Radioactive tracers in diagnosis of cardiovascular disease

Progress in

Cardiovascular Diseases VOL. XV, NO. 1 JULY/AUGUST 1972

Radioactive Tracers in Diagnosis of Cardiovascular Disease

Henry N. Wagner, Jr. and Buck A. Rhodes

A LMOST HALF A CENTURY AGO, Blumgart and Weiss used radioactive tracers to study circulation in patients with rheumatic and syphilitic heart

disease.‘+2 A radium salt solution was the radioactive tracer, and a cloud chamber was the detection instrument. Modern radiopharmaceuticals, such as 99mTc-labeled microsphereq3 and the scintillation camera exemplify some of the advances that have been made since these pioneering studies.

Although tracers such as radioactive sodium and radioiodinated albumin had been used occasionally in research studies of patients with edema, the first clinically useful study of cardiovascular disease was the scanning of patients suspected of pericardial effusion after the intravenous injection of radioiodinated albumin, a procedure first proposed by Rajali et al. in 1958.4

Lung scanning was introduced 5 yr later for the diagnosis of pulmonary em- bolism5*6 and is now widely used throughout the world, not only in the differen-

tial diagnosis of pulmonary embolism, but also in evaluating regional lung function in lung cancer, infections, and obstructive lung disease.

The scintillation camera, invented by Anger7 and commercially available in 1963, soon had a profound effect on tracer studies in the diagnosis of cardiovascular disease. In contrast to the rectilinear scanner, which has a radiation detector that moves back and forth across the region of the body being studied, the scintillation camera has a circular field of view approximately 11 inches in diameter. The detector does not move, spatial localization of the tracer being achieved by an array of 19 photomultiplier tubes that are attached to the scintillation detector. Because the spatial distribution of the radioactive tracer is measured continuously, serial images of a bolus passage of tracers intravenously injected through the heart and great vessels could be made, a procedure referred to as nuclear angiocardiography.

With “9mTc-labeled human serum albumin the intracardiac distribution of

From the Deparrmenr of Radiological Sciertces. The Johns Hopkins Medical Insrirurion.\. Bal- timore, Md.

Supported by USPHS Granr GM 1054X. Henry N. Wagner, Jr., M.D.: Professor ofRadiological Sciences, Radiology. and Medicitlr. Thr

Johns Hopkins Medical Iturirulions. Baltimore, Md. Buck A. Rhodes. Ph.D.: ds.~i.~[anr Profes.wr

ofRadiological Sciences. The Johns Hopkins Medical Institutions. Baltimore, Md.

Progress in Cardiovascular Diseases, Vol. XV, No. 1 (July/August), 1972 1

2 WAGNER AND RHODES

Table 1. Circulatory Diseases in Which Radioactive Tracers Are Useful in Diagnosis

Cerebral thromboembolism

Arteriovenous malformations of bram

Aneurysms of brain

Thyrotoxic heart dwase

Aneurysms of great vessels

Pencardral effusion

Pericardial cysts

Myocardial infarction

Ventricular aneurysm

Cyanotrc congenital heart disease

Left-to-right intracardiac shunts

Pulmonary venous hypertension

Hypoplastrc pulmonary arteries

Dextrocardia

Asplenia

Primary aldosteronism

Unilateral renal disease

Pulmonary thromboembc

Congestive heart failure

Anemia

Hypovolemia

Polycythemia

Venous obstruction

Arterial insufficrency

Leg ulcers

Gangrene

the tracer during specific parts of the cardiac cycle can be monitored with the scintillation camera, using electrocardiographic voltages such as the QRS complex to activate the camera only during systole or diastole, a procedure called “gating” the camera.B Ejection fraction can be measured and areas of myocardial akinesis documented in patients who have had a myocardial infarction.

Other areas in which advances were made included the use of the particle distribution principle to study the systemic as well as the pulmonary circulation. The distribution of blood flow to the legs in patients with peripheral vascular or Paget’s disease was examined. lo Regional myocardial blood flow was measured

with radioactive gases,” particles, 12-16 and ionic tracers such as 43K17 and ‘zgCs.‘8 Finally, anatomic arteriovenous shunting across the lungslg and in the systemic circulation could be determined with microspheres, as well as with soluble tracers. Table 1 lists the major uses of radioactive tracers in cardiovascular disease. Some of these will be reviewed in this article.

COMPARTMENTAL VOLUMES

The volume of blood within a given part of the circulatory system can be determined by injecting a radioactive tracer, such as albumin, red blood cells, or a substance (e.g. ionic l131n) that is bound by plasma proteins, and measuring the spatial distribution of radioactivity within the area of interest. In such studies, time is relatively umimportant unless we wish to relate the circulatory volumes to particular parts of the cardiac cycle. It is necessary only that the tracer be allowed sufficient time to distribute itself throughout the circulation prior to making the measurements, although the spatial resolution of the measurements is also an important consideration. To measure total plasma or blood volume, it is necessary only to draw a sample of blood and relate the plasma or red blood cell radioactivity to the amount of radioactive tracer injected. Total plasma or red blood cell volume is computed by the principle of indicator dilu- tion.

Among the earliest clinical uses of radioactive tracers was the measurement of total red blood cell and plasma volumes. Such procedures are useful in the differential diagnosis of patients with high hematocrits to distinguish between true and relative polycythemia, and occasionally in the pre- and post-operative evaluation of blood loss. The relative number of such studies remains low, probably related to the reliability of other signs of polycythemia Vera, such as

RADIOACTIVE TRACERS 3

splenomegaly and increased platelet count, and the common use of central venous pressure measurements in surgical patients.

To measure the volume of blood within a specific region, such as the left ventricle, the radiation detection system must be able to resolve adequately the radioactivity within the ventricle from the radioactivity in surrounding struc- tures that contain blood. A specific diagnostic problem can be viewed in terms of the spatial and temporal resolution required for its solution. If we are interested in a fast process, such as the fraction of the left ventricular volume ejected with each beat of the heart, the temporal resolution of the detection system must be a fraction of a second, whereas if we are only concerned with the volume of blood within a region such as the leg, the temporal resolution need not be great. Functional resolution, a third type, is the selection of the particular functions that we wish to measure. To diagnose pulmonary embolism, we select a tracer that will measure regional pulmonary arterial blood flow, while in patients suspected of alpha-i antitrypsin deficiency, we are interested in regional ventilation and select a tracer such as ‘33Xe.

At present, the instruments used to obtain spatial resolution are the rectilinear scanner and the scintillation camera. While adequate for many purposes, the spatial resolution is still quite poor. Rectilinear scanners and cameras can resolve two parallel lines about 1.5 cm apart, although special devices such as the pinhole collimator can increase the spatial resolution so that lines 0.75 cm apart can be distinguished. Resolution in depth is even poorer, but can be improved by the use of multiple views, and tomographic techniques which are now being evaluated.

Figure 1A illustrates the improvement in image quality that results from the use of improved radiopharmaceuticals and instruments. Figure 1B is a rectilinear scan performed in 1960 with a 3-inch diameter sodium iodide crystal and 100 &i of 1311 human serum albumin injected intravenously. The black areas represent the distribution of the tracer within the blood pool of the heart. Al- though we see a clear zone of decreased radioactivity surrounding the heart, little else is discernable. A typical image obtained today with a scanner with a 5-inch diameter crystal and 99mTc-albumin is of better quality. We can identify left ventricular hypertrophy, an enlarged left atria1 appendage and probably a giant left atrium. The improved image quality is the result of the increased number of photons making up the image as the result of the use of 99mTc. Be- cause of its rapid radioactive decay, millicurie rather than microcurie amounts can safely be administered.

The use of a radioactive tracer to detect a pericardial effusion requires only an intravenous injection and the result is available within minutes. Little training is required in interpreting the images, although experience is required in distinguishing effusions superimposed on cardiac dilatation from ventricular hypertrophy without effusion. Pericardial effusions resulting from infections, such as tuberculosis or myxedema, are readily apparent because they are characterized by an abnormally small intracardiac blood pool, together with the zone of decreased activity surrounding the heart. Pericardial cysts or tu- mors usually result in displacement of the cardiac blood pool to one side in a manner that can be distinguished from an effusion. Many use the scintillation camera together with 99mTc-pertechnetate to diagnose pericardial effusion.

4 WAGNER AND RHODES


Since pertechnetate diffuses promptly out of the vascular compartment into the interstitial fluid, observations are made of the tracer’s passage through the great vessels immediately after intravenous injection, rather than letting the tracer distribute itself throughout the vascular compartment as with an intravascular tracer such as 99mTc-albumin or ionic 113mIn. The latter substance binds to plasma transferrin and remains within the vascular compartment. For the diagnosis of pericardial effusion, we prefer the use of rectilinear scanner and an intravascular tracer. The zone of best resolution with the scanner is several inches below the chest wall, rather than at the surface, as is the case with the scintillation camera. Even normal persons may have an apparent zone of decreased activity surrounding the cardiac blood pool when examined with the scintillation camera.

The relative blood volume in the venous pools of the legs and the rates in which these volumes change with position and exercise can be used in the diagnosis of peripheral vascular disease. 2o--22 In a group of 19 volunteers, 21-38 yr old without clinical evidence of venous disease, we used a radioactive blood pool label and external radiation detectors to measure the relative changes in calf blood volumes and the times required for these changes. In the rapid change from horizontal to 45” upright position, there is a gradual rise in the volume to 145% f 14% (1 SD) the horizontal volume, taking an average of 21 set to reach one-half of this volume, and more than 14 min to reach equilibrium. With exer-

cise, the volume of blood within the calf falls to 76% A 6% (1 SD) of the volume prior to exercise. On inverting the subjects to 45” head-down position, the calf blood pool is reduced to 70% & 12% (1 SD) of the horizontal volume.

Occlusive venous disease both alters the magnitude of these relative volume changes and decreases the rate of change in volume when the subject is tilted to the 45” head-down position. In a subject with acute unilateral venous thrombosis (Fig. 2). the relative calf blood volume of her diseased leg increased to only

u.w.- acut. L venous thrombosis

/ I -1 / I u

T;E- sue

Fig. 2. Peripheral blood pool dynamic study. After intravenous administration of 3 mCi of ssmTc- albumin gamma ray detectors ere focused over calf muscles of each leg and counts are recorded as patient is tilted or exercised. Tracings show relative right (R) and left f L) calf muscle blood volumes as subject is tilted from horizontal to 45” head-up position. Note that thrombosed leg

drains blood more slowly than normal leg; 30 set v. 5 set T ) E is time required for the count rate to decrease from upright value to upright value minus one-half change of volume in going from upright to horizontal.

6 WAGNER AND RHODES

Table 2. Changes in Peripheral Blood Pool Dynamics Indicative of Venous Disease

Abnormallry Calf Blood Pool

Incompetence of venous system

Incompetent perforating vessels

(ankle blow-out syndrome)

Venous thrombosis or congestive

heart failure

Increased pool we with more rapld

flllmg and large volume changes wth

posmon

Pool volumes may be normal except

m speclflc areas affected by the I”-

competent vessels-during exenxe

the volume mcreases m the affected

areas

Decreased pool size with slowed drainage

and reduced volume changes wth

posltion: thrombosis - unilateral

abnormahttes: congestive heart fallwe

-. bilateral abnormalmes

104% of the horizontal volume when tilted 45” to upright. Her normal leg increased to 125%. She required 70 set to drain her thrombosed leg, compared to 15 set for her normal leg.

Peripheral venous disease due to incompetent valves is also detected by the radiometric monitoring of changes in the relative blood volumes. Subjects with postphlebitic legs show rapid filling when tilted from horizontal to 45” head up. During exercise they show little or no decrease in relative calf volume. Areas affected by incompetently perforating vessels (ankle blow-out syndrome) show increased volume during exercise.

Table 2 shows changes in peripheral blood pool dynamics which are indicative of venous disease. The safety and simplicity of measuring changes in muscle blood volumes with radioactive tracers is useful in the initial diagnostic workup of patients, as well as in the evaluation of response to therapy.

GATED STUDIES OF INTRAVASCULAR VOLUMES

Instead of simply depicting the intravascular volumes of the heart averaged over the entire cardiac cycle, to look for pericardial effusion, it is possible to use the electrical events of the patient’s own electrocardiogram to activate the scintillation camera only during specific parts of the cardiac cycle. In such studies we may look at the left ventricular contour during systole or diastole only. The patient is viewed in the right anterior oblique position, so that the boundaries of the left ventricle lie outside those of the right ventricle. As in the search for a pericardial effusion, the tracer used is Y9mTc albumin which is first allowed to distribute itself throughout the vascular compartments prior to ex- amination of the patient.

The purpose of such studies is to determine the contractility of the heart and to obtain information such as ejection fraction or to detect areas of myocardial akinesis. Figure 3 is the study of a patient with myocardial infarction in whom the apex of the heart did not contract during systole, while the rest of the left ventricle did. The advantage of this type of study relative to contrast angiography is its safety and simplicity; it can be performed at daily or even hourly intervals. The radiation dose is far less than that with fluoroscopy. At present it is being evaluated in patients with acute myocardial infarction.

RADIOACTIVE TRACERS

Fig. 3. Gated heart scan. A and C, diastole; B and D. systole. Drawing on right shows how images are analyzed.

CARDIAC STRUCTURE

When a child or young adult has unexplained cyanosis or a cardiac murmur, the differential diagnosis includes the possibility of congenital heart disease. The definitive diagnosis may require cardiac catheterization and contrast angiography, but such procedures are not without risk, particularly in newborn cyanotic infants. If the physician could be reasonably certain that the infant were suffering from respiratory distress syndrome, myocardial disease, or central nervous system disease, cardiac catheterization and contrast angiography might be avoided and the child’s chance of survival would probably be increased. On the other hand, prompt diagnosis of patients with certain types of cyanotic congenital heart disease and congestive heart failure during the first month of life may be life saving.

At Johns Hopkins Hospital, nuclear angiocardiography has been shown to be of value in the differentiation of cardiac and noncardiac cyanosis in newborn infants.23 The technique consists of continuous monitoring with the scintillation camera of the passage of an intravenously injected bolus of sodium pertechnetate (99mTc) or human serum ablumin (99mT~) as it passes through the cardiac chambers and lungs. The types of images that are obtained are shown in Fig. 4. Although the structural detail is poor compared to contrast angiography, we can usually identify the superior vena cava, right atrium and ventricle, pulmonary artery and lungs, and finally, the left ventricle and aorta. To identify a structurally normal heart, we look particularly for a clear space between the superior vena cava and pulmonary artery in the early frames, which will subse- quently be filled as activity fills the ascending aorta. We look for filling of the lungs immediately after visualization of the pulmonary artery without any evidence of activity in the abdominal aorta. In normal persons, activity is not seen in the region of the left ventricle until after the lungs have begun to fill.

The characteristic findings in a 7-mo-old infant with transposition of the great

WAGNER AND RHODES

Fig. 4. Nuclear angiocardiogrv, normal study. Upper frames: right heart phase. Lower frames: left heart phase. Lower right: equilibration image.

arteries is shown in Fig. 5. In the anterior view, a vessel can be seen arising from the right ventricle, instead of the usual separation of the pulmonary artery from the superior vena cava 3.1 set after intravenous injection. Activity can also be seen in an abdominal vessel (the aorta) prior to the filling of the lungs. The latter sign is seen particularly well in the lateral view which is obtained immediately after the anterior view.

Other abnormalities that can be detected by nuclear angiocardiography are summarized in Table 3. Table 4 gives the nuclear angiocardiographic findings useful in the differential diagnosis of certain cardiac malformations. In infants suspected of serious heart disease but with a structurally normal heart, the tracer study correctly demonstrates normal anatomy. Major advantages of such studies are safety and simplicity. The entire study can be completed within minutes with only an intravenous injection. The radiopharmaceuticals used have no pharmacological effect. Prompt demonstration of abnormalities such as transposition of the great arteries can expedite cardiac catheterization and, at times, balloon septostomy. With a provisional diagnosis made prior to catheterization, the time required and irradiation associated with fluoroscopy and catheterization can be reduced.

Although in properly selected cyanotic infants, the tracer procedure has been shown to be of value, we have not yet had the opportunity to explore another potential use of nuclear angiocardiography: the differentiation of patients with so-called innocent murmurs from those with potentially serious heart disease.

RADIOACTIVE TRACERS

TcV RV

Fig. 5. Nuclear angiocardiogram in 7-mo infant with transposition of great arteries with spetal defect; tine frames, anterior view. Aorta (Ao) arises from right ventricle (RV), filling the space beside the superior vena cava (SVC); right-to-left interventricular shunt; faint visualization of pulmonary artery (PA) and lung after left ventricle ILV).

A hypothetical example is a teenager who, during a school physical examina- tion, is found to have a cardiac murmur. When this occurs, the physician must decide whether to permit vigorous sports, or to recommend procedures such as cardiac catheterization to clarify the diagnosis. We postulate that nuclear angiocardiography may be able to fill an important role between the clinical examina- tion of the patient and the more complicated, invasive procedures, in a manner analogous to the screening role of lung scanning in the diagnosis of pulmonary embolism.24~25

REGIONAL MYOCARDIAL BLOOD FLOW

Myocardial imaging after intravenous administration of the radioactive tracer 43KC1 shows decreased concentration of the nuclide in areas of myocardial

Table 3. Abnormalities That Can Be Detected by Nuclear Angiocardiography

(1 I Ddferentiation of cardiac from pulmonary

disease m newborn patients with cyanosis

(2) Prelimmary identification of transposmon

of great arteries, truncus artenosus. and

hypoplastvz right or left ventricle

(3) Differential diagnosis of “Innocent” murmurs

(4) Detection of aneurysms of great vessels

(5) DetectIon of pulmonary arteriovenous

flstulas

Table

4.

Su

mm

ary

of

Nucle

ar An

gioca

rdiog

raph

ic Fin

dings

in

Diffe

renti

al Di

agno

ses

of

Certa

in Ca

rdiac

M

alfor

mati

ons

RA

RV

PA

Lung

LA

. LV

A0

Norm

al he

ari

Norm

al siz

e

Tran

spos

ition

of

grea

t

arter

ies

Norm

al siz

e

Trun

cus

arten

osus

Norm

al siz

e

Pulm

onar

y

atres

ia wi

th

intac

t ve

ntricu

lar

sept

um,

hypo

-

plasti

c RV

Larg

e, wi

th

reflu

x int

o

WC

Aortic

atr

esla

Norm

al appe

aranc

e

Outlin

e of

bo

dy

and

pulm

onar

y ou

tflow

tract

RV

body

no

rmal

size;

no

pulm

onar

y

outflo

w tra

ct

RV

body

no

rmal

size.

No

pulm

onar

y

outflo

w tra

ct

Small

Norm

al ap

peara

nce

Origi

n fro

m

RV:

empt

y

spac

e be

side

svc

Not

visua

lized

afte

r RV

filling

: fai

nt

outlin

e af

ter

LV

filling

Not

visua

lized

afte

r RV

filling

No

visua

lizatio

n

Norm

al appe

aranc

e

Abno

rmal

persi

stenc

e of

ac

tivity

du

e to

lar

ge

L +

R sh

unt

Visua

hzati

on

afte

r RV

an

d PA

Faint

ac

tivity

afte

r LV

an

d PA

Visua

hzati

on

afte

r fill

ing

of

trunc

us.

Visua

lizatio

n

afte

r ao

rtic

filling

via

PD

A

Norm

al ap

peara

nce

Outlin

e af

ter

lung

phas

e

Outlin

e be

fore

lung

phas

e via

intra

card

iac

R -

Lshu

nt

Outlin

e be

fore

lung

phas

e via

inter

ventr

icular

R -

Lshu

nt

Outlin

e be

fore

lung

phas

e via

inter

atnal

R 4

Lshu

nt

No

visua

lizatio

n

Arise

s fro

m

LV;

later

al vie

w:

poste

rior

origi

n. fro

m

LV.

Anter

ior

view

outlin

es

afte

r RV

.

fills

spac

e be

slde

SVC:

lat

eral

view.

arise

s an

terior

ly.

from

RV

Outlm

e of

tru

ncus

afte

r LV

. fill

ing

spac

e be

slde

SVC

Later

al vie

w

anse

s po

sterio

rly

from

LV

Asce

ndm

g ao

rta

not

seen

; ac

tivity

in

abdo

mina

l ao

rta

afte

r PA

, via

PD

A

Abbre

viatio

ns

RA.

right

at

num

. RV

. rig

ht

ventr

icle.

PA.

pulm

onar

y ar

tery

; LA

. lef

t am

um;

LV.

left

ventr

icle:

Ao.

aorta

. PD

A.

paten

t du

ctus

aTten

osus

. IV

C.

Infer

ior

vena

0

cava

: SC

V.

supe

rior

vena

ca

va

z 0 -


Fig. 6. Myocardial scan obtained after injection of ‘3KC1, showing decreased radioactivity in infarcted region of myo-

cardium.

ischemia or infarction. Figure 6 shows the left anterior gamma camera image of a patient with extensive anterior and inferior myocardial infarction.

The particle distribution principle used for lung scanning has aIso been used to study regional myocardial blood flow. Compared to lung scanning, such studies are more complex since the particles must be injected into the systemic circulation via cardiac catheter. The potential toxicity is also much greater. In lung scanning, intravenous injection of approximately 100,000 microspheres has a wide margin of safety because we obstruct only a fraction of a per cent of the pulmonary arterioles, and the collateral circulation is rich. There is cor- respondingly greater risk in myocardial scanning with particles.

The principal use of regional myocardial blood flow measurements to date has been in the pre- and postoperative evaluation of patients with myocardial infarction treated with saphenous vein bypass. A typical study is illustrated by a 68- year-old man with angina pectoris and congestive heart failure studied at the Loma Linda University Medical Center. Arteriogram revealed occlusion of the right coronary artery. In order to evaluate the status of the capillary bed distal to the occluded artery, radioiodinated human serum albumin particles were injected via cardiac catheter into the right coronary artery and technetium-labeled albumin particles were injected into the left coronary artery. Anterior, right anterior oblique, left anterior oblique and lateral views of the particles’ distribution was determined. Figure 7 shows typical views. There was persistently absent perfusion to the area supplied by the posterior descending artery, mark- edly impaired perfusion in the area supplied by the circumflex system, and impaired perfusion in the distal left anterior descending artery. Because of the poor status of the collateral circulation, as demonstrated in the radioactive particle study, the decision was made that the patient would probably not benefit from a surgical procedure.

12 WAGNER AND RHODES


Although these studies are still investigational, preliminary results attest to their safety and the usefulness of the data provided. It is likely that they will be used more and more in the future.

PULMONARY ARTERIAL BLOOD FLOW

Since its introduction in 1963, lung scanning has become the most widely performed radioactive tracer study of the cardiovascular system in clinical medicine. Why has lung scanning become so popular, when prior tracer methods for measuring regional pulmonary arterial blood flow, such as the use of radioactive 133Xe, remained restricted primarily to research laboratories‘? One reason is that lx3Xe studies were used chiefly in patients with obstructive lung disease rather than pulmonary embolism. Another reason is that, in 1963, rectilinear scanners were available in embryonic nuclear medicine depart- ments throughout the country. Thus, lung scanning with radioactive particles could be performed with equipment at hand. A final reason is related to the techniques themselves. With the original 133Xe method, blood flow measurements were made in a limited number of regions depending on the number of detectors employed, and the data were presented in numerical form, rather than as images. With the lung scan, regional blood flow was depicted in the form of an image, and the spatial resolution of the perfusion defects was greatly improved. Lesions as small as 2 cm in diameter could be detected and their size, shape, and position could be depicted in an easily understood form. A typical lung scan in a patient with pulmonary embolism is depicted in Fig. 8. The patient was injected with 2 FCi of 99mTc-labeled human serum albumin microspheres intravenously. Since the microspheres have an average diameter of 25 cc, they are removed from the circulation by the first capillary bed which they en- counter (the average diameter of capillaries is about 8 P). After intravenous injection, the microspheres are removed by the lung, and the regional concentra-

Fig. 8. Lung scan posterior view in patient with pulmonary embolism.


tion of radioactivity is directly proportional to regional pulmonary arterial blood flow.

One of the most important findings of lung scanning is that patients with all types of lung disease whether infectious, neoplastic, obstructive, or thrombo- embolic have decreased pulmonary arterial blood flow in the involved regions. Such lesions are not avascular or even hypovascular, but pulmonary arterial blood flow is reduced, and nutrient blood flow is provided chiefly by the bronchial arteries, which in the absence of right-to-left intracardiac shunting, do not contain radioactive particles injected intravenously.

Why is regional pulmonary arterial blood flow reduced in all pulmonary diseases? At times there is mechanical obstruction, e.g., a bronchogenic carcinoma obstructing one of the pulmonary veins, or fibrosis resulting from pulmonary infection. At times, reduction in regional pulmonary arterial blood flow is related to alveolar hypoxia which results in arteriolar constriction and redis- tribution of unoxygenated blood to the more normal areas of lung.

The universality of perfusion defects in all types of lung disease has led to con- fusion in the interpretation of lung scans. How, one might ask, can lung scanning be helpful in the diagnosis of pulmonary embolism when all focal lung disease results in perfusion defects? The importance of this question justifies a detailed description of how lung scanning can be used in the differential diagnosis of pulmonary embolism.

First, let us consider a common error. A patient is referred to the nuclear medicine department because of suspected pulmonary embolism, and the nuclear medicine physician sees a perfusion defect in the lung scan. He reports to the referring physician that the findings are “compatible with pulmonary embolism.” When the referring physician receives this report time after time he begins to wonder why he keeps referring patients since he can predict the report. Belief in his own omniscience is shattered, however, when he orders a pulmonary arteriogram for such patients and no evidence of pulmonary embolism is found. Should he rely only on the arteriogram for the diagnosis of pulmonary embolism? This policy is unsatisfactory because of the great number of patients with suspected pulmonary embolism. Performing cardiac catheterization and pulmonary arteriography in all these patients is not only undesirable but impossible. When interpreted properly, lung scanning can play an important role.

Before discussing interpretation of lung scans, a word about measurement of arterial oxygen saturation as a screening procedure for pulmonary embolism is needed. This test is not specific, since congestive heart failure, chronic obstructive pulmonary disease and other cardiopulmonary abnormalities can result in low arterial oxygen saturation. What about its sensitivity in pulmonary embolism? In the large series of patients with proven pulmonary embolism studied in Phase I of the Urokinase Pulmonary Embolism Trial conducted by the Na- tional Institutes of Health, 12% of the patients with proven pulmonary embolism had arterial oxygen saturation over 80 mm Hg.

Is lung scanning more sensitive? Several years ago, we studied a series of 21 patients in whom the clinical diagnosis of pulmonary embolism was sufficiently certain that a pulmonary arteriogram was performed despite a normal four- view (anterior, posterior and both lateral) lung scan. None of the patients had

RADIOACTIVE TRACERS

Fig. 9. Lung scan posterior view in patient with pulmonary 1

venous hypertension. I

arteriographic evidence of pulmonary embolism. On the other hand, when the multiple view lung scan was interpreted as “high probability of pulmonary embolism,” 75% of the patients had filling defects in the contrast media at sub- sequent arteriography, and the remainder were abnormal, although the arteriographic findings were less specific. What criteria were used in the interpretation of the lung scans? All perfusion defects were not interpreted as being due to pulmonary embolism. Attention was paid to the characteristics of the perfusion defect in order to increase the relative specificity of diagnosis.

The criteria that we use to interpret lung scans are as follows: (1) If the four- view scan is completely normal, it is interpreted as having “no evidence of pulmonary embolism.” (2) If the blood flow to the tops of the lungs is greater than to the bases, with no evidence of perfusion defects in corresponding segmental arteries, the interpretation is “probable pulmonary venous hypertension without evidence of pulmonary embolism” (Fig. 9). (3) If a zone of decreased perfusion corresponds to one or more fissures, at times associated with increased blood flow at the top half of the lungs compared to the bases, without segmental perfusion defects, the interpretation is “probable pulmonary congestion or pleural effusion without evidence of pulmonary embolism” (Fig. 10). (4) Gen- erally decreased activity in one entire lung, seen best in the posterior compared to the anterior view, without segmental defects, is interpreted as “probable pleural effusion without evidence of pulmonary embolism.” (5) Symmetrical perfusion defects, e.g., at both apices or at both bases, are interpreted as “probable parenchymal lung disease, rather than pulmonary embolism.” (6) If there are one or more perfusion defects corresponding with segmental arteries either in association with a normal chest radiograph or a radiograph showing abnormalities, such as an elevated diaphragm, linear densities, small pleural effusions or hemispheral


Fig. 10. Lung scan right

lateral view of patient with pleural effusion.

densities at the periphery of the lungs, the interpretation is “high probability of pulmonary embolism,” provided the patient does not have obstructive lung disease. The clinical history, timed vital capacity (FEV,), and regional ventilation measurements using *33Xe help determine whether the patient has obstructive lung disease. If he does, the interpretation is either “obstructive lung disease; we cannot say whether the patient has superimposed pulmonary embolism”; or “obstructive lung disease; no evidence of pulmonary embolism.” This depends on whether or not the perfusion defects are segmental (first interpretation) or nonsegmental (second interpretation). (7) If activity is seen in both kidneys after the injection of radioactive particles or microspheres, the interpretation is “right-to- left intracardiac shunt.” Such patients, if young adults, frequently are suffering from tetralogy of Fallot and have regional perfusion defects due to hypoplastic arteries (Fig. 1 I). (8) If all perfusion defects correspond with areas of infiltration, such as consolidation, the interpretation is “probable pulmonary infection.” Of course, the clinical manifestations are of great importance in the differential diagnosis of pneumonia and pulmonary embolism. (9) If blood flow to one entire lung is absent, the interpretation is “high probability of neoplasm,” since hilar bronchogenic carcinoma is more likely than pulmonary embolism. (10) If the perfusion defects follow a nonsegmental distribution with decreased blood flow in the medial parts of the lung, the interpretation is “pulmonary edema.” These findings are often seen in association with increased relative blood flow to the tops of the lungs and decreased blood flow along the fissures. If the patient has segmental perfusion defects superimposed on this or other patterns, the interpretation may be “pulmonary embolism superimposed on the underlying congestive heart disease.”

Serial studies are often helpful. Nearly all patients with acute pulmonary embolism have a changing perfusion pattern within several days. Defects may im- prove or disappear while new ones may appear. If the perfusion defects remain unchanged, it is unlikely that the patient has acute pulmonary embolism, al-


Fig. 11. Lung scan poste- .;: ; rior view in patient with tetral-

ogy of Fallot.

though he may have had embolism that occurred more than 3 mo prior to study. Parenchymal lung disease is often stable, although changing patterns may be ob- served in diseases, such as acute or chronic bronchitis.26

PERIPHERAL ARTERIAL BLOOD FLOW

Over the past decade, peripheral arterial reconstructive surgery such as femoral to popliteal artery bypass grafts have transformed treatment of femoral- popliteal occlusive disease. The selection of suitable patients remains a problem. The failure of arteriography to successfully predict the success of surgery in particular patients has led to an attempt to use radioactive tracer techniques to supplement the structural information obtained by arteriography with measurements of regional capillary perfusion. There are two general methods using radioactive tracers for determining capillary perfusion. One approach is the measurement of the rate of clearance of a diffusable tracer to determine blood flow to a localized area. The other approach is the microsphere distribution method to determine relative regional perfusion. Table 5 lists current and potentially useful studies of the peripheral circulation using radioactive tracers.

Local muscle or skin blood flow is determined from the disappearance rate of locally injected diffusible materials such as “.?Kr or laaXeT27.2x or by measuring the accumulation of radioactivity following intravenous injection of nondiffusible radiopharmaceuticais such as ‘“1I-albumin.2” It is necessary in assessing the de-


Table 5. Current and Potentially Useful Studies of Peripheral Circulation

lh.ease

Occlusive arterial

disease

Leg ulcers

Varicose veins

Gangrene

A-V fistula

Thrombosis

Type of Study

Intravenous radionuclide

artenography

Leg scan

Peripheral blood pool

dynamrc study

Leg scan


dynamic study

Leg scan

A-V shunt quantification


dynamic study

Scanning for thromboemboli

Use

lnitlal diagnosis when

contrast anglography

IS contramdicated

Differential diagnosis and

evaluation of revascularation

Detection of Incompetent

perforators as cause

To estimate prognosis

of healing

Evaluation of management

Planning of surgery

Detection and evaluation

of surgery

Initial dragnosis and

differentation from

cellulitis

Detection of thrombi

gree of arterial circulatory impairment to make measurements both at rest and at maximum vasodilation. Vasodilation is induced by whole-body warming, tem- porary sympathetic blockade, as with anesthesia, using 1% procaine, voluntary or electrically induced exercise,30 or by occluding the arterial inflow for 3-5 min prior to the test to induce reactive hyperemia. Normally, blood flow at rest lies

between 1.8 and 4 ml / 100 ml tissue / mm and increases by a factor of IO-20 during maximum vasodilation if there is no arterial insufficiency.

Relative regional perfusion is determined from radioisotope scans of the extremities following intraarterial injections of 99mTc or “3mIn-albumin microspheres or 13*1 macroaggregates of albumin.31

Initially, injections were made into each femoral artery, but it soon became apparent that a preferable technique was to inject microspheres labeled with 99mTc into the abdominal aorta via a translumbar needle. In this way, compari- son of the blood flow between the two legs, as well as within each leg, could be more readily made. In addition to delineating the regional distribution of blood flow, measurements of anatomic arteriovenous shunting could be made by monitoring the fraction of the injected dose that traversed the peripheral circulation to be eventually taken up by the pulmonary capillary bed.

The normal perfusion to the resting limb in a comfortable environment is expected to be distributed in proportion to the muscle masses. In patients without evidence of peripheral vascular disease in at least one leg, the scan showed radioactivity distributed chiefly to muscle. The normal perfusion scan is also seen in patients whose vascular disease is not severe enough to alter resting blood flow.‘0,3’

Abnormal leg scans include (I) diffuse distribution of radioactivity associated with generalized occlusive disease. In this case the blood flow is distributed primarily to skin rather than muscle masses. (2) Focal areas of decreased radioactivity as seen in patients with occlusive disease affecting primarily the distri-


bution of certain branch arteries. (3) Focal areas of increased radioactivity. This is seen in areas of bone diseases such as Paget’s disease,32 fibrous dysplasia or osteoarthritis. Also hyperperfusion is seen in skin affected with dermatitis or in association with healing ulcers or wounds. One of the most promising uses of leg scanning is in patients with ischemic lesions of the lower extremities. In 21 patients whose limbs were in jeopardy, 13 showed increased activity, i.e.. hyperemia associated with the lesion. All of these healed with conservative therapy. Eight did not show hyperemia, and seven of these eventually required amputation because of nonhealing.

Figure 12 shows the leg scan of a man with arteriosclerosis, which is not signif- icantly altering the distribution of his blood flow at rest, i.e., this radioactivity is distributed proportionally to the muscle masses as is seen in the normal scan. Skin lesions in the areas of the knee show up as hot spots on the scan. Figure 13 shows more severe occlusive vascular disease, but the lesion on the left foot shows hyperemia, which indicates that there is probably enough blood supply to the area to permit healing with conservative treatment.

Perfusion scans of the extremities and quantification of arteriovenous shunting with YqmTc microspheres have contributed to our understanding of Paget’s

Fig. 12. Leg and lung

scans anterior and posterior views obtained after injections of ssmlc-microspheres into each femoral artery and into a superficial vein. Venous injection was made in order to quantitate peripheral arterio- various shunting.


R Fig. 13. Leg scan after aortic injection of ssmTc-mi- crorpheres. Patient has arteriosclerosis and hyperemia sur-

rounding ulcer on left foot.

disease of bone.32 The increased venous oxygen concentrations and increased cardiac output were formerly thought to be due to arteriovenous shunting through the diseased bone. By comparing the scans with x-rays, we see that the diseased bone is indeed hyperperfused. No significant arteriovenous shunting was detected in the seven patients whom we studied. Thus, the hemodynamic changes are due to increased flow through the capillary bed of Pagetoid bone, rather than through anatomical arteriovenous anastomoses greater than 15~ in diameter. Figure 14 shows the leg scan of a patient with Paget’s disease localized to the left femur. It is interesting to speculate whether a form of treatment might be based on the finding that the blood flow to the involved region in patients with Paget’s disease is going through capillary-sized vessels rather than through anatomical arteriovenous shunts. If larger quantities of microspheres were injected into an artery leading to the involved region, perhaps regional blood flow could be reduced and pain and cardiovascular effects be diminished.

Arteriovenous shunt quantification has revealed that shunting through the


Fig. 14. Leg scan in patient with Paget’s disease of left

femur. Aortic injection. R

L

extremities is not usually associated with occlusive vascular disease. The microsphere method is sensitive enough to detect anatomic A-V shunting in excess of 3%.34 This method appears to be potentially most useful in following patients with AV fistulae and hypertrophic pulmonary osteoarthropathy.35*36 We detected an 11% shunt in a patient with a high cardiac output otherwise unexplained.

DETECTION OF THROMBOEM BOLI

The detection of thromboemboli with radioactive tracers which specifically localize thromboemboli is feasible. Several substances are being evaluated for this purpose. Iodinated fibrinogen is useful in detecting forming clots.37-3Q How- ever, fully formed thrombi incorporate fibrinogen less readily, thus limiting its usefulness.3s*40 Clots also pick up radioactive particles when the radiopharmaceutical is injected so that the material flows by the clot.4’ This can be used as an adjunct to lung scanning, in which case the radiopharmaceutical is divided into


two doses and injected into veins of the right and left feet. Both the lungs and the legs are scanned. Areas of uptake of radioactivity in the legs are noted at the sites of thrombosis. However, phlebitic lesions and varicosities may also result in focal points of radionuclide uptake.42

Radioiodinated antifibrin localizes in thromboemboli.43~44 Although patients have not reacted to injections of this radiopharmaceutical, it is potentially antigenic. Scans showing the clot sites are obtained I~-4 days after the injection. The blood levels of circulating tracer is high for several days; this nontarget back- ground limits the use of this agent45 as it does 13’1-labeled plasmin.

Radioiodinated streptokinase has been shown by autoradiographic techniques to be incorporated into blood clots. *‘Sag Recently, we have demonstrated that this radiopharmaceutical can be used to localize preformed pulmonary emboli in dogs.*’ Clots 1-48 hr old are readily visualized by scanning within 30 min after the injection of the tracer. Radiolabeled urokinaseSo also shows promise as a blood clot scanning agent. Labeled platelets and white blood cells are being evaluated for this purpose.

REFERENCES

I. Blumgart, H. L., and Weiss, S.: Studies on

the velocity of blood flow. III. The velocity of blood Row and its relation to other aspects of the circulation in patients with rheumatic and

syphilitic heart disease. J. Clin. Invest. 4: 149,

1927. 2. ~. and ~: Studies on the velocity of

blood flow. VII. The pulmonary circulation time

in normal resting individuals. J. Clin. Invest. 41399. 1921.

3. Wagner, H. N.. Jr.. Rhodes, B. A., Sasaki,

Y., and Ryan. J. P.: Studies of the circulation with radioactive microspheres. Radiology

4:374, 1969. 4. Rejali. A. M., Maclntyre, W. J., and

Friedell, H.L.: A radioisotopic method of visualization of blood pools. Amer. J. Roentgen.

79:129, 1958. 5. Wagner, H. N.. Jr., Sabiston, D. C.. Jr.,

Iio, M.. McAfee. J. G., Meyer, J. K., and Lan- gan. J. K.: Regional pulmonary blood flow in

man by radioisotope scanning. JAMA 187:601,

1964. 6. ~-, , McAfee, J. G., Tow, D. E.. and

Stern, H. S.: Diagnosis of massive pulmonary

embolism in man by radioisotope scanning. New Eng. J. Med. 271:377, 1964.

7. Anger, H. 0.: Scintillation camera. Rev. Sci. Instrum. 29:27, 1958.

8. Strauss, H. W., Hurley, P. J., Zaret, B. L..

Pitt, B., and Wagner, H. N., Jr.: Measurement of systolic and diastolic cardiac chamber volumes without cardiac catheterization. J.

Nucl. Med. 11:364, 1970.

9. Zaret, B. L., Strauss, H. W., Hurley,

P. J.. Natarajan, T. K.. and Pitt. B.: Scinti- photographic method for detecting regional ventricular dysfunction in man without cardiac

catheterization. New Eng. J Med. 284:1 165, 1971.

IO. Rhodes, B. A.. Greyson. N. D.. White.

R. I., Giorgiana, F., Williams, M.. and Wagner, H. N., Jr.: Leg scanning - characteristic per-

fusion patterns and clinical usefulness. Unpub- lished.

Il. Ross, R. W., Ueda, K., Lichtlen. P. R.,

and Rees, J. R.: Measurement of myocardial blood flow in animals and man by selective in-

jection of radioactive inert gas into the coronary arteries. Circ. Res. 15:28. 1964.

12. Endo, M., et al.: The direct diagnosis of

human myocardial ischemia using 13’I-MAA via selective coronary catheter. Amer. Heart J.

80:498, 1970. 13. Schelbert, H. R., Ashburn, W. L.. Cove]].

J. W., Simon, A. L., Braunwald, E.. and Ross, J. Jr.: Feasibility and hazards of the intra- coronary injection of radioactive serum al-

bumin macroaggregates for external myocardial perfusion imaging. Invest. Radio]. 6:379, 197 I.

14. Poe, N. D.: The effects of coronary arterial injection of radioalbumin macroaggre-

gates on coronary hemodynamics and myocardial function. J. Nucl. Med. 12:724. 1971.

15. Ashburn, W. L.. Braunwald, E., Simon. A. L., Peterson, K. L.. and Gault, J. H.: Myo- cardial perfusion imaging with radioactive-

labeled particles injected directly into the coro-


nary circulation of patients with coronary artery disease. Circulation 44:85 I, 197 I.

16. Maseri, A., Manceni. P., Contini, C., Pesola. A., and Donato, L.: Method for the

estimation of total coronary flow by 9QT~ tagged albumin microspheres. J. Nucl. Biol. Med. 15:-

5x. 1971.

17. Hurley, P. J.. Cooper, M., Reba. R. C.. Poggenburg, K. J., and Wagner, H. N., Jr.: ‘3KCl: A new radiopharmaceutical for imaging

the heart. J. Nucl. Med. 12:516. 1971.

18. Yano, Y., Van Dyke, D.. Budinger, T. F., Anger, H. 0.. and Chu, P.: Myocardial uptake

studies with ‘29Cs and the scintillation camera. J. Nucl. Med. I I:1 I, 663, 1970.

19. Strauss, H. W., Hurley, P. J., Rhodes, B. A., and Wagner, H. N.. Jr.: Quantification

of right-to-left transpulmonary shunts in man. J. Lab. Clin. Med. 74:4, 1969.

20. Tow, D. E., Wagner, H. N., Jr., and

North, W. A.: Detection of venous obstruction

in legs with 99mTc-albumin. J. Nucl. Med. 8:277. 1967.

21. Rutherford, R. B., Krishna Reddy, C. M.. Walker, A. G., and Wagner, H. N., Jr.: A

new quantitative method of assessing the func-

tional status of the leg veins. Amer. J. Surg. 122:594, 1971.

22. Greyson. N. D., Rhodes, B. A., Williams, G. M.. and Wagner, H. N., Jr.: Radiometric

detection of venous diseases. Unpublished.

23. Wesselhoft, H., Hurley. P. J., Wagner, H. N., Jr., and Rowe, R. D.: Nuclear angio-

cardiography in the diagnosis of congenital disease in infants. Circulation 45:77, 1972.

24. Mason. D. T., Ashburn. W. L., Harbert.

J. C., Cohen, L. S., and Braunwald, E.: Rapid sequential visualization of the heart and great vessels in man using the wide-field Anger scintil-

lation camera. Circulation 39: 19, 1969.

25. Kriss, J. P., and Matin P.: Diagnosis of congenital and acquired cardiovascular diseases

by radioisotope angiocardiography. Trans. Ass.

Amer. Physicians 82: 109, 1969. 26. DeL.and, F. H.. and Wagner, H. N., Jr,:

Atlas of Nuclear Medicine, Vol. II. Lung and

Heart. Philadelphia, W. B. Saunders. 1970.

27. Kety, S. S.: Measurement of regional circulation by the local clearance of radio-

active sodium. Amer. Heart J. 38:321. 1949. 28. Lassen. N. A., Lindberg, I. F.. and Dahn.

I.: Validity of the xenon-133 method for measurement of muscle blood flow evaluated by simultaneous venous occlusion plethysmography.

Circulation Res. 16:287, 1965. 29. Krieger, H., Storaasli, J. P., MacIntyre.

W. J., Holden, W. D. and Friedell, H.: The use of radioiodinated human serum albumin in

evaluating the peripheral circulation. Ann. Surg. 136:357, 1952.

30. Pavoni. P.. Moen, T., Rhodes, B. A., and Wagner, H. N., Jr.: Changes in *33Xe clear-

ances resulting from electrically induced muscle

contractions. I. Study in dog. J. Nucl. Biol. Med. 15:16, II. Study in man. J. Nucl. Biol. Med. 15:19. 1971.

31. Izquierdo, G. F., Cuaron. A., Guerrero.

M.. Cobos. D., Trevino, H., and, Ramirez de Cervantes, M. E.: Scanning of the peripheral

circulation of the limbs. J. Cardiovasc. Surg.

(Torino)9:47, 1968. 32. Greyson. N. D., Rhodes, B. A., Hamilton,

C. R., Jr.. White, R. I., and Wagner. H. N..

Jr.: The absence of arteriovenous shunts in Paget’s disease of bone. Unpublished.

33. Gardner, T. J., Rhodes, B. A., Greyson.

N. D.. and Williams, G. M.: The clinical use-

fulness of leg scanning in arterial insufficiency using radioactive microspheres. Unpublished.

34. Rhodes, B. A.. Rutherford, R. B., Lopez-

Majano, V., Greyson, N. D., and Wagner, H. N.. Jr.: Arteriovenous shunt measurements in ex-

tremities. J. Nucl. Med. In press. 35. ~~: Blood flow through arteriovenous

anastomoses. In Horst, W. (Ed.): Frontiers of

Nuclear Medicine. Berlin, Springer-Verlag. 1971. p. 262.

36. Rutherford, R. B., Rhodes. B. A.. and

Wagner, H. N.. Jr.: The distribution of extrem- ity blood How before and after vagectomy in a

patient with hypertrophic pulmonary osteo-

arthropathy. Dis. Chest 56:19. 1969.

37. Hobbs. J. T.. and Davies, J. W. L: De-

tection of venous thrombosis with I-131 labeled

fibrinogen in the rabbit. Lancet 2: 134, 1960.

38. Atkins, P.. and Hawkins, L. A.: Detec- tion of venous thrombosis in the legs. Lancrt 2:1217, 1965.

39. Flanc, C.. Kakkar, V. V., and Clarke.

M. B.: The detection of venous thrombosis of the legs using lZsI labeled fibrinogen. Brit. J. Surg. 551742. 1968.

40. Seeker-Walker, R., and Potchen. E. J.:

Radiology of venous thrombosis-current status. Radiology lOl:449, 197 I.

41. Webber. M. M., Bennett, L. R.. Cragin.

M.. and Webb, R., Jr.: Thrombophlebitis

demonstration by scintiscanning. Radiology 97:620. 1969.

12. Rosenthall, L., and Greyson, N. D.: Ob- servations on the use of 99mTc-albumin macro-


aggregates for detection of thrombophlebitis. Radiology 94:413. 1970.

43. Spar, I. L.. Goodland. R. L., and Schwartz. S. I.: Detection of performed venous

thrombi in dogs by means of ‘311-labeled antibodies to dog fibrinogen. Circulation Res.

171322. 1965. 44. Reich, T.. Reynolds. B. M.. Healy. M..

Wang, M. C. H.. and Jacobson, J.: Detection of

venous thrombosis in the human by means of radioiodinated antifibrin-fibrinogen antibody. Surgery 60:121 I, 1966.

45. Spar, I. L.. Perry. J. M., Benz, L. L.. DeWeese, J. A., Mahoney, E. B., Izzo, M. J.,

Schwartz, S. I., and Yu, P. N.: Detection of left atria1 thrombi. Amer. Heart I. 78:731. 1969,

46. Ouchi, H., and Warren, R.: Detection of

intravascular thrombi by means of I-131 labeled plasmin. Surgery 5 I :42. 1962.

17. Gross, R.: Findings with labeled strep- tokmase in vitro and in viva. In. Proceedings of

9th Congress of European Society of Haematol-

ogy. Lisbon, 1963. Basel. S. Karger. p. 1342.

48. Pfeifer. G. W.: Distribution and placental

transfer of r3’1-streptokinase. Aust. Ann. Med.

Suppl. 19:18, 1970.

49. Siegel, M. E., Malmud, L. S.. Rhodes,

B. A., Bell, W. R., and Wagner. H. N., Jr.: Scanning of thrombo-emboli with 13’1-streptokinase. Radiology, in press.

50. Rhodes, B. A., Turahi. K. S , Bell, W. R..

and Wagner, H. N . Jr.: Radioactive urokinase

for blood clot scanning. J. Nucl. Med. In press.

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Radioactive tracers in diagnosis of cardiovascular disease