Indicator-dilution methods in the diagnosis of congenital heart disease

Indicator-Dilution Methods in the Diagnosis of Congenital Heart Disease

By H. J. c. SWAN L T H O U G H studies of tile circulation based on the dilution of an identifiable substance ha~e,, been carried out for more than 60 years, the use of this technic in the problems of diagnosis and investigation of congenital heart disease is of relatively recent introduction 1 and development 2'3 by Wood and his associates. Yet over the past year or so the increasing nmnber of publications concerning various applications of indicator-dilution methods in congenital and acquired heart disease (for example, references 4 and 5) indicates a widening appreciation of tile value of this tool in the study of abnormal circulation. This paper is based on experiences with the continuous determination of concentration of an indicator dye at one or more specific points in the circulation. Identical principles apply to the use of radioactive indicatorsP The similarities in principle that underlie dispersion of material in the central circulation visualized by angiocardiographic means and by indicator-dilution time-concentration curves should also be recognized. The basic determinants of an indicator-dilution curve may be more easily understood from a consideration of figure 1A, which illustrates the dispersion of material during its first passage through a complex circulation following its injection as a single bolus at point A. In this schematic figure, velocity is considered constant and the effect of laminar flow is ignored. Since the circuit illustrated consists of a few short paths, a larger number of pathways of intermediate lengths, and a small number of long pathways, some material will reach the outflow rapidly. A greater part traversing pathways of intermediate length will enter the outflow at an intermediate time, while that portion which has traversed long pathways enters the outflow at a still later time. The material that started at point A as a single bolus appears in a dispersed form in the outflow (B) as a concentration-distance curve (shown immediately below). If a sample of the fluid-indicator mixture is drawn continuously at a single point in the outflow, then a concentration-time curve is obtained. Under most circumstances, such a dilution curve will not differ significantly from the concentration-distance curve of indicator in the parent stream. An indicator-dilution curve can usefully be regarded as a family of the differing transit times required for particles to pass from injection to sampling site. This dispersion of transit times is a reflection of the lengths of anatomic paths, the velocity of flow through them, the volume of blood between injection and sampling sites, and the characteristics of flow through the blood This study was supported in part by Research Grant No. H-3532, National Institutes of Health, Public Health Service. From tile Mayo Clinic and Mayo Foundation, Rochester, Minn. Tile Mayo Foundation, Rochester, Minn., is a part of the Graduate School of the University of Minnesota. 143

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Fie. 1.--A. Schematic representation of the central circulation showing tile effects of paths of differing anatomic lengths on material introduced into a complex circulation (flow from left to righi:). Tile difference in t'raversal times alone can explain the dispersion of indicator injected as a single bolus at position A, when it arrives in tile outflow to the system at B. Immediately beneath the outflow a concentration-distance curve is inscribed which reflects these differing traversal times. Sampling at a point in the outflow converts the concentration-distance curve to a concentration-time curve. (Reproduced from Wood, E. H., Swan, H. J. C.; and Helmholz, H. F., Jr.2) B. Concentration-time dilution curve obtained in arterial blood of a normal subject. Increasing concentrations of dye are shown as a downward deflection. Note the rapid increase to a peak of concentration followed by a slower decrease toward zero concentration. However, dye is not cleared completely from the circulation but further, successively more damped, dmnges in concentration occur owing to the arrival of indicator that has already traversed systemic capillaries at least once. vessels a n d d e t e c t i n g i n s t r u m e n t . F r o m s u c h a d i l u t i o n c u r v e one c a n d e t e r m i n e t h e v o l u m e r a t e of flow t h r o u g h t h e system, t h e v o l u m e o f tlle system, t h e fastest a n d m e a n c i r c u l a t i o n t i m e s a n d tile p r e s e n c e or a b s e n c e of a b n o r m a l c i r c u l a t o r y p a t h w a y s . T h e c l a i m t h a t " t h e r e c o r d i n g of tile d i l u t i o n of a n ind i c a t o r d u r i n g its initial t r a v e r s a l of a c i r c u l a t i o n pro{,ides m o r e i n f o r m a t i o n

INDICATOR-DILUTION ~IETIIODS AND CONGENITAL IIEART DISEASE

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concerning the status of this circulation than does any other single variable at present simply recorded in cardiovascular physiology'' can readily be defended. Immediately below, in figure 1B, is slmwn an indicator-dilution curve recorded in a normal subject following injection of indicator into the pulmonary artery with detection at the radial artery. The "'appearance time" is the interval between the instant of injection and the instant of first detection of dye at the sampling site. The "build-up" time is the interval over which concentration increases rapidly to a peak, and is followed by a less rapid decline toward zero concentration. The least concentration is in turn followed by a peak of concentration (the recirculation concentration) due to indicator which, having traversed systemic capillaries, has again circulated through the hmgs and is making a second appearance at the systemic arterial sampling site. When the circulation is rapid, as in small children, or in adults with increased cardiac output, several successive peaks of concentration may be seen caused by dye on successive circulations past the detecting point. INDICATORS

By definition all indicator substance can be detected in the blood stream, and should bc accurately quantitatable. To be practically usable, it must not cause an), cardiovascular reaction in the body following its introduction. Further, it must be nontoxic; it should be soluble in water, the vohtmc of injcctate should bc small, and usnally the indicator should bc completely retained within the vasctdar system for at least one complete circulation. Substances that are uscd as indicators include (1) radioactive indicators such as iodinated (I TM) human serum albumin G and radiophosphorus, r (2) indicator dyes with high spectral absorption in the red region of the visible spectrum at a wavelength of 640 millimicrons, which include Evans blue, indigo carmine s and methylene blue2 and (3) dyes with a high spectral absorption in the infrared region of the.spectrum at 800 millimicrons, such as cardiogreen3 ~ In tlie red region of the visible spectrum (640 millimicrons) the difference in transmission of light by reduced and by oxygenated hemoglobin is nearly maximal. A detector for an indicator absorbing light in this region (for example, Evans blue) is unable to distinguish between changes in the concentration of dye and changes in the concentration of reduced hemoglobin, so that in the presence of changing oxygen saturation of arterial blood it may be imi~ossible to tell whether a deflection on an inscribed curve is due to dye or to reduced hemoglobin. This problem is of major importance in the application of dilution technics using photometric dyes in the presence of right to left shtmts of large magnitude or hypoxia, or in the recording of dilntion curves from the venous side of the circulation. The introduction of cardiogrccn was designed to circumvent these difficulties, and it appears to bc the ideal indicator material for the diagnostic application of dilution curves. *Available from Ilynson, Westcott and l)u,ming, Baltimore, Md.

146

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This paper will be confined to a consideration of dilution curves recorded by means of a photocell oximeter, which has been well described. 11 However, these considerations apply equally well to other technics, such as the use of continuous sampling of blood for the detection of radioactivity.G Curves recorded by using the whole-blood oximeter have advantages in terms of absolute "calibration and fidelity over curves recorded indirectly by the ear oximeter for diagnostic and investigative purposes. -~ Currently available detectors* for cardiogrecn can be made to have a high dynamic response, although the relatively slow system provided by the conventional oximeter is adequate for tile great majority of applications. GENERAL PRINCIPLES CONCERNING TIIE APPLICATION OF DILUTION TECttNICS TO TIIE STUDY OF HEART DISEASE

Before proceeding with dctailed discussion of the applicatiou of dilution technics to congcnital heart discasc, it might be appropriate to placc thcsc technics in their propcr perspective. In our laboratory, during study using cardiac cathetcrization, indicator-dilution curves arc obtaincd i,l vcry ncarly cvcry patient and arc regarded as a part of, and not as a substitute for, this prcccdure. A cardiac catheter is a hollow tube which makes possible the measurement of pressures within the heart and vascular system and through which blood samples may bc witladrawn from the chambers of the heart and great vessels for the dctcrmination of oxygcn content, or the prcscnce of foreign gases le or blood-indicator mixtures. It also permits the injection of material that may be detected by roentgenographic or photometric technics. To attempt to distinguish bctwccn the relative diagnostic value of "cardiac catheterization" and "indicator-dilution technics" would imply a basic limitation of the former term and a misconception of the application of the latter. With the advancement of knowledge as to the particular symptomatology, physical signs, and electrocardiograpllic and roentgenologic characteristics of the various forms of congenital heart disease, the problems of diagnosis wliich necessitate hemodynamic study are being restricted more and more to two groups of patients. The first group includes tlmse with minimal cardiovascular disorder, but with equivocal clinical, rocntgcnologic or clcctrocardio~ graphic signs, in whom exclusion of organic disease may be extremely difficult. The second group comprises those patients with complex malformations in whom the positions taken by a Cardiac catheter, the measurement of pressures, and the determination of oxygen concentration in a few locations in the heart and great vessels may add little to the clinical evaluation. The use of indicator-dilution technics and selective angiocardiographic procedures greatly cxtends the interpretations possible following hcmodynamic study in such patients. The facilities available for, and the organization of, tlle cardiac catheterization procedure must permit the injection o f an indicator and the *Available from Waters Corporation, Rochester, Minn., and Gilford Instrument Labora9tories, Inc., Elyria, Ohio.

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recording of a dilution curve with a minimum of delay. Thus it should be possible to include the recording of 10 or more dilution curves durifig a hemodynamic study without prolonging it unduly, hnmediate knowledge of the physiologic data obtained during a procedure would appear essential to the intelligent diagnostic study of complex cardiac malformations. On integrating this information with a knowledge of the clinical data, the operator is in a position to select appropriate injection and sampling sites so as to reach a diagnosis most readily. The practical details of the applications of these technics have been described elsewhere.1.'-' A dilution curve is a profile of transit times from injection site to sampling site. As shall be demonstrated, much may be deduced from the study of such curves, but when certain lesions and defects are unassociated with altered transit times their presence will not be detected by these methods. Further, errors of technic and interpretation are not uncommon in the introduction of a new and unfamiliar method. I~IGIIT TO L E F T SIIUNTS

All abnormally short transit time for some of tile indicator from tile point of injection to tlie point of detection is tile basis of a dilution curve characteristic of a right to left shunt (fig. 2A). Injection of indicator at or upstream to a defect through which a right to left shunt is occurring results in an abnormal dilution curve in tile systemic arterial system. Such a curve shows an appearance time that is shorter than normal, because of a component due to indicator that escapes in the right to left direction across tlle intracardiae defect. This is followed by a second concentration peak due to that material which traverses the longer, normal pathway through tile lung. In general, the size of the initial deflection is related to the magnitude of tile shunt, but errors in values for tile average right to left shunt may occur because of (1) preferential injection of material toward or away from the defect, (2) phasic variations in tile magnitude of the shunt associated with the cardiac or respiratory cycles and (3) errors associated with the form of calculation used. The calculation used in this laboratory 13 depends upon reasonable resolution of the abnormal dilution curve into two identifiable portions: that due to t h e shunted dye and that due to the dye which has traversed the pulmonary circulation. If sufficient separation of these portions has occurred and is recorded at the sampling site, then a reasonably accurate estimate of the magnitude of the shunt is usually obtained. Shunts of a very large magnitude (more than 50 per cent of systemic flow) are usually underestimated by this method. In the presence of moderate desaturation of systemic arterial blood, good agreement is obtained between right to left shunts 6f moderate magnitude calculated from the dilution curve and those calculated from the oxygen saturation of systemic arterial, pulmonary venous and systemic venous blood samples in the conventional manner, a4 In the absence of significant desaturation of systemic arterial blood (values by Van Slyke analysis, 95 to 99 per cent), initial deflections equivalent to right to left shunts of 2 to 10 per cent of systemic blood flow have been repeatedly demonstrated from the in-

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ferior vena cawl in patients proved to have interatrial defects. Comparatiffe data to test the accuracy of these calculations lmve not been obtained by an independent technic. Localization of right to left slmnts.lr'---A right to left shunt may be localized by the recording of an abnormal dilution curve following injection of indicator Iniection into: Pulmonory

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at or upstream to the site of the defect through which the shunt is occurring, while a normal curve is obtained following injection into the c h a m b e r downstream from the site of the shunt (fig. 2A and B). In practice, tiffs has been one of the most important diagnostic applications of indicator-dilution technics. Errors in localization b y this method have been rare, and on restudy their occurrence was usually evidently avoidable. Specific problems are most conveniently considered in relation to the level at which the shunt occurs. AORTICOPULMONARY CO-XtMUNICATIONS. A right to left shunt m a y occur through an aorticopulmonary communication w h e n the pressure in the pulmonary artery equals that in the aorta. If the communication is a patent ductus arteriosus, the r i g h t to left shunt occurs preferentially into the descending aorta following injection into the pulmonary arterylC; w h e n the shunt is small, dye m a y be detected only in the descending aorta-femoral artery system, while no early-appearing dye is detected in blood sampled simultaneously at the right radial artery. \Vhen the quantity of early-appearing dye in the descending aorta-femoral system is large and no early-appearing dye is detected at the right or the left radial artery, then the presence 0f an associated coarctation of the aorta proximal to the patent ductus should be strongly suspected. If the right to left shunts detected at the aortic-femoral and radial-artery systems a p p e a r to b e equal in magnitude, then the shunt m a y not b e occurring through a patent ductus arteriosus, but through either an aorticopulmonary septal defect or through a ventricular septal defect, dye having refluxed

FIc. 2.--A. Schematic representation of the central circulation in ventricnlar septal defect and pulmonary stenosis to illustrate the dcnmnstration and localization of right to left shunts by means of indicator-dilution technics. Below each diagram, dilution curves characteristic for the two injection sites are shown. When dye is injected into tile root of tile puhnonary artery (left panel), indicator particles have to traverse the normal pathway through the hmgs to reach tile sampling site in the systemic circulation. When, however, indicator is injected into the right ventricle, some indicator can "bypass" the pulmonary circulation and enter the root of the aorta immedately via ttie defect. The indicator particles traversing the short pathway have shorter transit times and arrive in the systemic circulation more rapidly than the remaining indicator which traverses tlle pulmonary circulation. (Reproduced from Wood, E. H., Swan, H. J. C., and Marshall H. W. 3) B. Indicator-dilution curves recorded at femoral and radial arteries demonstrating the localization of a right to left shunt at the atrial level. These curves and all other original tracings reproduced in this paper have been cut from the original record and remounted in relation to the instant of dye injection to eliminate the time delay required for the blood-indlcator mixture to traverse the needle or catheter from the point of sampling to the point in the detector system at which the concentration of indicator is measured. These particular curves illustrate (1) the identity of curves recorded at two sites in the systemic arterial system, (2) the normal appearance time of the curves recorded following injection into the right ventricle, which shows some prolongation of the disappearance phase consistent with a left to right shunt of moderate magnitude, (3) the early appearance of dye following its injection into the inferior and superior venae carat and (4) tbe greater magnitude of the right to left shunt obtained following injection into the inferior as opposed to the superior vena cava. These curves permit the following conclusions: (1) there is a left to right but no right to left shunt distal to the tricuspid valve, (2) there is no significant regurgitation at the level of the tricuspid valve, (3) there is an interatrial communication and (4) this interatrial communication i's probably in the region of the fossa ovalis.

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through an insulficicnt puhnonary valve. Shunts at the radial and femoral arteries, both of equal and of unequal magnitude, have been found in cases of aorticopulmonary septal defect. The second possibility may be clarified when indicator is injected into the ventricular chamber. Equal right to left shunts detected at the radial and femoral arteries and significantly greater i n magnitude than following injection into the pulmonary artery suggest the presence of ventrieular septal defect with pulmonary valvular regL~rgitation. VENTRICULAH SFI'TAL DEFECT. In ventricular septal defect it is possible to obtain dilution curves of different contour when indicator is injected at different sites in the right ventricle. For quantitation of a right to left shunt at ventricular level, measurement is best made on the curve obtained following injection into the right atrium or superior vena cava because of the possibility of a selective injection of indicator toward or away from the defect in the case of intraventricular injection. In single ventricle it is unusual to obtain fi'om any site in the ventricle a curve that does not show some evidence of right to left shunt. However, dilution curves do not provide a practical differential between ventricular septal defect and common ventricle. INTERAT1UALCO~XI.XIUNICATIONS.A right to left shunt that is not sufficient to cause significant desaturati0n of systemic arterial blood is usually demonstrated in patients with an atrial septal defect in the fossa ovalis) 7 In the majority of cases this shunt can be demonstrated fi'om the inferior vena cava, while from the superior vena cava no right to left shunt or only the shunting of a smaller amount of superior caval blood can be detected (fig. 2B). In the remaining cases, either there is no right to left shunt from either eava or, uncommonly, a right to left shunt of equal magnitude is demonstrated fi'om both superior and inferior venae cavae. Here selective injection of indicator into the defect from the superior vena cava must be avoided. When the right to left shunt from the superior vena cava is significantly greater than that from the inferior vena cava, the presence of a defect situated cephalad to the fossa ovalis and associated with anomalous connection of the pulmonary veins of the right upper and middle lobes to the junction of the superior vena cava and right atrium is likely) s The problem of the total or partial forms of anomalous pulmonary venous drainage will be discussed in a later section. In the presence of tricuspid regurgitation associated with an interatrial communication through which a right to left shunt is occurring, a ventricular septal defect may be erroneously diagnosed on file demonstration of a right to left shunt following injection of dye into the right ventricle. If an injection of indicator is made close to an incompetent tricuspid valve, a portion may regurgitate into the right atrium from the right ventricle and be shunted right to left. However, if further dilution curves are recorded following injection into the inferior and superior venae cavae, the quantity shunted right to left will usually be greater from the inferior cava than from the ventricle. Also the difference in the magnitude of shunt between the cavae will be evident. The possibility of such an crier will then be obvious. Further injections of dye at different sites within the ventricle shonld clarify the true nature of the malformation. To summarize, our experience indicates that the use of indicator-dilution

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curves to localize defects througla which a right to left shunt is occurring is the most reliable method at present available for this differentiation. As witla any other method, errors in such diagnostic applications are minimized witla tile experiences gained in tlle routine use of these technics. The magnitude of right to left shunts of less than 50 per cent of systemic blood flow can apparently be satisfactorily quantitated by application of a simple scmiempirical analysis 1~ in man), instances. For larger shunts and in tile presence of a coexisting left to right shunt of considerable magnitude, sizable errors can result. However, this is apparently tile most accurate method of quantitation of small shunts at present available. L E F T TO R I G t l T StlUN'I-S

In the prcscncc of a left to right shunt, although some indicator particlcs havc normal transit times to the sampling sitc, othcr particles recirculate through the lungs and hence have prolonged transit times. The indicatordilution curves recorded in systemic arterial blood are characterized by normal appearance and build-up times, a reduced peak deflection, a prolonged disappearance phase and frequently by the absence of an identifiable peak of dye concentration duc to systemically rccirculatcd indicator (fig. 3). The reduced concentration is associated with the increased dilution in the blood flow through the central circulation. Indicator is not cleared on one circulation, but recirculates via the defect through the pulmonary blood vcsscls. A constant fraction which is dcpendcnt on the relation of the magnitude of the left to right shunt to the pulmonary blood flow leaves the central pool on each circulation. This slow clearance of dye from the central circulation causes the prolongcd disappcarancc phase of the dilution curvc which merges with and obliterates the recirculation ccncentration. The general :features iust mentioned are characteristic not only of dihltion curves in the presence of left to right shunts but also of curves recorded in thc prcscncc of valvular regurgitation. I n the latter condition, comparable dynamic circumstances pertain since the indicator material is diluted in a volume of blood increased by the abnormal backflow associated with the valvular regurgitation, and the clearance of dye is delayed because of the effect of the large residual volume in which indicator nmterial is continuously mixed. In valvular rcgurgitation thc disappearance phase is smoothly prolonged and shows no breaks or smaller fuctuations of concentration on the disappearance slope such as are usually seen in the presence of a left to right shunt. The degree of distortion seen in a dilution curve refects the magnitude' of the left to right shunt. Dilution curves not significantly different from normal may be seen in the presence of small left to right shunts, while large left to right shunts are invariably associated with gross distortion of the dilution curves. The factors underlying the degree of deformity of the cnrvc are complex and probably defy precise formulation. As with right to left shunts, an empirical relationship with the attributes of simplicity and case of application has been established between the magnitude of the shunt and ccrtain components which may be measured directly from the dilution

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FIG. 3.--Demonstration and localization of a left to right shunt through a vcntricular septal defect by sampling from tlm arterial system and from selected sites in the right side of the heart. A. Schematic circulation, showing tile re-entry of dye into the pulmonary circulation and its early detection in the main pulmonary artery following injection into a distal pulmonary artery. To the left, representative dilution curves are inscribed. (Reproduced from Wood, E. H., Swan, H. J. C., and Helmholz, tI. F., Jr. -~ B. Dilution curves recorded in a patient with a left to right shunt of moderate magnitude (30 to 40 per cent of pulmonary blood flow) and without severe puhnonary hypertension. The disappearance phase of the curve recorded at the radial artery is indicative of the presence of a left to right shunt. Note that early-appearing dye is detected in the outflow portion and to a lesser extent in the inflow portion of the right ventricle, but not in the right atrium. This permits localization of the left to right shunt to the ventricular level, and demonstrates the incomplete mixing of the shunted dye-blood mixture, which is characteristic of ventricular septal defect opening into the outflow portion of the right ventricle. (Reproduced from Wood, E. tI., Swan, H. J. C., and Marshall, H. \V,3)

curves. 19 Reliable values m a y not be o b t a i n e d w h e n a l a r g e right to left shunt coexists. A l t h o u g h such empirical calculations h a v e b e e n criticized, they a p p e a r to p r o v i d e a practically useful m e t h o d for d e t e r m i n a t i o n of the a p p r o x i m a t e m a g n i t u d e of left to right shunts u n d e r the great majority of conditions usually encountered. W h e n a left to right Shunt is associated with valvular regurgitation, as in c o m m o n atrioventricular canal, or an intracardiae shunt is associated w i t h

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severe pulmonary hypertension and resulting insufficiency of tile pulmonary or tlle tricuspid valve, then tile distortion of the dilution curve will reflecf not only tile left to right slmnt but also the valvular regurgitation. In other words, certain indicator particles will remain in tile central circulation because of failure to escape from the large effective dilution volume as well as because of a tend.ency to rctravcrse the pulmonary circulation. Also, when a large right to left shunt is present and an iniection of indicator is made downstream to tile site of tile shunt the disappearance phase of the dilution curve may be distorted by a portion of indicator which has circulated through systemic capillaries, has returned to the heart, and passes rapidly to tile systemic sampling site via tile right to left shunt through tile intracardiac defect. For example, if dye is inicctcd into the pulmonary artery of a patient with a ventricular septal defect through which a large right to left and a small left to right shunt are occurring, then the disappearance phase of the resulting dilution curve may be principally distorted by systemically recirculated dye that has shunted right to left. Localization of a left to right sh~mt.--Two methods are available for the localization of a left to right shunt. The first is similar in principle to that described for a right to left shunt and requires tim injection of indicator at points upstream and downstream to tile chamber or vessel from which the shunt is occurring. When iniection is made downstream the resulting curve is of normal contour, whereas when injection is made at or upstream to the site of the shunt a characteristically abnormal curve is obtained. In the presence of an interatrial defect, inicction of indicator into the left ventricle will resulf in a dilution curve of normal contour recorded at a systemic artery (fig. 4A). Following injection of indicator into the left atrium or an)' position upstream to it, such as the pulmonary artery, the dilution curve will be of abnormal contour. In the same way dilution curves may be recorded at a systemic arterial sampling site after injections at different sites in tlle aorta and may serve to distinguisl~ between patent ductns arteriosus, aortico-puhnonary fistula and aneurysm of the sinus of Valsalva. The positioning of the catheter for such iniections usually involves catimterization of the aorta from a systemic artery and may require puncture of the left side of the heart. ~ Hence tile technic for the localization of left to right shunt involving injections of dye at and downstream to the defect is in practice more difficult than for the localization of right to left shunts. Fortunately, localization of tim site of a left to right shunt is possible by other tcchnicslm~ in the great majority of instances. The second method available for the localization of left to right shunts" consists in sampling dye from different positions in the heart and great vessels following injection of indicator into a distal pulmonary, artery. The application of this technic has been illustrated in figure 3A and B. Two cardiac catheters are used: one is passed into a distal pulmonary artery for injection of indicator and tile other is used to sample the resultant blood-indicator mixture from different sites in the heart and great vessels. Following injection of indicator into the distal pulmonary artery, tim material circulates tilrough tile pulmonary vascularbed and left side of tile heart and aorta. Should a

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Fro. 4.--A. Localization of the site of a left to right shunt at the atrial level by tile technic of upstream and downstream injections. Following tile injection of indicator into the left ventricle a dilution curve of normal contour is recorded. When, however, the catheter is withdrawn to tim left atrium and indicator injected at this site, a left to right shunt occurs thrmlgla the atrial septal defect and a curve of abnormal contours is obtained. (Reproduced from Wood, E. H., Swan, H. J. C., and Hclmholz, H. F., Jr. -~) B. Indicator-dilution curves permitting tim identification of a left to right shunt through both a patent ductus arteriosus and a ventricular septal defect in a p0tient in whom a clear difference in the oxygen saturation of blood samples drawn from the pulmonary artery and the right ventricle was not demonstrated (inset panel). In the left p,'uqel the dilution curve obtained at the radial artery shows a definite but slight abnormality. Note the instantaneous detection of dye in the puhnonary artery following its injection at the aortic root through a catheter advanccd from the femoral.artery. A small secondary peak is seen on the down slope of the main deflection, indicating rapid return of indicator to the pulmonary artery. This could be due to circulation of indicator to the left side of the heart and back to the pulmonary artery by way of the patent duetus. However, when the sampling catheter is withdrawn to the right ventricle and the injection repeated, a peak of concentration corresponding to the second peak of file previous curve is identifiable, thus defining the site of this shunting upstream to the pulmonary valve. When sampling is carried out in the right atrium, neither the first nor the second deflection is recorded, and this shunt may be localized to the ventricular septum.

INDICATOR-DILUTION ~IETIIODS AND CONGENITAL IIEART DISEASE

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left to right shunt exist, then indicator will re-enter the right side of tile heart and tile pulmonary circulation at tile site of tile intracardiae defect. Selection of sampling sites at tile root of the pulmonary artery, the outflow or tile inflow portion of tile right ventricle, tile right atrium and tile superior vena cava permits accurate determination of the position of entry of tlle shunted blood. In practice, this method of detection is of particular value in those cases in which tile magnitude of the left to right shunt is small. In a small number of patients the oxygen saturation of blood samples drawn in succession from the cavae and different sites in the right side of the heart and tile pulmonary artery may fail to give clear evidence of arterialization. Under this circumstance tile dcnaonstration of an intracardiae defect or tile exclusion of it can be of considerable importance. The detection of abnormally early-appearing dye in the pulmonary artery or right atrium following injection into a distal pulmonary artery denmnstrates tile presence of a left to right shunt and localizes tile site of a defect. By this means intracardiac shunts have been clearly demonstrated and estimated to be as small as 10 per cent of pulmonary blood flow. Snch estimations are based upon the proportion of total injected dye that has re-entered the pulmonary circulation, s When left to right shunts exist at more than one level in the central circulation, the certain demonstration and localization of these defects is possible as shown in figure 4B. INJECTION OF DYE INTO 1RIGIIT AND LEFT PUL~IONAHY ARTERIES. ~ V l l e n a left to right shunt is occurring through either a patent ductus arteriosus or a ventricular septal defect, no significant difference can be demonstrated between dilution curves recorded following injection into the right and leftmain pulmonary arteries. This, in general, holds true for cases of common atrioventricular canal. In atrial septal defect, however, dilution curves recorded from systemic arterial blood following injection into the right and left main pulmonary arteries are usually dissimilar (fig. 5). -~~ Tile right pulmona D, veins enter tile left atrium close to the interatrial communication, while tlle left pulmonary veins enter the left atrium some distance from it. Thus blood returning from the left lung will preferentially enter the left ventricle, while blood returning from the right lung will be preferentially shunted to the right atrium. The dilution curves obtained both from tile systemic artery and from the outflow of the right ventricle (fig. 5B) clearly demonstrate that the greater part of the flow from the right lung is shunted left to right, while a smaller fraction of blood from the left lung is so shunted. Dilution curves from different lobes of the right lung show further differing degrees of left to right shunting. Preferential shunting of blood from a lobe of the left lung exceeding that from the right lung is uncommon in atrial septal defect of the usual type. Equal shunting of the blood from each lung raises the possibility that an interatrial communication of the atrioventricular canal type may be 10resent or that there may be in addition partial anomalous connection of certain veins of the left lung. . ANO3IALOUSPUL.XIONAnYVENOUSCONNECTION.A hemodynamic situation somewhat analogous to that in atrial septal defect is the malformation in which the righ[ pulmonary veins connect anomalously to the right atrium at its junction with the superior vena cava and there is an associated intra-atrial communica-

156

IL j. c. SWAN Injection into: Right pulmonary artery

INJECTION INTO:

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FIa. 5.--Left to right shunts of different magnitude from right and left pulmonary arteries in atrial septal defect. A. Schematic diagram showing the paths taken by indicator following its injection into file right and left pulmonary arteries respectively. The proport_ion of indicator traversing a particular pathway is indicated by tim relative thickness of the arrow-headed lines. B. Indicator-dilution curves rccordcd from the outflow portion of the right ventricle and the right radial artery following injections into tho right and left pulmonary arteries. Note the small initial deflection at the radial artery and a correspondingly larger deflection in the outflow tract of the right ventricle. These deflections represent the fractions of injected material that first enter the left and right ventricles respectively, and are succeeded by deflections at each site which represent the fate of the dye that enters the main pulmonary artery; for injection into left pulmonary artery, the reverse pertains. tion located cepha!ad ill tlle atrial septum and above the region of tlle fossa ovalis2 s Injection of indicator into the right upper lobe and middle lobe ptdmonary arteries, tlle right upper lobe and middle lobe pulmonary veins and the superior vena cava will give dilution curves of similar contour, demonstrating that tile drainage route by way of which blood from tile pulmonary veins reaches the systemic arteries is similar to that o f the superior vena eava. Upon such comparisons the diagnosis of anomalous connection of the pulmonary veins to the superior vena eava may be m a d e with a high degree of confidence. In the same way the similarity of the dilution curve recorded following injection int6 a pulmonary vein with that recorded following injection into the inferior or superior vena eava, or both, indicates that the blood from this vein drains in a manner similar to that of the blood from tile eavae, suggesting an anomalous connection of that pulmonary vein to the inferior vena eava or to the right atrium. Dissimilarity of such curves, with a significantly larger proportion of pulmonary venous b l o o d passing to the left ventricle, suggests that the vein is normally connected to the left atrium.

I N D I C A T O R - D I L U T I O N ~XIETIIODS A N D C O N G E N I T A L I I E A R T DISEASE

ANOXIALOUS VENOUS CONNECTION OF TIIE nlCIIT

LUNG WITtIOUT

157

INTERATBIAL

COMMUNICATION. Such cases are uncommon but illustrate nicely the abnormality of the dilution curve associated with normal and prolonged transit times through tile pulmonary, circulation. In these cases indicator can reach the left atrium and systemic circulation only via the left pulmonary artery. Further, all indicator traversing the left pulmonary artery goes directly to the systemic arterial system. Hence the curve recorded following injection at this site is of normal contour. In contrast, the curve recorded following injection into the right pulmonary artery shows a prolonged appearance time owing to the interval required for indicator to pass through the right hmg and re-enter the right side of the heart and the pulmonary artery, from whence that portion which mixes and passes with blood traversing the left lung proceeds to the systemic sampling site. The curve }ecorded following an injection of indicator into the root of the pulmonary artery or the outflow portion of the right ventricle is usually a synthesis of the curves obtained following injection into the rigllt and left main pulmonary arteries. It is not always possible to manipulate the catheter into the particular pulmonary artery or branch of pulmonary artery into which it is desired to inject indicator. However, a catheter can almost always be made to enter one pulmonary artery and the dihition curve obtained compared with the curve recorded following injection just above or below the pulmonary valve. This comparison will indicate whether or not the drainage of blood from either lung is similar to or differs significantly from that of the other lung. VALVULAR REGURGITATION. Although valvular regurgitation is usually associated with acquired heart disease, not infrequently it exists in congenital heart disease. Insufficiency of tim aortic or mitral valves is sometimes associated with ventricular septal defect. Severe pulmonary hypertension resulting from intracardiae defects may be associated with insufficiency of eitller the pulmonary or the tricuspid valve. The abnormality of function underlying dilution curves characteristic of valvular regurgitation has already been described; the dilution curve has a normal appearance time, is of low amplitude and has a smooth prolonged disappearance phase. The degree of abnormality of such dilution curves depends not only on the magnitude of the valvular regurgitation but also on the Volume of the chamber into which regurgitation is occurring and the degree of mixing of the regurgitated blood with that contained in the upstream chamber, which may be related to the compliance of the chamber. -01 If either the degree of regurgitation or the volume of the 9chambers concerned is small, then clearance of indicator particles will not be delayed and any abnormality of the dilution curve will be minimal. Failure to recognize the importance of the variations in volume and the compliance of the upstream and downstream chambers has reduced the value of attempts -~2 to estimate quantitatively the magnitude of" the regurgitation from the abnormality of the dilution curve. Localization of valvular regurgitation can be attained by application of principles similar to those described for left to right shunts. First, when an injection is made into a chamber or site from which, and downstream to which, no regurgitation occurs, a normal dilution curve will be recorded in the

158

Ii. I. c. SwAN

systemic arterial blood. When tile injection of indicator is made at or upstream to the incompetent valve, an abnormal curve will be recorded. The second method consists in sampling the blood-dye mixture from different s{tes in the right side of tile heart following injection of indicator upstream to the sampling sites. A dilution curve of normal contour is recorded when sampling is carried out from sites in which the flow of blood is unaffected by the regurgitation, for example, from the pulmonary artery in a patient with mitral regurgitation. An abnormal curve will be recorded when sampling is carried out from the chamber into which regurgitation is occurring, or from points downstream from the site of the valvular regurgitation. A third method for the detection of valvular regurgitation consists in the iniection of indicator iust downstream to tile valve suspected of incompetence. The detection of abnormally earlyappearing dye in tile chamber upstream to tile site of injection permits identification of the presence of valvular regurgitation (fig. 6A and B). Inadequate mixing of tile injected material or nonrepresentative sampling of the bloodindicator mixture in the upstream chamber has caused both false positive and false negative identifications of regurgitation in cases of mitral valve disease. "z SPECIALAPPLICATIONSOF INDICATOR-DILUTIONCUI1VES

Special applications are based both on the fundamental contours of dilution curves previously described as characterizing the circulatory abnormalities associated with arteriovenous and veno-arterial shunts and valvular insufficiency, and on the similarity or dissimilarity of dilution curves obtained following injection of indicator or the recording of a dilution curve at Sites especially selected to supply specific information in regard to a particular problem at cardiac catheterization. 1Valttre of a central great vesseL--Occasionally in the presence of complex heart disease it is not possible by the usual criteria to decide whether a vessel entered by a cardiac catheter from tile right ventricle is the pulmonary artery or the aorta, as in single ventricle, ventricular septal defect with transposition of tile great vessels, aorticopulmonary septal defect, or common truncus arteriosus. Iniection of indicator with recording of a dilution curve at a systemic artery may clarify the nature of the vessel into which injection has been made (fig. 7). Should the great vessel be tile aorta or connect directly with the aorta, the dilution curve will be characterized by a short appearance time (1 to 3 seconds) and a large peak deflection. The disappearance phase of such a curve should show a rapid decline to or close to zero concentration. ~qlen a secondary deflection occurs on the disappearance slope it may indicate the presence ~ind magnitude of a circulation from the aorta to the pulmonary vessels by way of either a patent ductus arteriosus, abnormal pulmonary arteries, or bronchial collateral channels. If the vessel is the pulmonary artery, then the dilution curve is characterized by a longer appearance time, a smaller peak concentration and a disappearance phase that reflects any pulmonary recirculation which may be present. Pathwat.l~ of egress from the right ventricle.~In severe forms of cyanotic congenital heart disease in which the catheter may fail to enter a pulmonary artery the differentiation of the tetralogy of Fallot from pulmonary atresia

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Fzc. 6.--Localiz,ation of valvular regurgitation to the tricuspid valve. A. Diagrammatic representation of the circulation in tile presence of incompetence of the tricuspid valve. Note that when indicator is injected into the right ventricle a fraction of it appears instantaneously in file right atrium. (Reproduced from Wood, E. II., Swan, II. J. C., and Marshall, H. W. ~) B. Dilution curves recorded simultaneously at tile radial artery and at position B (right atrium) following injection of dye at point A in the mid portion of the right ventricle. The quantity of indicator detected in the right atrium is partially dependent upon the positions of injecting and sampling catheters, and estimations for the "regurgitant fraction'" are frequently open to error. m a y not be possible. Whether blood leaves tile right ventricle only via the aortic valve or also via a pulmonary artery can be determined b y comparison of dilution curves following injection above the aortic valve and into the right ventricle (fig. 8). If dilution curves recorded following injection into the aorta and into the right ventricle are identical, then a direct p a t h from tile right

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\b Fxc. 7A .~r~D B.--Diffcrentiation of the aorta from the pulmonary artery in tile presence of transposition of the great vessels, by dilution curves recorded at a systemic artery. \Vhen injection was made via the cardiac catheter into a position that was typical for the aorta (B, lower panel), an appearance time of 6 seconds, a reduced deflection and a prolonged disappearance phase to the dilution curve identified this injection as having been made into a pulmonary artery. When injection was made at a site typical for pulmonary artez3' (B, upper panel), a curve characterized by a short appearance time and a tall peak deflection was obtained, identifying this great vessel as the aorta. (Reproduced from \Vood, E. H., Swan, H. J. C., and Helmholz, H. F., Jr.2) ventricle to the p u l m o n a r y vessels p r o b a b l y does not exist (fig. 8A), that is, there is p u l m o n a r y atresia. W h e n the d i s a p p e a r a n c e p h a s e of the curve following injection into the right ventricle shows a s e c o n d a r y deflection t h a t is not o b t a i n e d w h e n d y e is injebted into the aorta, then a direct p a t h f r o m the right ventricle to the p u l m o n a r y vessels has b e e n d e m o n s t r a t e d (fig. 8B). 160

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Fie. 8.--Determination of the presence or absenco of a path of egress from the right ventricle to the lungs other than via the aorta. The example in file left half of the illustration (A) concerns pulmonary atresia in the presence of which contours of indicator-dilution curves obtained following injection at the aortic root and in the chamber of the right ventricle wiU be fundamentally the same. (Reproduced from Wood, E. H., Swan, H. J. C., and Helmholz, H. F., Jr. -~ In the presence, however, of a direct communication with the pulmonary artery (B), the dilution curve recorded following injection at the right ventricle will differ from that obtained following injection into the aorta in having a smaller peak deflection and in being characterized by distortion of the down slope of the curve dne to the passage of some indicator directly from the right ventricle into the pulmonary vessels by way of the main pulmonary artery.

Pathways of egress from the right atrimn.--In a similar manner, comparison of dihltion curves with injection into the left and the right atrium in the presence of an interatrial communication will demonstrate whether one or two pathways exist by which blood may leave the right atrium. If, for example, injection of dye into tile right atrium results in a curve of contour identical to that obtained with injection into the left atrium and left ventricle, no pathway from tile right atrium to tile pulmonary vessels exists other than via the left ventricle and the left atrium, and tricuspid atresia is present. Conditions affecting aortic root association with increased aortic r,noff.-Lesions affecting the aortic root and associated with increased aortic runoff include aortic regurgitation, aortic and mitral regurgitation, ruptured aorticsinus aneurysm to the left ventricle, right ventricle or right atrium, aorticopulmonary communications including patent ductus arteriosus, aberrant coronary arteries and various combinations of these lesions. Such anomalies can present differential diagnostic problems of great complexity. "~ The technics of catheterization of the aorta and the left side of the heart by using different combinations of injection and sampling sites in the great vessels and chambers of the right and left sides of the heart may permit the successful differentiation of these various conditions. Space considerations permit but one example, the demonstration of ventricular septal defect with an associated aortic regurgitation (fig. 9). In this patient, the dilution curve recorded at a systemic arterial sampling site fol-

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]owing injection of tile aortic root showed minimal abnormality. However, tile presence of early-appearing dye which had originated from the aorta was clearly demonstrated and tlle site of its entry localized to the ventricle. When dye was injected into a distal pulmonary artery its abnormally early arrival was detected in the main pulmonary artery and in larger amount than following injection into the aortic root. The dilution curve recorded in the Injection

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INDICATOR-DILUTION~IETtlODS AND CONGENITALIIEARTDISEASE

163

pulmonary artery following iniection into the left ventricle was similar to that following iniection into the distal pulmonary artery. The difference between these curves and that recorded following iniection into the aortic root is strong evidence for the presence of a ventricular septal defect as opposed to a n aneurysm of the sinus of Valsalva which had ruptured into the right ventricle. Such studies may b e required in a small proportion of cases in which accuracy of diagnosis of a high order is necessary, so as to select correctly those in which surgical therapy may result in benefit rather than in disaster. Total anomalolts ptdmonary venous drainage.---This dynamic abnormalit), may be associated with anomalous connection of all the pulmonary veins to the right atrium, or with common atrium. T h e diagnostic feature in this condition is the association of dilution curves of fundamentally similar contour following iniections at any location in the right side of the heart or the pulmonary vessels, of ~vhich those following injection at or upstream to the right atrium have significantly shorter appearance times than those obtained following injection distal to the tricuspid valve. These features reflect the relatively complete mixing attained at the atrial level between pulmonary and systemic venous blood, and since egress to the systemic circulation is only b y way of an atrial septal defect, particles iniected downstream to the tricuspid valve have a longer transit time in their passage to the systemic circulation than do particles injected upstream to this valve. SUhI~IAHY Indicator-dilution curves provide a most useful tool in the study of congenital heart disease during the cardiac catheterization procedure. T h e application of these methods to anatomic diagnosis is b y inference, based upon the different traversal times required by particles to pass from iniection to sampling sites. Accurate localization of the site of right to left shunts and a practically useful quantitation of the magnitude of the shunts can regularly be achieved. Left to right shunts can be successfully detected and quantitated.

Fic. 9.--Aortic regurgitation associated with ventricular septal defect. A. Diagrammatic representation showing the passage of indicator into the left ventricle following its injection at the aortic root. A fraction of the dye entering the left ventricle is shunted left to right into tile right ventricle and puhnonary artery, where its almost immediate appearance can be detected. (Reproduced from Wood, E. H., Swan, H. J. C., and Marshall, H. W. z) B. The dilution curves in the left panel were obtained following injections at the root of the aorta. Note that the detection of early-appearing dye in the pulmonary artery and in the outflow portion of the right ventricle but not in the right atrium permits localization of tile intracardiac shunt to the ventricular level. Since sampling was not carried out from the left ventricle, a ruptured aneurysm of tile sinus of Valsalva is not excluded with certainty on the basis of these curves (see text). Such dilution curves permit the conclusion that a left to right shunt of moderate magnitude exists at ventrlcular level. Comparison of the dilution curves obtained following injection at the root of the aorta and the left ventricle suggests that approximately 30 per cent of the indicator injected at the aortic root mixed completely with the blood in the left ventricle.

164

H.J.c. SWAN

Localization of the site of left to right shunts or of an i n c o m p e t e n t valve m a y be practically m o r e difficult, b u t w h e n d o u b t f u l b y other technics it can uniformly be a c h i e v e d b y these m e t h o d s . T h e m a g n i t u d e s of systemic a n d pulm o n a r y b l o o d flows can be estimated, a As with a n y other technic, limitations exist and errors in interpretation m a y occur. W i t h the a c c u m u l a t i o n of experience, such errors b e c o m e minimal and the limitations are m o r e clearly recognized. W i t h usage also comes recognition of the i m m e n s e a m o u n t of information that is a d d e d to the s t u d y of heart disease b y the intelligent application of indicator-dilution technics. REFERENCES 1. Nicholson, J. W., Ill, Burchell, H. B., and Wood, E. H.: A method for the continuous recording of Evans blue dye curves in arterial blood, and its application to the diagnosis of cardiovascular abnormalities. J.Lab.& Clin. Med. 37:353-364, 1951. 2. Wood, E. tL, Swan, H. J. C., and Helmholz, tL F., Jr.: Symposium on diagnostic applications of indicatordilution technics. Recording and basic patterns of dilution curves: Normal and abnormal. Proe. Staff Meet. Mayo Clin. 32:464..-477, 1957. 3 . - - , - - , and Marshall, H. W.: Technic and diagnostic applications of dilution curves recorded simultaneously from the right side of the heart and from the arterial circulation. Proc. Staff Meet. Mayo Clin. 33:536--553, 1958. 4. Braunwald, E., Tanenbaum, I L L . , and Morrow, A. G.: Localization of. leftto-right cardiac shunts by dye-dilution curves following injection into the left side of the heart and into the aorta. AmJ.Mcd. 24:203--208, 1958. 5. V~rarner, H. R., and Toronto, A. F.: Quantitation of backflow in patients with aortic insufficiency using an indicator technic. Clin.Sc. 6:29-34, 1958. 6. Pritchard, W. It., Maclntyre, W. J., Schmidt, W. C., Brofman, B. L., and Moore, D. J.: The determination of cardiac output by continuous recording system utilizing iodinated ( p a l ) human serum albumin. II. Clinical studies. Circulation 6:57"2-577, 1952. 7. Nylin, G., and Celander, H.: Determination of blood volume in the heart and hmgs and the cardiac output

8.

9.

10.

11.

12.

13.

14.

15.

through injection of radiophosplaorus. Circulation 1:76--83, 1950. Lacy, "~V. W., Ugaz, C., and Newman, E. V.: Tile use of indigo carmine for dye dilution curves. Circulation Research 3:570-574, 1955. Fox, I. J., and Wood, E. It.: Use of methylene blue as an indicator for arterial dilution curves in the study of heart disease. J.Lab.& Clin. Med. 50:598-612, 1957. - - , Brooker, L. G. S., Hcseltine, D. W., Essex, H. E., and V~rood, E. tL: Symposium on diagnostic applications of indicator-dilution technics. A tricarbocyanine dye for continuous recording of dilution curves in whole blood independent of variations in blood oxygen saturation. Proe. Staff Meet., Mayo Clin. 32:478--481, 1957. Wood, E. H.: Oximetry. In Glasser, O., Ed.: Medical Physics Chicago, Year Book Publishers, Inc., 1950, vol. 2., pp. 664-680. Morrow, A. G., Sanders, R. J., and Braunwald, E.: The nitrous oxide test: An improved method for the detection of left-to-right shunts. CirCulation 17:284-291, 1958. Swan, H. J. C., Zapata-Diaz, J., and Wood. E. H.: Dye dilution curves in cyanotic congenital heart disease. Circulation 8:70--81, 1953. Cournand, A., Baldwin, J. S., and tlimlnelstein, A.: Cardiac catheterization in congenital heart disease: A clinical and physiological study in infants and children. New York, Commonwealth Fund, 1949. Swan, IL J. C., and Wood, E. H.: Localization of cardiac defects by dye-dilution curves recorded aftcx injection of "1"-1824 at multiple sites

INDICATOR-DILUTION~IETIIODSAND CONGENITALIIEART DISEASE in file heart and great vessels during cardiac catheterization. Proc. Staff Meet., Mayo Clin. 28:95-100, 1953. 16. Burchell, H. B., Swan, H. J. C., and Wood, E. tI.: Demonstration of differential effects on pulmonary and systemic arterial pressure by variation .in oxygen content of inspired air in patients with patent ductus arteriosus and pulmonary hypertension. Circulation 8:681-694, 1953. 17. Swan, tt. J. C., Burchell, It. B., and \Vood, E. H.: The presence of venoarterial shunts in patients with interatrial connnunications. Circulation 10:705-713, 1954. 1 8 . - - , Kirklin, J. W., Becu, L. M., and \Vood, E. H.: Anomalous connection of right pulmonary veins to superior vena cava with interatrial communications: Hemodynamie data in eight cases. Circulation 16:54-66, 1957. 19. Carter, S. A., Bajec, D. F., Yannicelli, E., and Wood, E. H.: Estimation of leftto-right shunt from arterial dilution cnrves. J.Lab.& Clin.Med. In press. 20. Swan, H. J. C., Hetzel, P. S., Burchell, H. B., and Wood, E. H.: Relative contribution of blood from each hmg to the left-to-right shunt in atrial septal defect: Demonstration by in-

21.

22.

23.

24.

165

dieator-dilution technics. Circulation 14:200-211, 1956. Hoffman, J. I. E., and Rowe, G. G.: Some factors affecting indicator dilution curves in the presence and absence of valvallar incompetence. J. Clin.Invest. 38 (pt. 1): 138--147, 1959. Korner, P. I., and Shillingford, J. P.: The quantitative estimation of valvular incompetence by dye dilution curves. Clin.Sc. 14:553-573, 1955. Woodward, E. Jr., Swan, It. J. C., and Wood, E. tf.: S)anposium on diagnostic applications of indicator-dilution technics. Evaluation of a method for detection of mitral regurgitation from indicator-dilution curves recorded from the left atrium. Proc. Staff Meet. Mayo Clin. 32:525-535, 1957. Swan, H. J. C., Burchell, H. B., Linder, E., Birkhead, N. C., and Wood, E. H.: Technic and diagnostic applications of dilution curves recorded simultaneously from left and right sides of heart and arterial circulations following injections of indicator at selected sites in tile cardiac chambers and great vessels. Proc. Staff Meet. Mayo Clin. 33:581-595, 1958.