary angiography in pulmonary embolism, Am. J. Cardiol. 18:810, 1966: 6. Fred, H. L., Bruderi, J. A., Gonzalez, D. A., et al.:

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Arteriographic assessment of lung scanning in the diagnosis of pulmonary thromboembolism, N. Engl. J. Med. 275:1025, 1966. The urokinase-streptokinase pulmonary embolism trial (Phase II) results, J. A. M. A. 229:1606, 1974. The urokinase-streptokinase pulmonary embolism trial (Phase I} results, Circulation 47(Suppl. II):l-108, 1973. McDonald, I. G., Hirsh, J., and Hale, G. S.: Early rate of resolution of major pulmonary embolism, Br. Heart J. 33:432, 1971. Bookstein, J. J., and Silver, T. M.: The angiographic differential diagnosis of acute pulmonary embolism, Radiology 110:25, 1974. Moses, D. C., Silver, T. M., and Bookstein, J. J.: The complementary roles of chest radiography, lung scanning, and selective pulmonary angiography in the diagnosis of pulmonary embolism, Circulation 49:179, 1974. Winebright, J. W., Gerdeo, A. M., and Nelp, W. B.: Restoration of blood flow after pulmonary embolism, Arch. Intern. Med. 125:241, 1970. Shoop, J. D.: Why do a lung scan? J. A. M. A. 229:567, 1974. McNeil, B. J., Holman, L., and Adelstein, J.: The scintigraphic definition of pulmonary embolism, J. A. M. A. 227:753, 1974. Williams, 0., Lyall, J., Vernon, M., and Croft, D. N.: Ventilation-perfusion lung scanning for pulmonary emboli, Br. Med. J. 1:600, 1974. Browse, N. L., Clemenson, G., and Croft, D. N.: Fibrinogen-detectable thrombosis in the legs and pulmonary embolism, Br. Med. J. 1:603, 1974. Moser, K. M., Rhodes, P. G., and Hufnagel, C. C.: Chronic unilateral pulmonary artery thrombosis. Successful thromboendarterectomy with a thirty-month follow-up observation, N. Engl. J. Med. 272:1195, 1965. White, R. I., James, A. E., and Wagner, H. N.: The significance of unilateral absence of pulmonary artery perfusion by lung scanning, Am. J. Roentgenol. 61:501, 1971.

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