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The effect of mannitol infusion on cardiac output and renal blood flow after graded hemorrhage
The effect of mannitol infusion on cardiac output and renal blood flow after graded hemorrhage Worthington G. Schenk, Jr., M.D., N. Anders Delin, M.D.,* Lawrence Pollock, M.D., Kjartan B. Kjartansson, M.D., and John W. Boylan, M.D., Buffalo, N. Y.
l h e place of the osmotic diuretic, manni tol, in the armamentarium of the surgeon remains uncertain due, at least in part, to lack of information on the alteration in renal blood flow produced by this agent. Doubt concerning the accuracy of clearance methods for determination of renal blood flow after major hemorrhage increases the difficulty of obtaining valid information. This study is an investigation of the effect on cardiac output and renal blood flow of mannitol infusions given before, during, or after graded hemorrhage in experimental animals. Materials and methods Through a thoracotomy incision, a "C" core electromagnetic flow probef was placed on the ascending aorta of adult male mongrel dogs, weighing 15 to 24 kilograms, From the Departments of Surgery and Medicine, State University of New York at Buffalo, and the Edward J. Meyer Memorial Hospital, Buffalo, N. Y. Supported in part by a grant-in-aid from the National Heart Institute of the U. S. Public Health Service (HE-03181). Received for publication April 8, 1965. ♦Research Fellow of the United Health Foundation of Western New York. tElectromagnetic Probe Co., Winston-Salem, N. C.
24 hours prior to each study. On the day of study, the left renal artery was exposed through a retroperitoneal left flank incision under intravenous thiopental sodium anes thesia. At the same time, the ascending aorta probe cable connector was delivered from a subcutaneous position on the back where it had been placed at the previous procedure. With the use of a miniature "U" core probe* on the left renal artery and a probe switch box,f rapid sequential mea surements of either ascending aorta or left renal flow could be made by means of a noncannulating square wave electromagnetic flowmeter.f After reproducible flow values were ob tained three to five times in the control period, the animals were studied in four groups: (1) mannitol infusion only; 10 per cent mannitol solution given intravenously at 7 c.c. per minute for 1 hour (6 experi ments); (2) major bleeding (25 to 30 c.c./ Kg. body weight) followed by reinfusion of blood, then mannitol infusion, as above (3 experiments); (3) continuous mannitol infusion at same rate as above with simul taneous graded hemorrhage ranging from * Electromagnetic Probe Co., Winston-Salem, N. C. fCarolina Medical Electronics, Winston-Salem, N. C.
561
5 62
Journal of Thoracic and Cardiovascular Surgery
Schenk et al. EXPERIMENT
10 to 70 c.c. of blood per kilogram of body weight (4 experiments); (4) graded hemor rhage (10 to 40 c.c./Kg. body weight) followed by mannitol infusion as above (3 experiments). Flow studies were repeated at 5 to 10 minute intervals for 1 to 2 hours after each of the above experimental pro grams. Following each bleeding episode, a 15 to 20 minute period elapsed before the next set of flow measurements in order to permit adjustments to the new hypovolemic state.
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Since the prime question was whether a change in blood flow distribution occurred, the results are plotted to show alteration in left renal artery flow as a function of change in cardiac output. The heavy line shown in each illustration is the line along which all points would fall if renal blood flow changed in direct proportion to change in cardiac output. Any divergence from this line represents a preferential shift in blood flow either toward or away from the left renal area (depending on which side of the line the points fall). Group I—Mannitol only. The combined results of the 6 experiments in this group are shown in Fig. 1. The vast majority of
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Fig. 1. Effect of mannitol infusion in 6 normovolemic dogs. Most values fall close to the line of direct proportionality, that is, renal flow changed in direct proportion to change in cardiac output.
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2
-60
-40
20
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PERCENT CHANGE IN CARDIAC OUTPUT FROM CONTROL
Fig. 2. Effect of hemorrhage alone followed by effect of reinfusion of shed blood and mannitol infusion. Blood flow was always preferentially shifted toward the kidney by hemorrhage alone. Reinfusion of blood plus mannitol always in creased renal flow but with a concomitant distri bution shift away from the kidney.
experimental points are in close proximity to the heavy line, indicating that alteration in renal blood flow produced by mannitol infusion in this group is merely a reflection of change (usually increase) in cardiac out put. Group II—Single major bleeding fol lowed by reinfusion of shed blood, then mannitol infusion. The results of this portion of the study are shown in Fig. 2. The uncircled points are those following hemorrhage only. It will be noted that in every case there is a preferential relative shift of blood flow toward the kidney, that is, renal flow is reduced to a lesser extent than is cardiac output. After reinfusion of the blood and initiation of a mannitol in fusion, the values are circled. While renal flow was uniformly increased by the infusion, in every instance renal flow increased to a lesser degree than the in crease in cardiac output (i.e., blood flow was preferentially shifted away from the kidney). Group III—Continuous mannitol infu sion plus graded hemorrhage. These results
Volume 50
Mannitol infusion 5 6 3
Number 4 October, 1965
E X T E N T OF B L E E D I N G C C / k g A 15.5 8 29 C 37 NUMBERS INDICATE SEQUENTIAL MEASUREMENTS AT 5 M I N U T E INTERVALS
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Figs. 3-6. Effect of graded hemorrhage during continuous mannitol infusion. Readjustment periods of 15 to 20 minutes were permitted following each new bleeding before flow measure ments were resumed. A distribution shift toward the kidney occurred following hemorrhage of 30 c.c. per kilogram or less of about the same magnitude as resulted without mannitol (Fig. 2). With increasing hemorrhage this distribution shift disappeared.
Journal of
5 6 4 Schenk et al.
Thoracic and Cardiovascular Surgery
E X T E N T OF B L E E D I N G A 10 B C D E
CC/kg
14 19 23 37 EXTENT OF BLEEDING CC/hg
M DURING M A N N I T O L INFUSION
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NUMBERS INDICATE SEQUENTIAL MEASUREMENTS AT 5 M I N U T E INTERVALS
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Figs. 7-9. Effect of hemorrhage followed by effect of mannitol infusion. Mannitol increased renal flow but either as a direct function of cardiac output increase (Fig. 9) or proportionately less than cardiac output increased (Figs. 7 and 8).
are shown in Figs. 3 through 6. The sequen tial numbering of points indicates their temporal relationship while the lettering in dicates the degree of hemorrhage. It will be seen that with hemorrhage less than 30 c.c. per kilogram of body weight there is usually a preferential relative shift of blood flow toward the kidney. By comparison with
Fig. 2, it can be seen that this is roughly of the same magnitude as was seen with hemorrhage when no mannitol was given. As extent of bleeding increased, a preferen tial shift of flow away from the kidney was observed in each experiment although at somewhat varying degree of hemorrhage (30to50c.c./Kg.).
Volume 50
Mannitol infusion
Number 4
565
October, 1965
Group IV—Graded hemorrhage fol lowed by mannitol infusion. These results are seen in Figs. 7 through 9. In each in stance there was preferential relative shift of blood flow toward the kidney with hemorrhage less than 30 c.c. per kilogram of body weight, while no distributional shift was evident when hemorrhage ex ceeded 30 c.c. per kilogram. When the mannitol infusion was begun, it will be seen in Figs. 7 and 8 that renal flow increased but proportionately less than cardiac out put, that is, a relative shift away from the kidney occurred. In Fig. 9, renal flow in creased in almost exact proportion to in crease in cardiac output. Discussion The experimental groups were designed to simulate clinical circumstances in which renal support might be required. These circumstances are: (1) Anticipated blood loss (major surgical procedures in which blood loss is expected) ; is mannitol of value started prior to loss? (2) Unexpected blood loss: is mannitol of value (a) given alone prior to blood replacement, (b) given concomitantly with blood replacement? There is no doubt about the diuresis which mannitol produces, even at lowered blood pressure,2 and increased renal blood flow has been reported by several authors. 3 - 4 From the present evidence it is apparent that mannitol increased renal blood flow under each of the experimental situations, but that this flow increment was principally a function of increased cardiac output. When a regional flow distribution change resulted after use of mannitol, it was usually a relative shift away from the kidney (i.e., cardiac output increased more than renal blood flow increased). Wright and Gann 7 reported that infusion of mannitol without expansion of extracellular fluid volume did not increase renal plasma flow, and Murphy, Gagnon, and Teschan5 reported that the hemodynamic effects of mannitol appeared to be a result of plasma volume expansion. The latter also reported that fluctuation of
para-aminohippurate extraction following infusion of mannitol invalidated renal blood flow values obtained by that method as a reliable index of renal flow. It would seem that mannitol would offer little if its primary function were as a plasma volume expander, since the result is so transient and since better volume expanders, such as dextrans, are available. Prophylactic use of mannitol for diuretic purposes has been challenged in a report by Beall1 of 30 patients undergoing abdominal aneurysm resections which con cludes "the routine use of a mannitolinduced osmotic diuresis offers no signifi cant advantage." In discussion of this paper, Shumacker0 states that, "Solute diuresis does not lower the mortality after a mea sured period of renal ischemia in dogs." Whether such diuresis is of value in man remains to be established. Summary and conclusions 1. Mannitol infusions (10 per cent at 7 c.c./min. ) were given to dogs before, during, and after graded hemorrhage. 2. Ascending aorta flow and left renal artery flow were measured at frequent inter vals by means of the electromagnetic flowmeter. 3. Mannitol infusion regularly produced an increase in renal blood flow, but only as a reflection of increase in cardiac output. 4. When a shift in flow distribution oc curred with hemorrhage alone (30 c.c./Kg. body weight or less), blood flow was pref erentially shifted toward the kidney. 5. When a relative shift in flow distribu tion occurred after mannitol infusion, it was always away from the kidney. REFERENCES 1 Beall, A. C , Holman, M. R., Morris, G. C , Jr., and De Bakey, M. E.: Mannitol Induced Osmotic Diuresis During Vascular Surgery, Arch. Surg. 86: 34, 1963. 2 Boylan, J. W., and Schenk, W. G., Jr.: Minimal Glomerular Filtration Pressure, J. Clin. Invest. 42: 920, 1963. 3 Braun, W. E., and Lilienfield, L. S.: Renal Hemodynamic Effects of Hypertonie Mannitol
Journal of
5 6 6 Schenk et al.
Thoracic and Cardiovascular Surgery
Infusions, Proc. Soc. Exper. Biol. & Med. 114: 2, 1963. 4 Hosnik, W. J., Powers, S. R., Boba, A., and Stein, A. A.: Observations on the Effect of Mannitol on Renal Hemodynamics and 0 2 Tension in the Urine and Renal Vein, S. Forum 10: 872, 1959. 5 Murphy, G. P., Gagnon, J. A., and Teschan, P. E.: Renal Hemodynamic Effect of Mannitol
in Normotension and Hypotension, S. Forum 14: 99, 1963. 6 Shumacker, H. B.: Discussion of Beall et al.1 Arch. Surg. 86: 55, 1963. 7 Wright, H. W., and Gann, D. S.: Effect of Mannitol on Renal Hemodynamics During Extracellular Fluid Volume Depletion and Expansion, S. Forum 14: 97, 1963.
l h e place of the osmotic diuretic, manni tol, in the armamentarium of the surgeon remains uncertain due, at least in part, to lack of information on the alteration in renal blood flow produced by this agent. Doubt concerning the accuracy of clearance methods for determination of renal blood flow after major hemorrhage increases the difficulty of obtaining valid information. This study is an investigation of the effect on cardiac output and renal blood flow of mannitol infusions given before, during, or after graded hemorrhage in experimental animals. Materials and methods Through a thoracotomy incision, a "C" core electromagnetic flow probef was placed on the ascending aorta of adult male mongrel dogs, weighing 15 to 24 kilograms, From the Departments of Surgery and Medicine, State University of New York at Buffalo, and the Edward J. Meyer Memorial Hospital, Buffalo, N. Y. Supported in part by a grant-in-aid from the National Heart Institute of the U. S. Public Health Service (HE-03181). Received for publication April 8, 1965. ♦Research Fellow of the United Health Foundation of Western New York. tElectromagnetic Probe Co., Winston-Salem, N. C.
24 hours prior to each study. On the day of study, the left renal artery was exposed through a retroperitoneal left flank incision under intravenous thiopental sodium anes thesia. At the same time, the ascending aorta probe cable connector was delivered from a subcutaneous position on the back where it had been placed at the previous procedure. With the use of a miniature "U" core probe* on the left renal artery and a probe switch box,f rapid sequential mea surements of either ascending aorta or left renal flow could be made by means of a noncannulating square wave electromagnetic flowmeter.f After reproducible flow values were ob tained three to five times in the control period, the animals were studied in four groups: (1) mannitol infusion only; 10 per cent mannitol solution given intravenously at 7 c.c. per minute for 1 hour (6 experi ments); (2) major bleeding (25 to 30 c.c./ Kg. body weight) followed by reinfusion of blood, then mannitol infusion, as above (3 experiments); (3) continuous mannitol infusion at same rate as above with simul taneous graded hemorrhage ranging from * Electromagnetic Probe Co., Winston-Salem, N. C. fCarolina Medical Electronics, Winston-Salem, N. C.
561
5 62
Journal of Thoracic and Cardiovascular Surgery
Schenk et al. EXPERIMENT
10 to 70 c.c. of blood per kilogram of body weight (4 experiments); (4) graded hemor rhage (10 to 40 c.c./Kg. body weight) followed by mannitol infusion as above (3 experiments). Flow studies were repeated at 5 to 10 minute intervals for 1 to 2 hours after each of the above experimental pro grams. Following each bleeding episode, a 15 to 20 minute period elapsed before the next set of flow measurements in order to permit adjustments to the new hypovolemic state.
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After Hemorrhage A f t e r Reinfusion of Shed Blood and during Mannitol Infusion Amount of Hemorrhage CC/kg
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58 UJ
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Since the prime question was whether a change in blood flow distribution occurred, the results are plotted to show alteration in left renal artery flow as a function of change in cardiac output. The heavy line shown in each illustration is the line along which all points would fall if renal blood flow changed in direct proportion to change in cardiac output. Any divergence from this line represents a preferential shift in blood flow either toward or away from the left renal area (depending on which side of the line the points fall). Group I—Mannitol only. The combined results of the 6 experiments in this group are shown in Fig. 1. The vast majority of
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NO.
808
+ 40-
Results
_l
621
20 0 -20
PERCENT CHANGE IN CARDIAC OUTPUT FROM CONTROL
Fig. 1. Effect of mannitol infusion in 6 normovolemic dogs. Most values fall close to the line of direct proportionality, that is, renal flow changed in direct proportion to change in cardiac output.
-100-80
2
-60
-40
20
0
+20
+40
+60
PERCENT CHANGE IN CARDIAC OUTPUT FROM CONTROL
Fig. 2. Effect of hemorrhage alone followed by effect of reinfusion of shed blood and mannitol infusion. Blood flow was always preferentially shifted toward the kidney by hemorrhage alone. Reinfusion of blood plus mannitol always in creased renal flow but with a concomitant distri bution shift away from the kidney.
experimental points are in close proximity to the heavy line, indicating that alteration in renal blood flow produced by mannitol infusion in this group is merely a reflection of change (usually increase) in cardiac out put. Group II—Single major bleeding fol lowed by reinfusion of shed blood, then mannitol infusion. The results of this portion of the study are shown in Fig. 2. The uncircled points are those following hemorrhage only. It will be noted that in every case there is a preferential relative shift of blood flow toward the kidney, that is, renal flow is reduced to a lesser extent than is cardiac output. After reinfusion of the blood and initiation of a mannitol in fusion, the values are circled. While renal flow was uniformly increased by the infusion, in every instance renal flow increased to a lesser degree than the in crease in cardiac output (i.e., blood flow was preferentially shifted away from the kidney). Group III—Continuous mannitol infu sion plus graded hemorrhage. These results
Volume 50
Mannitol infusion 5 6 3
Number 4 October, 1965
E X T E N T OF B L E E D I N G C C / k g A 15.5 8 29 C 37 NUMBERS INDICATE SEQUENTIAL MEASUREMENTS AT 5 M I N U T E INTERVALS
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Figs. 3-6. Effect of graded hemorrhage during continuous mannitol infusion. Readjustment periods of 15 to 20 minutes were permitted following each new bleeding before flow measure ments were resumed. A distribution shift toward the kidney occurred following hemorrhage of 30 c.c. per kilogram or less of about the same magnitude as resulted without mannitol (Fig. 2). With increasing hemorrhage this distribution shift disappeared.
Journal of
5 6 4 Schenk et al.
Thoracic and Cardiovascular Surgery
E X T E N T OF B L E E D I N G A 10 B C D E
CC/kg
14 19 23 37 EXTENT OF BLEEDING CC/hg
M DURING M A N N I T O L INFUSION
,
NUMBERS INDICATE SEQUENTIAL MEASUREMENTS AT 5 M I N U T E INTERVALS
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Figs. 7-9. Effect of hemorrhage followed by effect of mannitol infusion. Mannitol increased renal flow but either as a direct function of cardiac output increase (Fig. 9) or proportionately less than cardiac output increased (Figs. 7 and 8).
are shown in Figs. 3 through 6. The sequen tial numbering of points indicates their temporal relationship while the lettering in dicates the degree of hemorrhage. It will be seen that with hemorrhage less than 30 c.c. per kilogram of body weight there is usually a preferential relative shift of blood flow toward the kidney. By comparison with
Fig. 2, it can be seen that this is roughly of the same magnitude as was seen with hemorrhage when no mannitol was given. As extent of bleeding increased, a preferen tial shift of flow away from the kidney was observed in each experiment although at somewhat varying degree of hemorrhage (30to50c.c./Kg.).
Volume 50
Mannitol infusion
Number 4
565
October, 1965
Group IV—Graded hemorrhage fol lowed by mannitol infusion. These results are seen in Figs. 7 through 9. In each in stance there was preferential relative shift of blood flow toward the kidney with hemorrhage less than 30 c.c. per kilogram of body weight, while no distributional shift was evident when hemorrhage ex ceeded 30 c.c. per kilogram. When the mannitol infusion was begun, it will be seen in Figs. 7 and 8 that renal flow increased but proportionately less than cardiac out put, that is, a relative shift away from the kidney occurred. In Fig. 9, renal flow in creased in almost exact proportion to in crease in cardiac output. Discussion The experimental groups were designed to simulate clinical circumstances in which renal support might be required. These circumstances are: (1) Anticipated blood loss (major surgical procedures in which blood loss is expected) ; is mannitol of value started prior to loss? (2) Unexpected blood loss: is mannitol of value (a) given alone prior to blood replacement, (b) given concomitantly with blood replacement? There is no doubt about the diuresis which mannitol produces, even at lowered blood pressure,2 and increased renal blood flow has been reported by several authors. 3 - 4 From the present evidence it is apparent that mannitol increased renal blood flow under each of the experimental situations, but that this flow increment was principally a function of increased cardiac output. When a regional flow distribution change resulted after use of mannitol, it was usually a relative shift away from the kidney (i.e., cardiac output increased more than renal blood flow increased). Wright and Gann 7 reported that infusion of mannitol without expansion of extracellular fluid volume did not increase renal plasma flow, and Murphy, Gagnon, and Teschan5 reported that the hemodynamic effects of mannitol appeared to be a result of plasma volume expansion. The latter also reported that fluctuation of
para-aminohippurate extraction following infusion of mannitol invalidated renal blood flow values obtained by that method as a reliable index of renal flow. It would seem that mannitol would offer little if its primary function were as a plasma volume expander, since the result is so transient and since better volume expanders, such as dextrans, are available. Prophylactic use of mannitol for diuretic purposes has been challenged in a report by Beall1 of 30 patients undergoing abdominal aneurysm resections which con cludes "the routine use of a mannitolinduced osmotic diuresis offers no signifi cant advantage." In discussion of this paper, Shumacker0 states that, "Solute diuresis does not lower the mortality after a mea sured period of renal ischemia in dogs." Whether such diuresis is of value in man remains to be established. Summary and conclusions 1. Mannitol infusions (10 per cent at 7 c.c./min. ) were given to dogs before, during, and after graded hemorrhage. 2. Ascending aorta flow and left renal artery flow were measured at frequent inter vals by means of the electromagnetic flowmeter. 3. Mannitol infusion regularly produced an increase in renal blood flow, but only as a reflection of increase in cardiac output. 4. When a shift in flow distribution oc curred with hemorrhage alone (30 c.c./Kg. body weight or less), blood flow was pref erentially shifted toward the kidney. 5. When a relative shift in flow distribu tion occurred after mannitol infusion, it was always away from the kidney. REFERENCES 1 Beall, A. C , Holman, M. R., Morris, G. C , Jr., and De Bakey, M. E.: Mannitol Induced Osmotic Diuresis During Vascular Surgery, Arch. Surg. 86: 34, 1963. 2 Boylan, J. W., and Schenk, W. G., Jr.: Minimal Glomerular Filtration Pressure, J. Clin. Invest. 42: 920, 1963. 3 Braun, W. E., and Lilienfield, L. S.: Renal Hemodynamic Effects of Hypertonie Mannitol
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Infusions, Proc. Soc. Exper. Biol. & Med. 114: 2, 1963. 4 Hosnik, W. J., Powers, S. R., Boba, A., and Stein, A. A.: Observations on the Effect of Mannitol on Renal Hemodynamics and 0 2 Tension in the Urine and Renal Vein, S. Forum 10: 872, 1959. 5 Murphy, G. P., Gagnon, J. A., and Teschan, P. E.: Renal Hemodynamic Effect of Mannitol
in Normotension and Hypotension, S. Forum 14: 99, 1963. 6 Shumacker, H. B.: Discussion of Beall et al.1 Arch. Surg. 86: 55, 1963. 7 Wright, H. W., and Gann, D. S.: Effect of Mannitol on Renal Hemodynamics During Extracellular Fluid Volume Depletion and Expansion, S. Forum 14: 97, 1963.