The myth of mixing

Annotations

The myth

of mixing

Since early in the use of indicator-dilution curves for diagnostic and experimental purposes, the myth has recurred that an indicator injected into a chamber is instantaneously mixed with all the contents of that chamber. I am sure that no individual with experience in mixing anything, from a school girl baking her first cake to the mathematician with his complicated equations concerning dispersion of indicator particles, believes that instantaneous mixing of two substances is ever achieved. .\nd yet papers continue to appear in reputable medical journals in which this assumption has been made, and elaborate superstructures have been built upon it. It would seem that some useful purpose might be served by evaluating a bit of the evidence against instantaneous mixing within the cardiovascular s)-stem, in the hope that it will do something to deter future flight of fantasy based on such an unlikely assumption. Since the early days of experimental embryology in sheep’ and selective angiography in human fetuses derived from therapeutic abortion,* it has been known that in the fetal circulation a stream of blood or contrast substance passes from the inferior vena ca\-a across the right atrium and through the forameu ovale, whereas another stream of blood from the superior vena cava, deflected by the tubercle of Lower, passes anteriorly into the right ventricle. .L\lthough there is discussion as to how pure these remain in transit, the basic concept has “streams” been widely accepted for many years. Any individual with expedience in cardiac catheterization samples at multiple sites in the right atrium, since he knows that, if a specimen is collected in prosimity to the ccxonarv sinus, its oxygen saturation is low; if a sample ‘ls aspirated from the stream of oxygenated blood which passes up the inferior vena cava from the kidney, the oxygen saturation is high; and if the stream of blood passing from the liver to the right atrium is sampled, the oxygen saturation is intermediate. Furthermore, in subjects with atrial septal defect, specimens collected from the right lateral atria1 xall are frequently relatively desaturated, whereas those collected immediately by the defect or near the tricuspid valve may be ver) high in oxygen saturation. Indeed, in some subjects with atrial septal defect, osimetric determinations in the right atrium as compared to those in the right ventricle may mislead one into the aasumption that the orifice between the right and left sides of the heart exists between the ventricles, since the miring in the atrium is so poor that the

425

oxygenated stream is not adequately sampled, eyen in multiple specimens of blood. Another line of evidence which bears on mixing in the atrium is that obtained from indicator-dilution curves. It ib established that, in the presence of an atrial septal defect, injection of indicator into the inferior \-en:, cava may show a right-to-left shunt, whereas illjection into the superior vena cava does not. Or in some subjects the pattern may be reversed, with a right-to-left shunt appearing when injection is made into the superior vena cava, and none when the injection is made into the inferior vena IX\‘~~. The small localized jet of minor tricuspid insufficiency is known to all who have placed their fingel close to the atria1 side of an incompetent tricuspid valve. By means of cineangiocardiography aftthr injection of contrast substance into the right atrium, the contrast substance may be seen to swirl about in the atrium, forming streams of greater and lesscl density but seldom if ever becoming evenly dispersed throughout. It is conceded that one ma!’ argue that foreign substances such as contrast medi,t do not mix readily; however, such highly diffusable substances as dissolved indocyanine green and the readily dispersible red blood cells supply needed evidence that the visual image obtained from tineangiocardiograms is reasonably accurate. The right atrium is no unusual chamber with respect to mixing, and similar examples ma)- be marshalled for the right ventricle. Immediately there comes to mind the differences in oxygen saturation in various portions of the right ventricle. One may be able to determine whether a small ventrirular septal defect is low in the muscular portion of the septum or high in its membranous part by the fact that the oxygen saturntion in one area of the x-entricle is consistently different from that in another area. Further information concerning inadequate mixing in the right ventricle is supplied in subjects with a tetralogy of Fallot in whom indicator substance injected into different parts of the ventricle may pass almost exclusively into either the pulmonary artery or the aorta. Indeed, it has recently been recommended that indicatordilution curves be used as a guide for injection of contrast substancc8 depending on whether one is more anxious to see the ventricular septal defect and the aortic root, or the outflow tract of the right \-entricle and the pulmonary arter!-. Similar o&r\-ations may be documented in the pulmonary artery. The jet of highly oxygenated blood coming through a small patent ductus arteri-

426

Annotations

osus may be utilized as a guide for passing the ~‘ardisc catheter through the ductus. Furthermore, in angiocardiograms of high quality the “washout at the Junction of the main and left pulmoarea” nary arteries may be diagnostic, since a jet of unopa&ed blood passes through the patent ductus into the pulmonary artery, diluting the contrast media at its point of entry. Similarly, one may recall \.ivid angiographic pictures of a localized jet through the stenotic pulmonic x,alve and of the considerable swirling of light and dark in the dilated proximal portion of the pulmonary artery. Those who have had occasion to observe a dilated, thill-walled, pulmonary artery during thoracotomy in a subject with a large shunt may recall observing blood flon through the wall of the vessel, where waves of OS!-genated and unoxygenated blood form phantasmagoric patterns of light and dark. Data concerning the left side of the heart are also available. Indeed, it is widely accepted that in the presence of an interatrial septal defect of the ostium secundum variety an indicator-dilution cur\-e recorded peripherally after injection of indicator into the right pulmonary artery should show a larger left-to-right shunt than a similar curve after injection into the left pulmonary artery. This is because there is not complete mixing in the left atrium, and the right pulmonary veins, attached closest to the site of the interatrial communication, frequent11 deliver more of their contents into the atream which passes into the right atrium than do the left pulmonary veins.’ Hou-ever, there are well-documented illstances in which, for no ob\-ious reason, indicator injected into the left pulmonary artery appears to recirculate more thau that injected into the right pulmonary artery. I%o other explanation is available, at present, than that some peculiar stream in the left atrium cxries blood from the left pulmonary veins through the atrium and across the septal defect, whereas blood from the right pulmonary veins passes down into the left ventricle and out to the systemic circuit. Furthermore, in the presence of an atria1 septal defect, indicator-dilution cur\-e:: recorded after injection into the left atrium ma? show no indication of a left-to-right shunt, since all of the dye may be caught in the stream of blood which passes directly through the mitral valve and is carried into the left ventricle. SimilnrlJ-, in the presence of mitral insufficiency, when contrast substance is injected into the left x-entricle, one ma! obserx-e a thin jet of dense contrast substance squirting back through the valve. Depending upon its size and the force with which it is regurgitated, the jet may spread in a mushroom-shaped cloud of ever-decreasing density throughout the left atrium, or it may be carried essentially undiluted through the left atria1 cavity and impinge on the posterior wall of the cavity, becoming disseminated at that point. The taking of samples at multiple points in the left atrium has established that in mitral insufficiency such streams also occur when indicator substance is injected into the left ventrick Similar information may he found concerning the left ventricle. Thus, it has been demonstrated that saline solution injected into the left ventricle and sampled at different sites indicates incomplete mising.F Results of similar tests for completeness

of left ventricular mixing after injection into the left atrium indicated that mixing was incomplete even under these circumstances.6 In subjects with tetralogy of Fallot, when cineangiocardiography is done wiLh injection into the right ventricle, it is almost routine to see contrast substance pass over the cephalic brim of the ventricular septum through the ventricular septal defect and into the outBol\ tract of the left ventricle. \Vhen left ventric~~lar systole occurs, this mass of contrast substance is carried out into the aorta. Depending upon the site of injection, the volume of the right-to-left shunt, and the size of the interventricular septal defect, the mass of contrast substance which crosses the septum may or may not pass far enough down into the left \.eutrirle to outline the septum completely. In some cases, one may see the entire septum, 1x11 in others, only its upper portion, since there is suc.h incomplete mixing in the left ventricle that onI\ the outflow tract is x%ualized. Similar]!-, when contrast substance is injected above the aortic ~nlve in the presence of aortic insufficiency, one may see only a slight wisp of regurgitation into the outflow tract of the left ventricle, or, in other cases, a large mass may pass through the aortic x-all~ and down to the apex of the left ventricle. U’ith injections of contrast material into the left ventricle itself it is frequently possible to see the negative shadow of a mass of blood pass through the mitral x-alvc and out of the aorta without e\-er mixing adequately with the intraventriculnr contrast suhstance. This observation has been used as an csplanation for the failure of an indicator-dilution curve recorded from the aortic root to show RI) ex’cn systolic plateau.’ One might add that the plateau on an indicator-dilution curve obtained by sampling at the root of the aorta or pulmonary artery, if diastolic, may well be construed as the result of the fact that during diastole there is essentially no flow in this region. If the system is stable, the immediate result of no flow should be that thr snmc c.oncentration of indicator is measured until more flolv occurs, i.e., with the nest s!,stole. If a good plateau occurred during svstole, one might well have evidence that mixing ;s good in the left ~-entricle, but this is not what has been demonstratctl.~ Indeed, if systolc and diastolc were indicated. OIE might well use some of the curves which have been used to calculate end-systolic and end-dinstolic~ x-olume in the ventricle, to sholv: either (a) that there is not complete mixing in the left ventricle, mtl, hence, there is considerable variation in the concentration of indicator passing the sampling site during systole; or (h) that the system used for recording the indicator-dilution curve is not sufficiently good to reveal a plateau which may exist during sq-stole, anti, hence, is inadequate to IW of value in sol\-inp the problem. It would seem to this observer that the time has come to face the fact that instantaneous, or complete, mixing is a myth. It does not seem that further progress cm be made hy more complicated analyses of indicator-dilution curves based on this myth. For those who are inclined to use information derived from indicator-dilution studies in a reasonable fashion, such an unreasonable basic assumption is not required, a1~1 the endi of truth and science

\\oultl seem to be served better by the ready admissioir that instantaneous mixing is never achieved, ;~ncl that under the worst circumstances there is \-IT>. poor mixing indeed. George G. Rowle, M.D. Department of Medicim 1 ~~~iw~sity of Il’isconsin Medical School ,Ifadison , Wis . REFERENCES 1. Barclay, A. E., Franklin, K. J., and Prichard, n1. M.: The foetal circulation, Springfield, Ill., 19-15, Charles C Thomas, Publisher. .! . Lind, J., and Wcgelius, C.: -Atria1 septal defects in children, an angiographic stud>,, Circulation 7:819, 1953. .i .lmorim, D. S., Weidman, b$T:. H., and Wood, E. H.: L-se of indicator-dilution curves for selection of site for injection of contrast medium

Role of the

for selective angiocardiography, I’roc. Staff Meet. Mayo Clin. 35:756, 1960. -I. Silver, A. Li:., Krklin, J. \V., and Wood, E. H.: Demonstration of preferential flow of blood from inferior vena cava and from right pulmonary veins through experimental atria1 septal defects in dogs, Circulation lies. 4:413, 1956. .5 Woodward, E., Jr., Swan, H. J. C., and Wood, E. H.: Evaluation of a method for detection of mitral regurgitation from indicator-dilution curves recorded from the left atrium, I’roc. Staff Meet. Mayo Clin. 32:525, 1957. 6. Irisawn, H., \Vilson, RI. F., and Rushmer, Ii. F.: Left ventricle as a mixing chamber, Circulation lies 8:183, 1960. 7. Swan, H. J. C., and Beck, \\..: \‘entricular non-mixing as a source of error in the estimation of ventricular volume by the indicatordilution technic, Circulation Res. 8:989, 1960.

pericardium

in the application

of the Starling

to unanesthetized

animals

Renewed interest in regard to the validity of the Frank-Starling mechanism in the intact healthy heart was stimulated chiefly by the challenging observations of Rushmer. Lising an elegant technique of continuously recording various parameters of ventricular performance in unanesthetized dogs, Rushmer noted that during muscular exercise or intravenous infusions of blood there was either no change or very slight increase in end-diastolic diameter (assumed to be closely related to volume) of the left ventricle.‘,* Furthermore, the classic concept that stroke volume increases appreciably ditring muscular activity was not confirmed either in unanesthetized dogs or in man with the use of more reliable methods of determining cardiac output.3-6 Some investigator@ have confirmed the latter observation, whereas others’ have failed to do so. The reasons for this discrepancy are still obscure. In explaining his findings, Rushmer has emphasiLed the important role of neural and hormonal influences on the performance of the intact heart in masking or obscuring the Starling mechanism, but the possible contribution of the pericardium has not received adequate attention. In the excellent textbook of Rushmer* there is practically no discussion of the functional significance of the pericardium. Also, during the 1955 Symposium on the Regulation of the Performance of the Heart,g the role of the pericardium in affecting the diastolic volume of the intact heart has been somewhat overlooked. Katz9 has listed four basic factors that determine the end-diastolic blood volume of the ventricles. To those might be added another factor

mechanism

for the intact heart, namely, the capacity and distensibility of the pericardium. Most of the studies on the Starling mechanism were carried out on isolated hearts in which the pericardium had been cut open, giving full freedom for the ventricles to distend. However, Sarnoff,Q~lo realizing the importance of this structure, demonstrated the “Starling curve” in open-chest dogs before and after opening the pericardium. Although considerable work has been done on the function of the pericardium in limiting acute distention of the heart,“-16 this role has not been given sufficient attention in connection with the observations of Rushmer in the unanesthetized animal. In 1925, Beck’2 studied the size of the heart in pericardiectomized dogs before and immediately after strenuous exercise. However, no observations were made during exercise, and since postural changes profoundly alter diastolic dimensions of the heart,? it is difficult to draw conclusions from such experiments. In view of all this, it would be important to have data on ventricular performance, obtained by refined methods such as those of Rushmer, in unanesthetized animals from which the pericardium has been removed. Such studies may shed more light on our understanding of the differences between the responses of the isolated and the intact normal ventricles to various forms of physiologic stress. Henry S. Badeev, M.D. School of Medicine America?t Unioersity of Brirlct Beirut, Lebanon