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Circulation Research APRIL VOL. XXIV 1969 NO. 4 An Official Journal of the American Heart Association Factors Affecting Shunting in Experimental Atrial Septal Defects in Dogs By John E. Douglas, M.D., Judith C. Rembert, B.S., Will C. Sealy, M.D., and Joseph C. Greenfield, Jr., M.D. Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 ABSTRACT Pulmonary and aortic blood flows were measured with electromagnetic flowmeters in ten unanesthetized dogs with chronic atrial septal defects. The calculated ratio of pulmonary to systemic flow reflects net bidirectional shunting. Data were obtained during alterations in rate produced by both atrial and ventricular pacing and during changes in vascular resistance produced by drug administration. Results indicate that control ratio of pulmonary to systemic flow depends on the size of the defect. Pacing either atrium at rates between 210 and 240 beats/min invariably produced both a sustained augmentation of pulmonary flow and a diminished aortic flow. Ventricular pacing had a similar qualitative response. Angiotensin, methoxamine, and phenylephrine depressed aortic and augmented pulmonary flow. Nitroglycerin, histamine, and isoproterenol reduced the ratio of pulmonary to systemic flow. These data indicate that the degree of shunting is dynamic in nature. Increasing heart rate and consequent shortening of diastole appears to impair filling of the left ventricle more than that of the right and results in an increased left-to-right shunt. Drugs which elevate peripheral vascular resistance increase the ratio of pulmonary to systemic flow. Conversely, lowering the systemic resistance decreases the ratio. ADDITIONAL KEY WORDS pulmonary blood flow electromagnetic flowmeter tachycardia systemic blood flow angiotensin phenylephrine methoxamine nitroglycerin histamine isoproterenol cardiac pacing • In clinical practice the volume of blood that is shunted from left to right across an atrial septal defect is commonly estimated either by the direct Fick method or by indicator-dilution techniques. In the application of these methods it is assumed that a From the Departments of Medicine and Surgery, Duke University Medical Center, and the Department of Medicine, Durham Veterans Administration Hospital, Durham, North Carolina 27705. This study was supported in part by U. S. Public Health Service Grant HE-09711 from the National Heart Institute and a grant from the North Carolina Heart Association. Dr. Douglas was a Postdoctoral Fellow of the U. S. Public Health Service (no. HE23,257-02.) Dr. Greenfield is the recipient of a Career Circulation Research, Vol. XXIV, April 1969 relatively steady state or constant flow exists. In addition, repeated determinations of the shunt flow by these techniques are subject to a moderate margin of error. Thus studies of the effects of various acute procedures on the shunt flow in atrial septal defects in man have been limited. Several observations suggest that the amount of shunting is not in a static Development Award from the U. S. Public Health Service (no. 1-K3-HE,28,112.) The work was presented at the Southern Society for Clinical Investigation, New Orleans, Louisiana, January 27, 1968. Received July 15, 1968. Accepted for publication February 11, 1969. 493 494 Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 equilibrium. There is clinical evidence that changes in both heart rate and rhythm may alter shunt flow in patients with atrial septal defects (1-3). Respiratory maneuvers, exercise, and changes in vascular resistance also have been shown to alter the shunt hemodynamics (4-6). The limitations imposed by the methods for measuring shunt flow in man have stimulated the study of experimental atrial septal defects in animals where pulmonary and systemic flow can be measured continuously (7). However, previous work has been largely confined to acute preparations in which the effects of surgery and anesthesia were unavoidable (7, 8). This report describes the effects on pulmonary and systemic blood flow produced by changes in heart rate, changes in vascular resistance, and administration of isoproterenol in awake dogs with surgically produced, chronic atrial septal defects of varying sizes. Method Following the induction of anesthesia with pentobarbital, 30 mg/kg, a right transverse thoracotomy was performed in a group of mongrel male dogs weighing 14 to 25 kg. During occlusion of venous inflow to the heart, an atrial septal defect was made through a right atriotomy by excising a circular segment of the membranous interatrial septum 0.5 to 1.5 cm in diameter. The atriotomy was repaired, and a pacing electrode was implanted in the right atrium. The chest was closed, and the dogs were allowed to convalesce for 6 to 8 weeks. At this time they were subjected to a left thoracotomy employing similar anesthetic techniques. The roots of the aorta and pulmonary artery were dissected free. Statham electromagnetic flowmeter Q-type transducers were placed around the aorta and pulmonary artery, particular caution being taken to avoid constriction or torsion of either vessel. A strip of silastic sponge was secured proximal to each transducer to serve as a cushion and to retard erosion of the vessel. Pacing electrodes were sewn to both the left atrial appendage and to the right ventricle near the interventricular sulcus. The three pacing electrode wires and the leads of the electromagnetic flowmeter transducers were brought under the skin and exteriorized. The chest was closed, and the animal was allowed to recuperate for 4 to 6 days. During this period the transducers adhered to the vessel wall, thus restricting movement of the electrodes. This aids in maintaining a constant flow baseline and in minimizing the DOUGLAS, REMBERT, SEALY, GREENFIELD ECG artifact. The dogs were given 10 to 20 mg of morphine sulfate intravenously. Using lidocaine hydrochloride as a local anesthetic, a femoral artery and vein were exposed. Lehman catheters were inserted via these vessels into the right atrium, right ventricle, and the thoracic aorta. During the study the dogs were awake, recumbent, breathing spontaneously, and only minimally restrained. Intravascular pressures were measured with Statham no. P23Db transducers. A standard ECG (usually lead II) was obtained. All recording of data was carried out on a Sanborn Model 850 eight-channel, direct-writing oscillograph. Both mean and pulsatile blood flows were recorded from the aorta and pulmonary artery using a Statham Model M-4000 multichannel electromagnetic flowmeter. Zero flow was assumed to be present at the end of diastole. During the course of study nine different electromagnetic flowmeter transducers were used. These were calibrated in vitro in multiple occasions by passing measured flows of normal saline through them in a known period of time (9). The calibration factor for the flow transducers, i.e., flow per unit electromagnetic flowmeter signal, remained within a standard deviation of ± 7.0% throughout the study. The flowmeter calibration was found to be linear (±2.0%) over the range of flows encountered in this study. Since this study was designed primarily to assess the changes in shunting produced by various procedures, the absolute accuracy of the flowmeter calibration is not as critical as the linearity. Although comparison of the control values of flow in the pulmonary artery with that in the aorta may be subject to a moderate error, the changes following each procedure should be accurately recorded. During the control period, blood samples were obtained from the aorta for determination of the oxygen content by a modification of the technique described by Hickam and Frayser (10). Although not all measurements were made in every dog, the general protocol was as follows: At the beginning of the study, control pressure-flow data were recorded for approximately 30 minutes. Before each procedure the blood flows and pressures were allowed to return to or near the control state. Data were recorded continually before and during each experimental state. Electrical pacing of both atria and the ventricle was accomplished using the implanted electrodes and two Grass Instruments Model S-4-B stimulators and isolation units. The pacing rates were increased in increments of 30 beats/min from an initial rate of 120 beats/min to 300 beats/min. Each pacing rate was maintained for 5 minutes, unless the animal's mean systemic blood pressure remained below 60 mm Hg. At the higher atrial Circulation Research, Vol. XXIV, April 1969 SHUNT FLOW IN ATRIAL SEPTAL DEFECTS 495 TABLE 1 Control Data Diam. of O: Dog (mm) ASD sat. (%) Heart rate (beats/min) 1 2 3 4 5 6 7 8 9 10 0 2 6 6 8 10 12 12 13 15 93 94 96 92 95 90 84 94 92 94 105 100 120 105 120 135 145 140 120 145 Ao BP syst./diast. (mm Hg) RV B P syst. (mmsyst. H g ) Aortic blood flow range (ml/min) 150/100 145/70 155/80 140/70 135/85 160/80 130/70 120/85 140/80 120/75 50 50 60 75 70 75 50 60 50 50 1930-2170 2240-2480 1080-1370 2240-2640 2260-2600 1500-2150 2550-2780 1460-1840 800-900 1960-3040 Pulmonary blood flow range (ml/min) 1800-2100 1980-2500 1050-1600 2300-2750 2120-2580 1600-2100 3500-3850 2300-2750 1700-2100 2600-4000 Maximum change shunt Range of flow P/S ratio (ml/min) 0.9-1.0 0.9-1.0 0.9-1.2 0.9-1.1 0.9-1.1 1.0-1.3 1.4-1.6 1.5-1.8 2.0-2.3 1.1-1.5 50 95 370 340 300 500 440 390 335 500 Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 ASD = atrial septal effect; Ao BP = aortic blood pressure; RV = right ventricle; P/S ratio = ratio of pulmonary to systemic flow. The last column tabulates the maximum change inflowacross the defect in each dog during the initial control period. pacing rates, variable atrioventricular (A-V) block frequently occurred. To evaluate the effects of an irregular ventricular rate on shunt dynamics, data were recorded also during a period of AV block. Several animals were given 1.0 mg of atropine sulfate when A-V block persisted at rapid pacing rates, and the atrial pacing was then repeated. To alter the hemodynamic relationships of the vascular system, the following drugs were given sequentially either as an infusion or as a single bolus: angiotensin amide, 2.0 ^g/min; methoxamine, 1.0 mg; phenylephrine, 0.5 mg; histamine phosphate, 27.5 fig; nitroglycerin, 0.2 mg; and isoproterenol hydrochloride, 2.0 fj.g. Following completion of each study, the dogs were killed with pentobarbital. Autopsies were performed, and the hearts were examined to check the placements of the pacing electrodes and flow transducers. The atria were opened, and the septal defect was measured and photographed. The ventricular septum was examined for possible congenital defects. The following data were either measured directly from the recording or computed: systolic, diastolic, and mean aortic pressure; mean pulmonary and aortic blood flow; right ventricular systolic pressure; and heart rate. The ratio of mean pulmonary blood flow to mean aortic flow was calculated. The net shunt flow was calculated as pulmonary flow minus aortic flow. Changes in shunt flow were determined by comparing the value of shunt flow during the procedure with that of the control period immediately preceding it. During the initial 30-minute control period before any procedure, the maximum change in the shunt was tabulated. Following each procedure pressure-flow data were analyzed during periods where a "steady state" was present for at least a Circulation Research, Vol. XXIV, April 1969 30-second period. If this condition was not achieved, data were used from the period of maximum change in the shunt. Standard statistical analysis of the data was carried out on an IBM Model 1130 digital computer. Results Hemodynamic data recorded during the initial control period are given in Table 1. The oxygen saturation data indicate that all the dogs except no. 7 were reasonably well saturated while breathing room air. This would tend to exclude the presence of a large right-to-left shunt, but certainly some degree of right-to-left shunt could have been present. These data will yield only the total magnitude of the shunt. In general, the net left-to-right shunt was roughly proportional to the size of the atrial septal defect. There was considerable variation in the pulmonary and systemic flow among the dogs from moment to moment during the initial control period. The data in column 10, Table 1, reflects the variability of the shunt flow for each dog. For example, in dog no. 6 there were periods when there was no shunt detectable, although at other times pulmonary flow was 25% greater than aortic flow. Data recorded during atrial and ventricular pacing are listed in Table 2. The control rates are essentially the same as those given in Table 1. Pacing from either the left or the 496 DOUGLAS, REMBERT, SEALY, GREENFIELD TABLE 2 Atrial and Ventricular Pacing Dog 2 3 5 6 8 9 Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 10 1 2 3 5 6 8 9 10 1 3 5 6 8 9 10 3 5 6 8 Pacing site V A V V A V A V A V A A V A V V A V A V A V A V A V A V V A V A V A V A V A V A V A V Mean aortic BP (mm Hg) 180 89 105 118 108 111 83 97 82 106 101 94 210 120 98 109 109 110 120 81 106 88 112 104 90 84 240 118 110 108 113 102 116 86 84 90 111 120 88 114 270 98 102 91 86 78 80 Mean pulmonary flow (ml/min) Beats/min 2280 1710 1270 2470 2200 1680 2770 2480 2380 1860 3980 Beats/min 2010 2260 1490 1430 2310 2390 2100 2850 2660 2510 1930 4070 2250 Beats/min 1940 1590 1530 1340 2500 2260 1870 2700 2770 2560 1930 3530 2350 Beats/min 1640 2500 2260 1960 2310 2480 Mean systemic flow (ml/min) P/S ratio 2470 1670 1150 2870 1660 1261 1990 1350 1000 760 3040 0.9 1.0 1.1 0.9 1.3 1.3 1.4 1.8 2.4 2.4 1.3 2010 2440 1310 1310 2700 1690 1230 1860 1530 1010 750 1800 1680 1.0 0.9 1.1 1.1 0.9 1.4 1.7 1.5 1.7 2.5 2.6 2.3 1.3 2010 1670 1420 1130 1940 1150 1380 1290 1530 1010 550 1680 1630 1.0 1.0 1.1 1.2 1.3 2.0 1.4 2.1 1.8 2.5 3.5 2.1 1.4 1980 1720 1030 1370 1170 1100 1.7 1.4 2.2 1.4 2.0 2.2 Circulation Research, Vol. XXIV, April 1969 SHUNT FLOW IN ATRIAL SEPTAL DEFECTS 497 TABLE 2 (cont.) Dog Mean aortic BP (mm Hg) Pacing site 9 A V 3 5 8 10 A V V A Mean pulmonary flow (ml/min) 3340 126 1670 94 300 Beats/min 1610 91 1830 56 2220 72 2100 45 Mean systemic flow (ml/min) P/S ratio 1200 400 2.8 4.2 690 1140 830 580 2.3 1.6 2.7 3.6 Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 Data obtained during atrial (A) and ventricular (V) pacing. P/S ratio = ratio of pulmonary to systemic flow. Control heart rates before each pacing interval were comparable to those in Table 1. Note that the net left-to-right shunt increased with faster pacing rates, particularly in the dogs with larger defects. This is most readily appreciated by comparing the respective P/S ratios. right atrium produced comparable results. In most instances atrial pacing at 150 and 180 beats/min augmented total cardiac output without appreciably changing the ratios of pulmonary to systemic flow. At 210 to 240 beats/min an increase occurred in the left-toright shunting in dogs 6, 8, 9, and 10 (Table 2). The difference between the ratios of pulmonary to systemic flow at 180 and 240 beats/min is significant, P<0.01. Figure 1 illustrates the typical response in dogs with atrial septal defects during pacing at 240 beats/min. Note the abrupt augmentation of pulmonary flow at the onset of pacing. Atrial pacing at rates of 270 and 300 beats/min usually resulted in a decreased left and right ventricular output. However, aortic flow decreased to a greater extent than pulmonary with a consequent further increase in the ratios of pulmonary to systemic flow. During pacing, both the aortic pressure and the right ventricular pressure remained relatively unchanged until the highest pacing rates when they both fell proportionally. When A-V block occurred during rapid atrial pacing, invariably the ratios of pulmonary to systemic flow returned to or near control levels. During ventricular pacing, the same qualitative changes in shunting occurred as with atrial pacing (Table 2). Ventricular pacing, however, generally resulted in a reduced cardiac output when compared with atrial Circulation Research, Vol. XXIV, April 1969 pacing at the same rate. Left ventricular pulsus alternans frequently developed when pacing the ventricle at 210 beats/min or faster. Figure 2 illustrates an example of "total" left ventricular alternans which occurred during ventricular pacing. Figure 3, the typical response following a dose of phenylephrine, illustrates the rise in aortic pressure, the fall in aortic flow and the slight rise in pulmonic flow. Table 3 summarizes the pressure-flow responses to various vasopressors. Angiotensin, methoxamine, and phenylephrine all produced a rise in systemic blood pressure, a fall in aortic flow, an increase in pulmonary flow in most dogs, and an increase in the ratio of pulmonary to systemic flow. The increase in left-to-right shunt ranged from 140 ml/min in dog no. 2 with a 2-mm atrial septal defect to nearly 2,000 ml/min in dog no. 10, with a 15-mm defect. This relationship is highly significant (P < 0.001). During the drug-induced hypertension, all of the dogs showed an increased left-to-right flow except no. 9. In this dog with a control ratio of pulmonary to systemic flow of 2.6, both the pulmonary and aortic flows fell approximately 500 ml/min during the response to phenylephrine. The shunt flow, however, remained constant. Thus the ratio of pulmonary to systemic flow during hypertension rose. In Figure 4 a typical response to transient DOUGLAS, REMBERT, SEALY, GREENFIELD 498 200 Arterial Pressure mm Hg 100 ° 50r BEGIN PACE STOP PACE Atrial Pressure mm Hg --•-,>>,- ECG Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 Aortic Flow Puls. ml /sec \ Aortic Flow Mean 200 ml/mi r Pulmonary Flow Puls. ml/sec 150 Pulmonary Flow Mean 2000 ml/min ..,.;.;.,•.* A/-A,V T 0L I sec FIGURE 1 The response of dog no. 6 to atrial pacing at 240 beats/min. With the onset of pacing, mean pulmonary flow increases abruptly and mean aortic flow drops. hypotension is illustrated. Reducing systemic pressure by the administration of histamine or nitroglycerin resulted in a significant decrease (P<0.001) in left-to-right shunt. The aortic flow increased, and a variable change occurred in pulmonary artery flow. Heart rate increased in all dogs. Right ventricular pressures remained the same or rose moderately with histamine and nitroglycerin (Table 4). Data obtained during isoproterenol infusion are given in Table 5. There was always both an inotropic and chronotropic response to isoproterenol given intravenously. Aortic diastolic pressures dropped in 8 animals and remained the same in one. Aortic systolic pressure rose in 5 and fell in 4. Peak right ventricular pressure rose in 7 dogs. Pulmonary flow (column 6, Table 5) increased as little as 50 ml/min (dog no. 4) or as much as 1300 ml/min (dog no. 2), the average increase being 800 ml/min. Aortic flow, however, increased to an even greater extent than Circulation Research, Vol. XXIV, April 1969 SHUNT FLOW IN ATRIAL SEPTAL DEFECTS 499 200p \ Ventricular Pacing Arterial Pressure mmHg inn OL 100 Right Ventricular Pressure mmHg 5 0 - "•• 0 50 Right AtriaI Pressure mmHg ECG Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 Pulmonary Flow Puls. ml/sec Pulmonary Flow Mean ml /min 150 0 5000 r Aortic Flow Puls ml/sec Aortic Flow Mean ml /min 160 p. 7500 DOG # 5 I sec FIGURE 2 The response of dog no. 5 to ventricular pacing at 240 beats/min. Mean pulmonary flow falls slightly with the onset of ventricular pacing and returns within 30 seconds to approximately prepacing levels. Pulmonary artery pulsus alternans is visible from the beginning of pacing. Mean aortic flow falls with the onset of pacing and "total" pulsus alternans occurs. pulmonic, and as a result the ratios of pulmonary to systemic flow fell (column 7). The amount of shunted blood fell significantly (P<0.01) in 8 of the 9 dogs. In dog no. 9, although the ratio of pulmonary to systemic flow decreased substantially, there was a slight increase in left-to-right shunting. Discussion It is obvious that over a prolonged period of Circulation Research, Vol. XXIV, April 1969 time the output of both ventricles in the mammalian heart must be balanced. As has been shown by Franklin and co-workers (11), this balance is extremely sensitive, and the disparity between the outputs of either ventricle lasts for a few heart beats at the most. In the presence of an atrial septal defect some equilibrium between the two circuits is mandatory, but their outputs may be persistently unequal. Since with a large atrial septal DOUGLAS, REMBERT, SEALY, GREENFIELD 500 jPhenyteph'' Arterial Pressure mm Hg Right Ventricular Pressure mmHg Right Atnal Pressure mmHg 50 50 25 mftimmmm 0 Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 ECG — — Aortic Flow Puls ml/sec Aortic Flow Mean ml/min 2000 r0L Pulmonary Flow Puls. m i /sec Pulmonary Flow Mean ml/min 2000 r DOG # 6 lOsec FIGURE 3 Response of dog no. 6 to phenylephrine given intravenously. Within 5 seconds after the elevation of aortic pressure, aortic flow begins to fall and pulmonary artery flow begins to rise. The greatest reduction in aortic flow and the major change in net shunt flow occurs within 15 seconds after the hypertensive response. defect, one can assume that the atria are a common chamber, filling will occur preferentially into the ventricle with the least impedance to blood flow. Several factors favor flow into the right ventricle. Since the area of the mitral orifice is only 50 to 6035 that of the Circulation Research, Vol. XXIV, April 1969 501 SHUNT FLOW IN ATRIAL SEPTAL DEFECTS TABLE 3 Response to Vasopressor Drugs RV BP Heart rate (beats/min) 155 130 120 115 120 115 95 130 120 130 180 170 200 170 150 130 130 130 130 140 150 150 145 140 200 180 Dog Status (mm Hg) syst. (mm Hg) 2 CA DA CA DA CA DA CM DM 140/90 205/165 60 50 155/80 205/140 160/105 205/150 150/80 200/135 145/90 200/140 150/95 195/150 150/100 200/150 140/80 160/110 120/70 150/110 125/75 180/120 55 3 4 5 6 Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 Ao BP syst./diast. 7 8 9 10 CA DA CA DA CP DP CM DM CA DA CP DP CA DA CP DP CA DA 145/100 205/155 175/100 190/140 135/95 160/130 65 75 80 70 80 80 80 75 90 70 90 55 55 65 70 65 80 50 85 50 75 55 60 Mean pulmonary flow (ml/min) Mean systemic flow (ml/min) 2870 2100 3010 2100 1110 1120 2870 2970 2030 3380 2470 2750 1085 1960 2500 2080 2310 3290 2920 2990 2930 2630 2330 2450 2600 2490 1930 3250 3600 820 2630 2140 2120 2640 2370 2140 1960 1000 2160 1230 1940 1170 1570 830 1550 580 900 630 960 400 2950 1330 P/S ratio 1.0 1.0 1.0 1.4 1.1 1.4 1.0 1.3 1.0 1.3 1.0 2.5 1.0 1.9 1.7 2.5 1.9 3.5 1.7 4.0 2.7 4.1 2.6 4.8 1.1 2.7 Change in shunt flow (ml/min) + 140 + 265 + 590 + 830 + 510 + 1500 + 1160 + 400 + 680 + 670 + 420 NC + 1970 Ao BP = aortic blood pressure; RV = right ventricle; P/S ratio = ratio of pulmonary to systemic flow. In column 2 the experimental status is listed. The control data for the interval immediately before the administration of each drug are labeled "C," and the effects of the indicated drug are listed under "D." M = methoxamine; A = angiotensin; P = phenylephrine. Note that an increase in the P/S ratio occurred in every instance (column 8). The change in the total shunt concomitant with the pressor response is given in column 9. This value is obtained by subtracting systemic from pulmonary flow for both the control and experimental intervals. Control value of shunt is then subtracted from experimental shunt flow and the final result tabulated. A positive sign indicates an increase in the net amount of shunting from left to right. NC signifies that no change occurred. tricuspid (12), under conditions of high cardiac output, relative mitral stenosis may appear before relative tricuspid stenosis. In addition, the left ventricular wall is less compliant than that of the right ventricle. Thus, during tachycardia when the diastolic filling period is markedly shortened, left ventricular filling will be more impeded than the right. Under such circumstances, if the atrial septum is intact, left atrial pressure rises and augments left ventricular filling. In the presence of a large atrial septal defect, such as in dogs 7 to 10, however, the left atrial Circulation Research, Vol. XXIV. April 1969 pressure is not able to rise appreciably above the right atrial pressure, and the left-to-right shunt may therefore increase. Even with a smaller defect where the atrial pressure might not be equal, the same hemodynamic considerations should apply. It is of interest that several authors (1, 2) have been impressed by the morbidity associated with the onset of arrhythmias, particularly with atrial fibrillation, in patients previously asymptomatic with atrial septal defects. Our results would lend support to the concept that the appearance of exertional dyspnea, fatigue, or other cardiac DOUGLAS, REMBERT, SEALY, GREENFIELD 502 Nitroglycerine 200 Arterial Pressure mmHg 100 0 100 Right Ventricular Pressure mmHg Right Atrial Pressure mm Hg 50 i. , 0 50 25 Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 0 ECG Aortic Flow Puls. ml/sec l50r 0 Aortic Flow Mean ml/mm 2000 0 Pulmonary Flow Puls. ml/sec 150 0 Pulmonary Flow Mean ml/min C 2000 n[L 20 sec FIGURE 4 Response of dog no. 6 to nitroglycerin given intravenously. Simultaneous with the drop in arterial pressure, the aortic flow increases with little or no change in pulmonary flow. symptoms in patients with a rapid ventricular rate might be due to an increase in left-toright shunting. In our dogs there was no change in the shunt during rapid atrial pacing when A-V block occurred if the ventricular rate slowed. Thus, it appears that within the Circulation Research, Vol. XXIV, April 1969 503 SHUNT FLOW IN ATRIAL SEPTAL DEFECTS TABLE 4 Response to Vasodilator Drugs Dog 1 2 3 4 5 Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 6 7 8 9 10 Status CH DH CH DH CN DN CH DH CH DH CH DH CN DN CH DH CH DH CN DN CH DH Ao BP syst./diast. (mm Hg) RV BP syst. (mm Hg) Heart rate (beats/min) Mean pulmonary flow (ml/min) Mean systemic flow (ml/min) ratio 145/100 124/60 150/80 110/45 170/90 150/60 170/115 120/60 130/80 90/45 170/115 140/60 170/105 150/70 120/65 85/45 110/70 120/50 150/110 140/90 125/90 95/40 55 100 55 100 65 70 60 60 105 130 110 175 110 140 125 125 1350 1970 2200 2960 970 1190 2920 2890 1420 2040 2240 3240 870 1520 2650 3300 1.0 1.0 1.0 0.9 1.1 0.8 1.1 0.9 70 80 75 100 70 80 55 70 65 85 70 75 55 60 125 140 135 170 130 180 145 180 125 150 120 175 145 185 1840 1940 2070 2580 1870 2460 2280 3590 1530 2410 860 1480 2760 2940 1.4 1.2 1.3 0.9 1.3 0.9 1.6 1.3 1.8 1.3 3.0 2.2 1.3 1.1 2610 2400 2680 2400 2340 2310 3650 4660 2760 3140 2600 3120 3600 3230 P/S Change in shunt flow (ml/min) NC — 240 -430 -680 -310 -790 -620 -300 -500 -100 -550 Data tabulated as in Table 3. H = histamine; N = nitroglycerin. Note that the P/S ratios fall with the hypotensive response. The negative sign (column 9) indicates a decrease in the amount of net left-to-right shunting. limitations of this study an ineffective atrial contraction does not increase the left-to-right shunt. Tanenbaum and Pfaff (8) and more recently Weldon (7) have demonstrated increased left-to-right shunting and consequent increased ratios of pulmonary to systemic flow in dogs during the administration of systemic vasopressor drugs. McCredie (4), however, did not obtain this response in man with either methoxamine or norepinephrine. With norepinephrine, despite a rise in aortic blood pressure of 25 to 30 mm Hg and a stable heart rate, McCredie failed to detect a change in the ratio of pulmonary to systemic flow. Our results, therefore, confirm those of Tanenbaum and Pfaff (8) and Weldon (7) and not those of McCredie (4). Since all dogs had substantial reductions in their ratios of pulmonary to systemic flow with Circulation Research, Vol. XXIV, April 1969 systemic vasodilators, despite the variable changes in peak right ventricular pressure, the change in shunting under these conditions is probably due to the drop in peripheral vascular resistance. In dogs 2, 3, 4, and 6 the ratio actually fell below 1.0 and suggests that there was right-to-left shunting. The increased cardiac output from both the left and right side in response to cardiac inotropic drugs is essentially the same as observed in intact dogs (9). Weldon (7), noting a drop in the ratio of pulmonary to systemic flow in his acute atrial septal defect preparations, attributed the decreased left-toright shunting to a decrease in right ventricular distensibility. However, isoproterenol may reduce left-to-right shunting by enhancing left ventricular compliance, thus increasing the ease of left ventricular filling. It is of interest that the chronotropic response to DOUGLAS, REMBERT, SEALY, GREENFIELD 504 TABLE 5 Response to Isoproterenol Dog Status Ao BP syst./diast. (mm Hg) 2 CI DI CI DI CI DI CI DI CI DI CI DI CI DI CI DI CI DI 150/65 130/65 150/80 190/65 145/100 120/80 135/90 115/55 155/100 195/65 100/60 85/45 120/80 165/60 145/105 180/50 120/70 155/40 3 4 5 6 Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 7 8 9 10 RV BP syst. (mm Hg) Heart rate (beats/min) Mean pulmonary flow (ml/min) Mean systemic flow (ml/min) 50 105 60 110 50 50 65 80 75 110 115 180 115 190 120 125 145 155 180 205 125 180 130 160 140 200 145 220 2510 3890 1040 2160 2700 2750 2470 3250 2100 2410 4090 5100 2700 3575 2490 3200 3380 4500 2700 4260 1120 2460 2520 2960 2300 3480 1610 2710 3650 6000 1420 2895 860 1450 2250 4100 70 100 50 105 50 100 P/S ratio 0.9 0.9 0.9 0.9 1.1 0.9 1.1 0.9 1.3 0.9 1.1 0.9 1.9 1.3 2.9 2.2 1.5 1.1 Change in shunt flow (ml/min) — 180 -220 -390 -400 -790 -1340 -600 + 120 -730 Data tabulated as in Table 3. I = isoproterenol. All nine dogs had a tachycardia and a reduced P/S ratio following isoproterenol administration. The net left-to-right shunt fell in 8 of the 9 dogs. isoproterenol produced tachycardias equal to those which, when pacing, increased left-toright shunting. Despite this chronotropic response, systemic vascular resistance and myocardial properties are changed to such an extent that instead of increasing left-to-right shunting, isoproterenol produced a decrease. Regardless of the technique of calibration, absolute values of blood flow measured with an electromagnetic flowmeter are subject to a moderate margin of error as noted in the method (9). For example, if the two transducers were each off by two standard deviations in opposite directions, then a 28% error in the baseline pulmonary and aortic flow values might be found. This also assumes that the calibration in vivo is similar to that in vitro which is certainly another potential source of error. One point validating the flowmeter data is the good agreement between pulmonary and aortic flow noted in dog no. 1 without a defect and in dogs 2, 3, and 4 with small defects. Although the aboslute values of blood flow may be questioned, as noted in the method, the linearity of the electromagnetic flowmeter (±2.0%) is quite good. Thus the changes in flow from control levels to that found during the various procedures are accurately measured. One of the major difficulties regarding the interpretation of the data in these studies is the elevation of 20 to 40 mm Hg above normal in right ventricular systolic pressure. Although this finding may be explained to some extent as artifact introduced by the catheter, the pressures are higher than normal (11). Since we did not measure pulmonary artery pressure, a degree of pulmonary stenosis produced by the flowmeter transducer may have been present, even though the vessel did not appear to be constricted at autopsy. The elevated right ventricular pressure also may have been due to the left-to-right shunt. Whatever the cause, this finding would tend to lessen the degree to which the left-to-right shunt increased with tachycardia. Thus, one might expect the changes in shunting to be more dramatic in the patient with an uncomplicated atrial septal defect. Circulation Research, Vol. XXIV, April 1969 505 SHUNT FLOW IN ATRIAL SEPTAL DEFECTS Acknowledgments The authors wish to express appreciation to Mr. William Joyner and Mrs. Maxine Mangum for their technical assistance. The department of Medical Illustration of the Durham Veterans Administration Hospital rendered valuable support. References 6. SWAN, H. J., MARSHALL, H. W., AND WOOD, E. H.: Effect of exercise in the supine position on pulmonary vascular dynamics in patients with left-to-right shunts. J. Clin. Invest. 37: 202, 1958. 7. WELDON, G. S.: Hemodynamics in acute atrial septal defects. Arch. Surg. 93: 724, 1966. 8. TANENBAUM, H. L., AND PFAFF, W. W.: Effect of pressor amines on experimental intracardiac shunts and valvular regurgitation. Diseases Chest 44: 485, 1963. 1. ADAMS, C. W.: A reappraisal of life expectancy with atrial shunts of the secundum type. Diseases Chest 48: 357, 1965. 2. MARKMAN, P., HOWTTT, G., AND WADE, E. G.: 9. GREENFIELD, J. C , JR., PATEL, D. J., MALLOS, A. J., AND FRY, D. L.: Evaluation of Kolin type electromagnetic flowmeter and pressure gradient technique. J. Appl. Physiol. 17: 372, 1962. Atrial septal defect in the middle-aged and elderly. Quart. J. Med. 34: 409, 1965. 3. TIKOFF, G., SCHMIDT, A. M., KIUDA, H., AND Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 HECHT, H. H.: Heart failure in atrial septal defect. Am. J. Med. 39: 533, 1965. 4. MCCREDIE, R. M.: Effect of transient resistance changes on atrial septal defects and other intracardiac shunts. Cardiovasc. Res. 1: 335, 1967. 5. STEPHENS, N. L., SHAFTER, H. A., AND BLISS, H. A.: Hemodynamic and ventilatory effects of exercise in the upright position in patients with left-to-right shunts. Circulation 29: 99, 1964. Circulation Research, Vol. XXIV, April 1969 10. HICKAM, J. B., AND FRAYSER, R.: Spectrophoto- metric determination of blood oxygen. J. Biol. Chem. 180: 457, 1949. 11. FRANKLIN, D. L., VAN CITTERS, R. L., AND RUSHMER, R. F.: Balance between right and left ventricular output. Circulation Res. 10: 17, 1962. 12. HULL, E.: Cause and effects of flow through defects of the atrial septum. Am. Heart J. 38: 350, 1949. Factors Affecting Shunting in Experimental Atrial Septal Defects in Dogs JOHN E. DOUGLAS, JUDITH C. REMBERT, WILL C. SEALY and JOSEPH C. GREENFIELD, Jr. Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017 Circ Res. 1969;24:493-505 doi: 10.1161/01.RES.24.4.493 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1969 American Heart Association, Inc. 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