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NOREPINEPHRINE INDUCED PULMONARY CONGESTION IN PATIENTS WITH REGURGITATION

Timothy J. Regan, … , Kenan Binak, Harper K. Hellems

J Clin Invest. 1959;38(9):1564-1571. https://doi.org/10.1172/JCI103935.

Research Article

Find the latest version: https://jci.me/103935/pdf NOREPINEPHRINE INDUCED PULMONARY CONGESTION IN PATIENTS WITH AORTIC VALVE REGURGITATION * By TIMOTHY J. REGAN, VALENTINO DEFAZIO, KENAN BINAKt AND HARPER K. HELLEMS (From the Cardiovascular Research Laboratories, Departments of Medicine, Wayne State Uni- versity College of Medicine, and City of Detroit Receiving Hospital, Detroit, Mich.) (Submitted for publication March 3, 1959; accepted May 14, 1959)

The regulation of venous blood flow into the METHODS and the effects of blood volume redistribution All subjects were studied in the fasting state approxi- upon cardiac function have not been amply defined. mately two hours after receiving 0.1 Gm. of pentobarbital While enhanced venomotor tone induced by nor- sodium. A double lumen catheter was used to measure epinephrine has been found to increase the volume pressures simultaneously from the pulmonary "capillary" and pulmonary artery. The "capillary" position was as- of a central reservoir in the dog (1), such a vol- sumed to be present when the catheter could not be ad- ume shift has not been demonstrated in man, ex- vanced farther in the lung bed, the tip did not move with cept inferentially by the finding of a decrease in the cardiac cycle and a compatible pressure pattern was the limb venous volume (2). obtained. A specimen of blood saturated with oxygen This type of alteration might be expected to af- was secured from the wedged catheter tip whenever this particularly was possible. fect cardiopulmonary , After serial oxygen consumptions showed constancy, in a situation where the volume of this central 15 mg. of Evans blue dye was injected into the pulmo- system has already been expanded. Such a state, nary artery and collected at two second intervals in a exclusive of congestive failure, occurs to a notable rotating fraction collector from a Cournand needle in the degree in aortic regurgitation where deficient valve brachial artery. Total collection time was about 50 sec- function fails to limit diastolic volume. Thus, a onds to accommodate the expected prolongation of the dye curve downslope, and was followed by a simultaneous study of the response to norepinephrine in eight recording of the systemic arterial, pulmonary arterial and patients with this clinical state has been contrasted "capillary" pressures with electrically integrated means. with the findings in seven normals. An infusion of norepinephrine, 0.2 ,ug. per Kg. of body weight per minute, was then begun through a polyethyl- ene tube lying in the subclavian vein and continued for 15 PATIENT MATERIAL minutes. The electrocardiogram and pressures from the Eight patients with isolated aortic regurgitation due to pulmonary "capillary," pulmonary artery and brachial , lacking clinical and hemodynamic evi- artery were recorded continuously. At 15 minutes, Evans dence of mitral stenosis, were selected for this study. blue dye was again injected. The effect of venous occlu- All had substantial left ventricular enlargement with the sion upon the norepinephrine response was assessed by point of maximum apical impulse occurring in the sixth repeating the infusion in four patients. Sphygmomanom- interspace, at, or within a few centimeters of, the an- eter cuffs had been applied to three extremities at dias- terior axillary line, while the electrocardiogram showed tolic arterial pressure levels 15 minutes previously and a left pattern in each instance. maintained during the subsequent 15 minute infusion. At the time of study, there were no symptoms or signs Since the assessment of the cardiac responsiveness to of , although three patients had had previ- filling pressure and arterial pressure elevation requires ous manifestations of decompensation and were subse- information on the volume of blood which the contracting quently well controlled on digitalis. Seven subjects were muscle ejects, the quantity partitioned into the forward chosen for control studies. All had normal by and regurgitant flow must be ascertained. While the , X-ray and the electrocardiogram. former is obtained with reasonable accuracy by the Hamilton method, the reliability of current methods for * This investigation was supported by Grant H-1492, estimating regurgitation in man is not established. The National Heart Institute, National Institutes of Health, method most thoroughly scrutinized is that devised by United States Public Health Service; Michigan Heart Korner and Shillingford (3). Association; and by the Receiving Hospital Research The validity of this method of estimating regurgitant Corporation. flow depends upon the thesis that the downslope of the t Research Fellow. Rockefeller Foundation (1958- descending limb of the indicator dilution curve is fixed 1959). for a given cardiac output and central volume. The pres- 1564 NOREPINEPHRINE INDUCED PULMONARY CONGESTION 1565

ence of valvular incompetence produces a decrease in the tion in the interpretation of dilution curves. The cham- gradient of this downslope which is used as a measure of ber size and elasticity factors during the infusion of regurgitant flow. norepinephrine are, in all probability, opposite in direction Minor variations of this gradient have been observed to those associated with the large error alluded to above between normal subjects with the same forward flow and for the following reasons. Epinephrine in the dog has central volume and place a limit on the accuracy of back- been shown with a cinefluorographic technique to increase flow quantification in a given patient (3). However, when the left ventricular diastolic area (10), and a similar sequential testing is performed, this inaccuracy is dimin- change may be inferred for norepinephrine from the rise ished (4, 5). While it is generally agreed that small val- in left ventricular diastolic pressures associated with its vular leaks are not reliably detected by this method (6), use (11). Similar pressure changes occur in man, judged gross leakage, sufficient to be clinically certain, is usu- by left atrial mean pressures (12). Since the distensi- ally detectable (5) and thus, the patients chosen were bility of the is increased by epinephrine (11), those who appeared to have a substantial, isolated, re- such pressure changes would imply a greater diastolic vol- gurgitant lesion of the aortic valve. Moreover, the modi- ume in the left ventricle. fication of this flow in the same model or patient may be The calculation of resistances to forward flow was fairly accurately detected, if sufficiently large, once one done by accepted methods, as was the total left ventricular already has an indicator dilution curve for comparative stroke work, with a correction for the contribution of fill- purposes describing the particular system to be modified ing pressure to the calculated ventricular work (13). (4, 5). Since the slopes of the dye curve may allegedly be Statistical significance was appraised by the Fischer "t' altered by inadequate flow rates to the fraction collector test method (14). (7), it is pertinent to note that the volumes collected in Since none of the patients selected had mitral stenosis, the control state were above this minimal rate. As the use of the pulmonary "capillary" mean pressure as a the collection volumes increased after norepinephrine, measure of the filling pressure of the left ventricle ap- with and without tourniquets, any change in the dye pears justified: first of all by its close correspondence to curve slope would also not be ascribed to this factor. the left atrial mean pressures in man (15); and sec- In addition, the qualitative contour of the curve has been ondly, by a sufficiently close correlation of this latter found not significantly altered despite varied sampling parameter with the end-diastolic pressure of the left ven- volumes obtained through simultaneous determinations tricle to minimize inaccuracy in the interpretation of the from the ear, radial and femoral arteries (8). relation of filling pressure to stroke work (16). Direct The calculation of the reciprocal of the slope predicted measurement of the force of ventricular contraction, show- for a given cardiac output and central volume (Hamilton ing a linear relationship with calculated stroke work dur- method) was derived from the Korner-Shillingford re- ing the changes induced by norepinephrine, justifies the gression equation based on 91 indicator dilution curves: use of this parameter as a measure of contractility (17). log 1/s = 0.8766 - 0.0614 (cardiac output) + 1.129 log vol- Calculation of the transaortic valvular pressure differ- ume. In the absence of valvular insufficiency or shunts, ence throughout was not feasible in the absence, these authors, based on studies in models and patients, in nearly all instances, of a suitable dicrotic notch in the claimed that 1/s is quite predictable. In a modification of brachial arterial curve to indicate the onset of diastole. the original method (6), the observed slope is calcu- Left ventricular pressure curves, not warranted in these lated from the semilogarithmically plotted curve: patients, would constitute the only means of timing the diastolic phase precisely. Thus, we have employed the - = t2 tl end-diastolic systemic arterial pressure in the control 1/s log1c1 -log c2 period and during norepinephrine infusion, comparing them with their respective pulmonary "capillary" pres- where t,, ct and t2, c2 represent the coordinates of two sures, as an indication of the relative change in the trans- points on the straight line downslope. By setting c, and c2 aortic valvular diastolic pressure difference. one logarithmic cycle apart, the denominator is reduced to 1, and the value for the equation is equal to the dura- RESULTS tion of descent of the downslope to one-tenth of a given point along its course. Total cardiac output is then de- Unusual reactions to the infusion of norepi- rived from the product of forward flow and the ratio nephrine were not encountered except for a brief I/s (observed)/l/s (predicted). The difference between episode of sinus in one patient and the the total and forward flows is attributed to regurgitant flow. transient occurrence of ventricular extrasystoles in The most serious objection to this method has been another, both occurring early and disappearing raised by the finding that regurgitation into the narrow some minutes before the injection of Evans blue rigid proximal chamber of an experimental model may dye. fail to distort the indicator dilution curve significantly As detailed in Tables I and II, a tendency for a from that occurring without valvular incompetence (9). Although such gross inaccuracy has not been reported decline in cardiac output and increase in central in man or animal studies, this situation bears considera- volume was noted in both groups, but in an in- 1566 REGAN, DEFAZIO, BINAK AND HELLEMS

TABLE I Hemodynamic response to norepinephrine in seven normal patients

Patient, Left Mean pressures Resistances Age, ventricular Race, Sex, Cardiac Central per stroke Brachial Pulmonary Pulmonary Peripheral Pulmonary B.S.A./M.2 Time output volume mih. work artery artery "capillary" arterial arteriolar min. L./min. L. Gm. M./ mm. Hg dynes-sec.-cm.' beat/M.2 E. S. 0* 5.39 1.54 70 46.1 80 1,187 41, NF 1.57 15 4.67 2.15 60 60.0 100 1,716 M. S. 0 4.35 1.64 80 47.5 103 13 5 1,893 147 38, WF 1.53 15 3.78 1.56 71 55.0 125 29 9 2,645 445 N. S. 0 8.69 1.94 85 62.7 90 15 6 827 83 36, WM 1.88 15 7.45 2.07 72 99.3 146 29 14 1,556 128 J. M. 0 5.67 2.45 71 56.1 90 1,262 41, NM 1.65 15 5.69 2.76 64 105.4 155 2,173 H. N. 0 7.80 1.70 87 55.9 85 15 7 871 82 34, NF 1.68 15 7.82 1.82 87 93.0 142 26 14 1,455 123 J. G. 0 4.34t 65 44.7 84 11 6 1,554 93 25, NM 1.58 15 3.19 48 49.2 97 20 11 2,438 226 S. D. 0 4.76 1.66 73 52.2 95 11 5 1,602 102 31, WM 1.61 15 4.62 1.77 67 94.4 162 15 9 2,802 104 Mean values 0 5.86 1.82 75.9 52.1 89.6 13 6 1,314 101.4 15 5.32t 2.02$ 67 79.4 132.4 24 11 2,112 205.2 p <0.001 <0.001 <0.001 <0.01 <0.01 <0.001 <0.01 * Control period. t Fick cardiac output. t No significant difference from control period. consistent manner. The significant pulmonary "capillary" pressure for the normal encountered in normals was not paralleled in aortic group, was the rise from 8 mm. Hg to 29 mm. Hg insufficiency. That substantial flow leaks oc- in those with aortic regurgitation. The major part curred in the patients with aortic insufficiency is of this change occurred after five minutes of nor- attested by the finding of a mean regurgitation, 61 epinephrine infusion and was usually complete by per cent of the aortic outflow. In the normal 10 minutes. As this increment exceeded that of group, no significant leak was exhibited. The in- the brachial artery diastolic pressure (mean 4 mm. fusion of norepinephrine was attended by a sig- Hg) wherever the regurgitant flow was dimin- nificant reduction of the calculated regurgitation, ished, a decline in the aortic-ventricular diastolic contributing to the finding of a decline in the total pressure difference could account for this flow flow. Since some leak probably occurs across change. The one patient (A. W.) with the small- the in most enlarged left ventricles, est control regurgitant volume exhibited an in- an anticipated accentuation with norepinephrine crease in leak associated with a rise in this pres- would not qualitatively modify the observed find- sure difference. ings (12). Whereas the small increment in the filling pres- In striking contrast to the 5 mm. Hg rise in the sure was associated with a substantial rise in the NOREPINEPHRINE INDUCED PULMONARY CONGESTION 1567

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ItL. H.B. A.". A.W. through left heart catheterization where slight ele- vations of mean atrial pressures in normals, and FIG. 1. EFFECTS OF VENOUS OCCLUSION UPON ACTION OF NOREPINEPHRINE substantial rises in pathologic hearts have been ob- The vertical lines designating pulmonary "capillary" served (21), that are quite comparable to the pressure correspond in time to the flow column immedi- striking increments of pulmonary "capillary" pres- ately above. sure found in this group with aortic regurgitation. Since pulmonary vein constriction would appear left ventricular stroke work for the normals, the eliminated as a major pathogenetic factor, a direct nearly fourfold pressure rise in the presence of myocardial depressant effect or displacement of aortic regurgitation involved no higher left ven- blood from the periphery remain as potential tricular performance level. In an effort to deter- mechanisms. Several sources of evidence would mine whether the response of the pathologic heart indicate the latter as most probable. could be attributed to volume displacement from Such a volume shift has been observed in the the periphery, tourniquets were applied to the ex- dog after norepinephrine with an increase in di- tremities of four patients. In these circumstances, rectly measured venous return (15) and in the as detailed in Table II and Figure 1, the 5 mm. volume of a reservoir placed distal to the left Hg mean rise in the pulmonary "capillary" pres- auricle (1). The. cardiopulmonary location of sure after norepinephrine corresponded to the this blood has been further evidenced by increased finding in normals, as did the substantial increment Hamilton central volumes and left ventricular end- in the left ventricular stroke work. Thus, hydro- diastolic pressure (11). That a translocation of static pressure levels usually associated with pul- blood from the periphery is involved in this process monary edema were effectively prevented by re- would appear to be the case, since limb volumes stricting the redistributive ability of the venous measured plethysmographically indicate a decline system. The increase in the aortic-ventricular (2, 22). diastolic pressure gradient was associated with From the foregoing data one would have ex- restoration of regurgitant volumes to control or pected to find an increase in the calculated cen- higher values, confirming the known relationship tral volume. The magnitude of the change ob- of transvalvular diastolic pressure difference to served does not itself confirm a significant central regurgitant flow ( 18). shift of blood. However, the technique of meas- Although the calculated vascular resistances urement here used does not provide absolute quan- clearly became elevated in both the total peripheral tification since it fails to account for volumes of arterial and pulmonary arteriolar beds in the blood not displaced by the flow process (23). normal, a change in the latter parameter failed to A similar disparity has been found in patients occur in the valvular insufficiency group after nor- with mitral stenosis where no significant increase epinephrine. In a more direct experimental ap- in calculated pulmonary blood volume occurred NOREPINEPHRINE INDUCED PULMONARY CONGESTION1561569 in spite of high pulmonary vascular pressures output would, of necessity, be disproportionately (24). Moreover, the presence of a methodical increased for a suitable cardiac response to oc- error of 15 per cent (25) would indicate that a cur at these filling pressure levels (16, 29), it is shift of 400 ml. may escape detection. A rapid difficult to gainsay the conclusion that myocardial increment of this size, in the presence of an already performance has been compromised. This repre- expanded volume, may affect the pressure-volume sents a relatively severe depression of the ven- relationship of the left and pulmonary tricular function curve, as it is usually shifted to artery sufficiently to give pulmonary pressures of a higher level by virtue of the direct myocardial the order observed, since the shape of the curve activity of most sympathomimetics (31). describing this relationship is such that the pres- While this study illustrates an inappropriate sure rise exceeds volume increments above an ill- translocation of blood in the presence of a defec- defined limit (26). It may also be noted that tive, though compensated myocardium, this ac- others have failed to find a significant volume in- tivity may actually contribute to the effectiveness crement after epinephrine in humans at dosage of norepinephrine in states (32). Con- levels inducing a rise in cardiac output (27), de- versely, the peripheral venoconstriction present spite the fact that this cardiac effect is largely de- in low output heart failure (33) would tend to pendent upon greater venous return (28). Fur- aggravate pulmonary congestion unless moderated ther, the fact that the striking changes in pul- bv methods of reducing venous return. monary "capillary" pressure were prevented by trapping blood volume in the extremities would SUMMARY support the thesis that the pressure rise after norepinephrine was due to volume displacement, To assess the pluripotential effects of norepi- despite the failure to find significant expansion of nephrine on the cardiovascular system of man, the the calculated central volume. response in the normal has been contrasted with As the directional change of the total output and that occurring in eight compensated patients with work of the heart with an incompetent aortic valve aortic valve regurgitation. Indicator dilution showed a decline in the face of elevated filling curves were obtained before and during the norepi- pressures, these findings correspond to those oc- nephrine infusion (0.2 Ag. per Kg. per minute) curring in low output heart failure (29). The in- to evaluate the cardiac output, regurgitant flow ability of this dilated, hypertrophied myocardium and central volume. Intravascular pressures from to respond normally to the effects of norepineph- the pulmonary "capillary," pulmonary artery and rine with an increase in stroke work may be at- brachial artery were recorded during the pro- tributable in part, at least, to the dual demands im- cedure. posed by an increased inflow load and outflow re- A disparity of response between the two groups sistance. Interference with the venous return was most manifest in the pulmonary "capillary" modifies this situation sufficiently to enable a con- and artery pressure alterations, a nearly fourfold tractility response indistinguishable from that oc- rise to pulmonary congestion levels in the aortic curring in the normal, presumably by avoiding ex- regurgitation group contrasted with a 5 mm. Hg cessive distention of the ventricle. This further mean rise occurring in the normal. Whereas verifies the similarity of this state of norepineph- this small increment of left ventricular filling pres- rine induced pulmonary congestion to low output sure was associated with a sizable stroke work in- heart failure where an enhanced performance of crease in the normal, no significant change in the myocardium also follows venous occlusion contractility was found in the aortic regurgitant (30). Whether interference with outflow resistance group, despite markedly elevated filling pressures. alone would similarly affect the cardiac response is Bradycardia and increased pulmonary arteriolar problematic. resistance, present in the normals, were also absent In evaluating the response of the cardiac output in this group. in this experimental situation, the major source of A consideration of the pathogenetic factors con- error resides in the estimation of the regurgitant tributing to this situation suggested that displace- volume. Since this segment of the total cardiac ment of blood from the peripheral venous system 1570 REGAN, DEFAZIO, BINAK AND HELLEMS was the predominant, if not sole, mechanism in the 9. Hoffman, J. I. E., and Rowe, G. G. Some factors induction of pulmonary congestion and diminished affecting indicator dilution curves in the presence left ventricular performance in this circumstance. and absence of valvular incompetence. J. clin. Invest. 1959, 38, 138. This interpretation received indirect support from 10. Rushmer, R. F., and Thal, N. Factors influencing data acquired in four patients during peripheral : A cinefluorographic study of angio- venous occlusion by tourniquet. Here, the pul- cardiography. Amer. J. Physiol. 1952, 163, 509. monary "capillary" pressure increment and the 11. Shadle, 0. W., Moore, J. C., and Billig, D. M. stroke work response after norepinephrine were of Effect of I-Arterenol infusion on "central blood vol- ume" in the dog. Circulat. Res. 1955, 3, 385. the same order exhibited in the normal. 12. Braunwald, E., Welch, G. H., Jr., and Morrow, A. G. A relationship of regurgitation to the aortic- The effects of acutely increased systemic resistance ventricular diastolic pressure difference is inferred on the left atrial pressure pulse: A method for from the observation that whenever the pulmonary the clinical detection of mitral insufficiency. J. ''capillary" pressure rise exceeded the systemic clin. 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