JOURNAL OF NUCLEAR MEDICINE 5:101-111, 1964

Measurement of Pericardial Fluid Correlated with the I'31-Cholografin®and IHSA Scan1'2

David M. Skiaroff, M.D., N. David Charkes, M.D., and Dryden Morse, M.D.

Philadelphia

INTRODUC1'ION Since its introduction in 1958 by Rejali, Maclntyre and Friedell (1), the radioisotope heart scan has become established as a safe, simple, and useful technique for the diagnosis of (2,3,4,8). Nevertheless, few studies have been reported concerning quantitative aspects of the method. Early in 1961, the Radioisotope Laboratory of the Albert Einstein Medical Center, Northern Division, instituted a program in conjunction with the Division of designed to evaluate the cardiac photoscan in patients under going open-heart surgery. It was proposed that a preoperative heart scan be per formed and the pericardial contents aspirated and measured in all such patients, and that criteria for heart scanning be established from these figures. To date, 23 operated patients have been so studied. In addition, data was available from post-mortem examination in six other patients, and five patients with pericardial effusion underwent diagnostic . An aditional three patients had massive pericardial effusions but were not tapped; these pa tients are also included in the series. Twenty-five other patients with cardiac dis ease, some with pericarditis, are not included in this study because pericardiocen tesis was not performed.

‘Presentedatthe 10thAnnual Meeting,Societyof NuclearMedicine,Montreal,Canada, June26-29,1963. ‘Fromthe Departmentsof Radiology(RadiationTherapy and NuclearMedicine)and ThoracicSurgery,AlbertEinsteinMedicalCenter,NorthernDivision,Philadelphia,Pennsyl vania. 101 102 SKLAROFF, CHARKES AND MORSE

From the data obtained from these 37 Patients certain standards have been established.Itappearsthatthe photoscanningtechniquecan be used to detect pericardial effusions of 300 cc or greater, and in individuals with small or normal , of 200 cc. METHOD At first,iodinatedhuman serum albumin-I13'(IHSA) in doses of 4-6 jzc/kg was employed as the scanning agent, as in the original investigations of Rejali et al (1). However, since April, 1961, we have employed I'31@Cholografin®and at present it is used exclusively. Twenty-three of the patients in this series! were scanned with P31-Cholografin and fourteen with IHSA. I'31-Cholografin is extracted from the blood by the polygonal cells of the liver and is then excreted into the biliary tree. The rate of extraction is such that 50 per cent of the initial blood concentration disappears within 4.8 hours' (5). The scan is beg-un 15 minutes after injection at the sternal notch and proceeds caudally, so that by the time the liver is reached (40-60 minutes) about 10-15 per cent of the Cholografin has been removed from the blood. Satisfactory scans have been obtained with doses of P31-Cholografin of 3-7 ,@c/kg and scan speeds of 16-18 cm/mm. Non-radioactive iodine in the form of Organidin® is adminis tered by mouth several hours prior to scanning to block the thyroid uptake of i' -u

1If 0.25 mg. Cholografin is injected.

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Fig.la (left):Photoscanof cardiacblood pooi of 53 year old white male with mitral stenosis, superimposed on 6.foot, AP, recumbent, split film. 32 cc of pericardial fluid was aspirated at open-heart surgery. Note activity in , pulmonary great vessels, lung fields, and liver. Difference between maximum transverse cardiac diameter of scan and x-ray images is 0.5 cm, ratio 0.97. I―@ChoIo grafin, 300 @c. Fig.lb (right):Cardioscanof30 yearoldwhitefemalewithacutebenignpericarditisand massive effusion. Diameter difference 7.0 cm, ratio 0.63. Note separation of cardiacbloodpoolfrom pulmonaryvasculatureand liver.I―Cholografin, 300 1@c. MEASUREMENT OF PERICARDIAL FLUID 103

The instrument used for thisstudy was the Picker Magnascanner (6), which is equipped with a 3 x 2 inch NaI(TA) crystal and pulse-height analyzer. The maximum count ratevaried somewhat with the dose, blood volume, cardiac size and geometry (4),but was approximatelybetween 6 and 15 cpm/@c (1800-6000 cpm). The count range differential was usually set at 40 to 60 per cent, with background determinedoverthelung fields.Low countrangedifferentialsettings were avoidedsincetheytendtoproduce a smallerimage. The scan was displayedboth on Teledeltospaper and on clearx-rayfilm, but only the latterwas used for diagnosticpurposes (photoscan).Localizing marks were made in the midclavicular lines at approximately the 4th intercostal space and recorded on the photoscan. Lead shots were then placed on the skin marks and two successiveexposuresmade of the chestat a 6-footdistancein the AP projection, the central ray passing through the lead markers alternately. Such splitfilmshave been shown to produce minimal distortionof the cardiacimage (2). The photoscan was then accurately superimposed on the roentgenogram and the maximum transverse cardiac diameters measured. Comparison of these para meters proved to be the best criterion of pericardial effusion.

TABLE I

CORRELATION OF CARDIAC PHOTOSCAN WITH VOLUME OF PERICARDIAL FLUID

ofNumberMean Ratio TransverseDifferenceDiametersPericardialMaximum Fluid*of Diameter, cmBetween sScan PatientsCardiac Diameters, cm (5) X-Ray (X) (X-S)/

15.4 17.5 2.1 .85 100 cc or less 24 (10.5-21.5)@ (12.0-23.6) (0.5-3.5) (.80-.96)

200 to 300 cc 3 Br—200 cc 1 15.0 19.0 4.0 .79 Hi—200cc 1 14.5 19.8 5.3 .73 Gr—300cc 1 10.0 13.0 3.0 .77

Morethan300cc 10 12.9 18.7 5.8 .69 (10.3-15.6) (13.0-22.0) (4.5-8.7) (.60-.79)

*Mcastired by aspiration of pericardial contents at open-heart surgery in 23 patients, at autopsy in 6, and by pericardiocentesis in 5. In 3 patients pericardial effusion was massive but was not measured. XxRa nge. 104 SKLAROFF, CHARKES AND MORSE

RESULTS Of the 37 patients, 13 had pericardial effusions of 200 cc or more. The other 24 patients all had severe cardiac disability, with hypertrophy and/or dilatation of one or more chambers. These latter patients, with effusions of 100 cc or less, were compared with the group of 13. Figure la demonstrates an P31-Cholografin photoscan superimposed on a split, 6-foot, AP, recumbent chest film of a patient with mitral stenosis. Thirty two cc of pericardial fluid was found at operation. The blood pools of the heart, aorta, pulmonary great vessels and lung fields are well visualized, and the liver has also been outlined. The cardiac blood pool almost, but not quite completely, fills out the cardiac silhouette on roentgenogram. In the 24 patients with cardiac hypertrophy and/or dilatation with 100 cc or less of pericardial fluid, the mean difference between the maximum transverse cardiac diameters on scan and x-ray was 2.1 cm and was always less than 3.5 cm. The ratio of the two diameters was always greater than .80 (mean .85). There were 13 patients with pericardial effusions of 200 cc or greater and in 11 of these, the difference between the maximum transverse cardiac diameters of scan and x-ray was greater than 4.5 cm. The ratio of the diameters in every case was less than .80 (mean .69). The causes of the pericardial effusions of these 13 patients were: acute myo cardial infarction (1 patient), active rheumatic carditis (2), carcinomatous peri carditis (1), acute benign pericarditis (6), and pericardial effusion of unknown etiology (1). With marked pericardial effusion (Fig. ib) a non-radioctive zone visibly sur rounds the cardiac blood pool, and separation from the pulmonary vasculature and from the liver can be demonstrated. These changes are more obvious when the scan is seen without superimposition on x-ray (Fig. 2). Three patients were found to have effusions of between 200 and 300 cc,

Fig. 2.: Same as Figure 1 except that scans are not superimposed on roentgenograms. Note that in pericardial effusion (right) the cardiac blood pool is separated from the liver and pulmonary vasculature. @ —

MEASUREMENT OF PERICARDIAL FLUID 105

and in two of these three patients the diagnostic criteria for pericardial effusion were not completely satisfied ( Table I ) . The first of these patients had moderate cardiomegaly ( transverse cardiac scan diameter 15.0 cm ) and was found to have 200 cc of fluid in the pericardial cavity at the time of open-heart surgery for mitral stenosis (Fig. 3). The difference between the maximum transverse cardiac diameters on scan and x-ray was 4.0 cm, which is greater than that of the 22 pa tients with effusions of less than 100 cc, but less than that of 11 patients with effusions of more than 300 cc. This was therefore a borderline result. Similarly, the diameter ratio of 0.79 was also borderline. Thus in the pres ence of cardiomegaly, a 200 cc effusion may not widen the x-ray silhouette enough to satisfy all the criteria for effusion which we have established. In the second patient, with a slightly smaller heart, a routine preoperative scan detected a pericardial effusion (Fig. 4), although there was no clinical evi

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Fig.3.:Heart scanof 52 year old negro femalewith mitralstenosis.Diameter difference 4.0 cm, ratio 0.79. At operation pericardial cavity contained 200 cc. Note that liver isnot separatedfrom cardiacblood pool.Transversescandiameterof 15.0cm is indicative of cardiomegaly. IHSA, 350 @c. 106 SKLAROFF, CHARKES AND MORSE dence of pericarditis. At open-heart surgery for mitral stenosis 200 cc of sero sanguinous fluid was aspirated from the pericardial cavity, and a fibrinous pen carditis was found. In this patient the diagnostic criteria for effusion were satis fied. In the third patient of this group the difference between the diameters was only 3.0 cm although the ratio of 0.77 was within the effusion range. This pa tient was a small, elderly female with a recent myocardial infarction. Her trans verse chamber size on scan, 10.0 cm, was the smallest of any of the 37 patients in the series and this feature contributed to the normal diameter difference. Three hundred cc of fluid was aspirated by pericardiocentesis, and at autopsy one week later extension of the infarct to the epicardium with 250 cc of serosanguinous pericardialfluidwas found. It is apparent, therefore, that in patients with effusions of 200-300 cc, a diag

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Fig. 4.: Routine preoperative heart scan of 42 year old white female with mitral stenosis and insufficiency. Diameter difference of 5.3 cm, ratio 0.73, is indicative of peri cardialeffusion,althoughtherewas no clinicalevidenceofpericarditis.At operation the pericardial cavity contained 200 cc of serosanguinous fluid and fibrinous pen carditis was found. F3@Cholografin,300 1zc. MEASUREMENT OF PERICARDIAL FLUID 107

nosis of pericardial effusion by radioisotope scanning will depend upon the size of the heart. Cardiac dilatation per se does not give rise to diagnostic problems in scan interpretation. Figure 5 is the scan of a patient with mitral stenosis and insuf ficiency in whom 60 cc of pericardial fluid was found at operation. The scan outline almost completely coincides with the x-ray silhouette.The transverse cardiac diameter difference is 1.5 cm and the ratio 0.94. Figure 6 demonstrates a pericardial effusion in a patient with cardiac dilatation and hypertrophy, and with carcinomatous invasion of the resulting in an. effusion of more than 350 cc (pericardiocentesis). The transverse cardiac diameters on scan and x-ray measure 14.5 and 19.5 cm respectively, (difference 5.0 cm, ratio 0.74) thus satisfy ing the diagnostic criteria for effusion. It is clear, therefore, that pericardial effusion can be diagnosed in the pres ence of cardiac hypertrophy and/or dilatation.

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Fig. 5.: E.V., 31 year old white female with marked cardiac dilatation and hypertrophy from mitral stenosis and insufficiency. Note close correspondence of scan and x.ray images, and merging of cardiac and hepatic blood pools. Diameter difference 1.5 cm, ratio 0.94. Sixty cc of pericardial fluid was found at operation. I'5I-Cholografin, 400 @,c. 108 SKLAROFF,CHARKESAND MORSE

DISCUSSION The results of this study indicate that pericardial effusions of more than 300 cc can be diagnosed accurately by radioisotope scanning, and in some cases, notably in those patients without cardiomegaly, as little as 200 cc may be de tected. These figures correlate well with the balloon phantom studies of Bonte and associates (3). These investigators were able to detect a 200 cc “effusion― surrounding a 400 cc isotope-filled balloon in a tank of water containing 1131. It is important to note that cardiac dilatation and/or hypertrophy per se do not interfere with accurate diagnosis of pericardial effusion, although it is obvious that more fluid is required to surround such a heart. We have never found the situation described by Maclntyre et a! (4) (Figs. 5 and 6 of their article) in which a marked discrepancy (diameter ratio less than .80) is noted between trans verse cardiac diameters of scan and roentgenogram in a patient with cardio megaly but without pericardial effusion. If care is taken to secure a 6-foot recum bent split film, as described here and by Wagner et al (2), the ratio of the trans

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Fig. 6.: Heart scan of a 72 year old white female with advanced metastatic carcinoma of breast. Note separation of cardiac and hepatic blood pools and marked distention of pencardial sac. Diameter difference 5.0 cm, ratio 0.74. Cardiomegaly (transverse cardiac scan diameter 14.5 cm) is also present. Pericardiocentesis yielded 350 cc of fluid containing malignant cells, but residual effusion remained. I3―Cholografin, 300 @c. MEASUREMENT OF PERICARDIAL FLUiD 109 verse cardiac diameters in patients with effusions of 100 cc or less will be greater than .80. A midrespiration film is desirable. Some variation can be expected in cardiac width depending upon the phase of the cardiac cycle in which the roent genogram is taken. Especially important, but less objective, is the determination of the scan width. The lateral border of the heart is never sharp for a variety of reasons: (1) constantmotionoftheheart; (2) respiration; (3 ) collimator resolution. One important factor contributing to this prob lem is scatter from the high-energy gammas produced by I's' in its decay (0.637 Mev—9 per cent; 0.722 Mev—3 per cent ) ( 7). Better cardiac scans could be at tamed by use of mono-energetic, lower-energy radioisotopes. Another factor contributing to poor resolution is the size of the collimator aperature. In the Picker 19-hole focusing collimator these measure 0.6 cm at the surface. (4) Not previously reported but of considerable importance is the activity contributed to the cardiac outline by the pulmonary vessels of the lower lobes. It is much easier to read a scan of a patient with a pericardial effusion for this reason, since the pulmonary vessels are then separated from the cardiac blood pool (2) ( Fig. 2). These adventitious counts may be minimized by judicious use of a background cut-off circuit, such as described by Maclntyre ( 4 ) and as pres ent in our instrument ( 6). (5) Contrastenhancement.AlthoughthePickerMagnascannercontainsa contrast enhancement circuit which has been favorably reported upon for heart scanning by some groups ( 2 ), we do not feel that it is of value in the type of study we have described, and in fact may be detrimental by obscuring the cardiac border. We have achieved a compromise between background cut-off and con trast enhancement by use of count-range differentials of 40-60 per cent, de pending upon the count rate, but we are presently modifying our instrument to eliminate the contrast-enhancement feature entirely if so desired, while re taining full use of the background cut-off circuit. We believe that this change will improve the diagnostic capabilities of our instrument. In any event, we recom mend that under no circumstances should count rate differentials of less than 30 per cent be used, since images tend to get smaller at these levels. Nevertheless,ithas been found possibleto establishcertainquantitative standards. The mean ratio of maximum transverse cardiac diameter of scan and x-ray images in our series, 0.85, is somewhat less than that given by Wagner et a!. (0.93) (2). The mean maximum transverse scan width of our 37 study patients was 15.4 cm, which is somewhat greater than Wagner's series (14.6 cm). How ever, a scattergram of our data reveals no consistent relationship between scan size and diameter ratio, so that difference in heart size is not a factor. It is prob able that many of the variables discussed above in connection with estimation of scan width play a role,since our technique for taking roentgenograms is almost identical to that of Wagner et a!. It is of interest that Wagner's statistics concern ing chamber ratiosof patientswith pericardialeffusionare similarto ours. 110 SKLAROFF,CHARKESAND MORSE

It cannot be emphasized too strongly that although pattern reading ( separa tion of cardiac blood pool from hepatic and pulmonary vasculature) is of value in detection of massive pericardial effusion ( Fig. 2), it will not reliably detect minimal effusions (200-300 cc ), since in such cases visible separation of the blood pools may be absent ( Fig. 3 ). Measurement of the maximum transverse cardiac diameter of scan and x-ray images and calculation of the difference and ratio of the values are the most reliable parameters for the diagnosis of pen cardial effusion. In this series, as in that of Wagner ( 2), no patient in whom the diameter ratio was normal ( .80 or greater ) was subsequently found to have more than 100 cc of fluid in the pericardial cavity. Conversely, every patient with a diameter ratio of less than .80 proved to have 200 cc or more of penicardial fluid; this ratio was as low as .60 in two pa tients. For effusions of 200 to 300 cc the ratio fell between .73 and .79. Correla tion of the diameter ratio with volume of effusion was not possible inasmuch as the full pericardial contents were not always measured, and in three patients with massive effusions in this series were not measured at all. Although Maclntyre et a! (4) have employed I'31-Cholografin in doses up to 1.5 mc for heart scanning, we have not found it necessary to do so. The max imum count rates produced by 300 j@cof this material have ranged from 1800 to 6000 cpm, rates which are satisfactory for scanning. With higher doses better resolution is possible, unless this advantage is sacrificed for a more rapid scanning speed. In orthopneic patients the higher dose is indicated. The whole body radiation dose from 113-Cholografin has been calculated to be about 5 per cent of that of a similar quantity of IHSA (4), and for this reason is the preferable compound. In addition, with P31-Cholografin the liver is better visualized, which aids in detection of fluid in the cardio-hepatic space. There are no other differences in the heart scan with either compound. The calculated whole body radiation dose from 300 @cof I131-Cholografin is 25 millirads (4), and from an equal quantity of I'31-IHSA, 450 to 570 millirads (2,4). P31-Cholografin or IHSA may also be used for the detection of chamber en largement, ventricular aneurysm, or aortic aneurysm (3,4,8). Marked enlargement of the cardiac silhouette on roentgenogram with a normal isotopic scan of the heart is not pathognomonic of pericardial effusion. Space-occupying lesions within the pericardium, such as lipomas (2) and cysts (9), and cardiac amyloidosis (9) may produce false-positive heart scans.

SUMMARY In 23 patients undergoing open-heart surgery in whom the penicardial con tents were accurately measured, and in 11 additional patients examined at autopsy or by penicardiocentesis, isotopic photoscans of the heart were made and the re sults were correlated. The most accurate means of diagnosis of pencardial effusion was found to be the ratio of the maximum transverse cardiac diameters on scan and roent genogram. In patients with less than 100 cc of pericardial fluid this ratio was greater than 0.80, and it was less than this in cases of effusion of 200 cc or more. MEASUREMENT OF PERICABDIAL FLUID 111

Measurement of the difference of these diameters, and visible separation of the cardiac blood pool from the pulmonary vasculature and liver aided in the diagnosis. Pencardial effusions of 200-300 cc or greater can be detected by isotopic photoscanning.Although cardiacdilatationand/or hypertrophy decrease the sensitivity of the technique somewhat, a definite diagnosis of penicardial effusion can be made even when cardiomegaly exists.

ACKNOWLEDGEMENTS We wish to express our appreciation to Dr. Paul Numerof of E. R. Squibb and Sons, Inc., for supplies of P31-Cholografin for this study. The technical assistance of Mrs. Tina Helock and Miss Barbara Cravitz is gratefully acknowledged.

REFERENCES 1. REJALI,A.M.,MAcINTi'aa,W. J.,AND FRIEDELL,H. L.:A RadioisotopeMethodofVisual ization of Blood Pools. Am. I. Roentgenol., Rad. Therapy and Nuclear Med. 79:129, 1958. 2. WAGNER, H. N., MCAFEE, J. G., AND MOZLEY, J. M.: Diagnosis of Pericardial Effusion by RadioisotopeScanning.Arch.mt. Med. 108:679,1961. 3. B0NTE, F. J.,ANDREWS, C. J.,ELMENDORF, E. A.,PRESLEY,N. L.,AND KROHMER, J.S.: Radioisotope Scanning in the Detection of Pencardial Effusions. Southern M. J. 55:577, 1962. 4. MACINTYRE,W. J., Caxspo, C. C., AND CHRISTIE, J. H.: The Use of Radioiodinated (lI-at) lodipamide for Cardiovascular Scanning. Am. I. Roentgenol., Rad. Therapy and Nuclear Med. 89:315, 1963. 5. FREIMAN, H. D., COHN, E. M., ANDSKLAROFF,D. M.: The Inadequacy of Radio-Iodinated (11*1) lodipamide as a Liver Function Test. I. Nuclear Med. 3:63, 1982. 8. HERRING, C. E.: A UniversalPhotorecordingSystem for RadioisotopeArea Scanners. J. NuclearMed. 1:83, 1960. 7. Bs@u, M. ANDBENDER,M. A.: Radiomercury (Hg'°') Labeled Neohydrin: A New Agent for Brain Tumor Localization. J. Nuclear Med. 3:83, 1962. 8. CHARKES, N. D., AND SELAROFF, D. M.: Radioisotope Photoscanning as a Diagnostic Aid in CardiovascularDisease.Presentedat the Third MultipleDisciplineResearchForum, 112thAnnualMeetingoftheAmericanMedicalAssociation,AtlanticCity,N.J.,June 16-20, 1963. 9. WAGNER, H. J.:personalcommunication.