Clinical Hemodilution Intentional Hemodilution, Biblthca Haemat., Νο. 41 ed. by K. MESSIER and H. SCΗΜτD-SCΗbΝ ΕΙΝ, pp. 239-247 (Karger, Basel 1975)
Moderate Preoperative Hemodilution, Mortality and Thrombus Formation in General Surgery LARS-ERIK GELIN and HJALMAR JANSEN Department of Surgery I, University of Gothenburg, Gothenburg
Introduction
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Tissue injury is regularly followed by an increased aggregability of the formed elements of blood and increased viscosity of blood, which impair the perfusion and produce stasis. This circulatory insufficiency is compensated for by an anemia of injury which in severity parallels the degree of the injury. This anemia is brought about by hemolysis of aggregated and stagnated cells. This anemia is to be regarded as a normal response to injury to compensate for increased viscosity of the blood in order to maintain tissue perfusion [1, 2, 5]. Thus, Nature uses hemolysis to produce hemodilution for flow purposes. Here I should like to stress Nature's wisdom to induce this degree of anemia with a hematocrit of about 30-270/0. This is the volume of cells which can be suspended in plasma with highly increased viscosity without increasing the whole blood viscosity above normal levels [4]. This degree of anemia fits very well with the data obtained by MESSIER and his group regarding the optimal total oxygen carrying capacity during experimental hemodilution [8]. It thus seems clear that the anemia of injury is a purposeful reaction of the body to maintain adequate perfusion. The aim of the following clincial investigation was to observe favorable and nonfavorable reactions from moderate preoperative hemodilution in general surgery.
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Table 1 Number of Mean Preoperative Hemodílution Number of Mortality, Lethal hemoglobin, agent deaths % emboli patients age, years g/100 ml 301 304 296
65 65 64
13.2 13.1 13.1
glucose dextran 70 dextran 40
19 13 10
6.3 4.3 3.4
4 1 0
Table 11 Cases Emboli
Glucose Dextran 70 Dextran 40
301 304 296
Thromboses Thromboembolism
major
minor
5 1 0
1 3 0
total 24 14 13
30 18 13
30 10 5.9 4.4
Material and Methods Α prospective series of 901 consecutive patients above 50 years of age undergoing major surgical procedures were divided into 3 groups according to a doubleblind method. The 3 groups of patients were given 500 ml of a test solution in the following way: group I glucose, group I1 dextran 70 and group III dextran 40. There was no difference in distribution of age, sex, surgical procedure or disease between the 3 groups. The preoperative hemoglobin value was 13.1 g/100 ml blood corresponding to hematocrit 390/0. The patients were analyzed concerning duration of operation, transfusions of whole blood during operation, bleeding during operation and the occurrence of thromboembolic complications and survival.
Results Mortality
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From table I appears the total death rate and the number of lethal pulmonary emboli observed in the 3 groups of patients. Hemodílution with dextran 40 decreased the mortality rate from 6.3 to 3.30/0. This influence on postoperative mortality might be ascribed to many factors. There
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was no difference in causes of death between the groups, except for major pulmonary emboli which occurred in 4 patients in the glucose-treated group and in 1 patient in the dextran 70 group. With consideration of a preventive effect of dextran on pulmonary embolism this difference in mortality rate still favors a more general improvement than prophylaxis of thromboembolic complications from the treatment with dextran 40. We have interpreted the lowered mortality as a consequence of improved tissue perfusion. Postoperative Thromboembolism The incidence of postoperative phlebographically verified thromboembolic complications are reported for the 3 groups in table II. As apparent, both dextran 70 and dextran 40 treated patients had about 500/0 lower incidence of thromboembolic complications as compared to the glucosetreated group. This difference is statistically significant. There was no statistical difference between dextran 70 and dextran 40 in this respect. This should favor the assumption that a specific antithrombotic property of dextran was acting. A nonsignificant lower incidence of postoperative thrombosis in the dextran 40 treated group suggests, however, that another mechanism might be as important, namely the flow-promoting effect. Therefore, a special study was initiated to evaluate this mechanism of action. Venous Flow Pattern in the Lower Extremity Before and After Operation
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24 patients undergoing cholecystectomy were divided into 2 groups of which 12 patients received 500 ml dextran 40 during the operation and the other 12 glucose. The venous flow pattern in the lower leg was studied with Ι3Ι J-Hippuran injected into a dorsal vein of the hallux, with registration of the appearance time over the femoral vein in the groin and the disappearance rate over the calf [7]. From this investigation it became apparent that in the control group the appearance time of the isotope in the groin was much faster after operation than before the operation. In the dextran 40 treated group the appearance time and the disappearance rate after operation were equal to the values observed before operation. This discrepancy between the 2 groups indicates that the deeper venous
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flow was more or less shunted off from effective flow in the control group but was properly maintained in the dextran 40 treated group [7]. This effect was verified at phlebography. Therefore, the thromboprophylactic effect of dextran in the per- and postoperative period might be ascribed to a flow-promoting effect in the deep venous system of the lower leg rather than to a specific antithrombotic effect [2].
Discussion and Conclusion Both mortality and thromboembolic complications decreased with moderate peroperative hemodilution with dextran 70 and dextran 40. The more marked effect both on mortality and on the incidence of thromboembolic complications favors the assumption that hemodilution with dextran 40 provided better perfusion and venous return flow than with dextran 70 [5]. This emphasizes the rheologic concept in hemodilution. Moderate hemodilution in elective general surgical practice is not only justified but advisable. References 1 GELIN, L.-E.: Studies in anemia of injury. Acta chir. scand. Suppl. 210, (1956). 2 BORGSTRUM, S.; Gειτκ, L.-E., and ZEDERFaLDT, Β.: The formation of vein thrombi following tissue injury. An experimental study in rabbits. Acta chir. scand. suppl. 247 (1959). 3 GELIN, L.-E.: Rheological disturbances following tissue injury; in COPLEY Proc. 4th Int. Congr. on Rheology, part 4, p. 299 (Interscience, New York 1965). 4 Gειτκ, L.-E.; RUDENSTAM, C.-M., and ZEDERFELDT, Β.: The rheology of red cell suspensions. Bibl. gnat. 7: 368 (1965). 5 LUI, R. C.; KOSTRZEWSKA, E.; BERGEITZ, S.-E., and GELIN, L.-E.: Rheology of human blood following treatment with dextran 40 and dextran 70. Bibl. anat. 10: 9 (1969). 6 GELIN, L.-E.: Reaction of the body as a whole to injury. J. Trauma 10: 932 (1970). 7 JANSEN, R.: Postoperative thromboembolism and its prevention with 500 ml dextran given during operation with a special study of he venous flow pattern in the lower extremities. Acta chir. scand. Suppl. 427 (1972). 8 MESSN.ER, K.; SUNDER-PLASSMANN, L.; KLbVEKORN, W. P., and ROEPER, K.: Circulatory significance of hemodilution. Rheological changes and limitations. Adv. Microcirc. 4.• 1 (1972).
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Prof. L.-E. GELIN and Dr. H. JANSEN, Department of Surgery I, University of Gothenburg, Gothenburg (Sweden)
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243
Discussion Moderator: L. E. GELIN
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H. SCHMID-SCHbNBEIN: The compensation of adverse rheological properties by reduction of hematocrit is something which is obviously widely used in nature. There is, of course, an effective filter placed in the circulation, namely the spleen. There is good evidence to support the notion that it can recognize these cells which have lost their fluidity. One of the most simple ways in which the red cells can loose their remarkable rheological properties is that they stick rigidly to one another, the doublet, the two of them behave like an ordinary, more or less rigid body. Chances are higher that there is much more trapping of these in the spleen. I would now like to address myself to your very interesting results about the clearance pattern of radioactive tracers from the venous bed in the legs. I am somewhat puzzled, how do you explain this finding? L. Ε. GEL IN: It is quite apparent to us — we will ask DAVID LEWIS about that — that it is a shunting off of deep venous flow. All venous off flow passes over the superficial venous system, where you can see after an operation that the flow goes very fast, and you can visualize it also by phlebography. This occurs, unless you do something specific to protect the deep venous system. H. SCHMID-SCHbNBEIN: And you imply then, since the overall flow is about the same, that the proof of a few rapid channels suggests that the major part of the vessels is not perfused at all. Let us assume for a moment that this is true; this again would then be a situation where indeed the concept of `collateral increase in apparent viscosity', I presented in my paper, might come into play. If I remember my anatomy correctly, the veins in the legs have frequent interconnections. And, in fact, there is a possibility that a yield shear stress of blood exists. Admittedly, this quantity is difficult to measure, and therefore, at present, we do not know for sure whether or not blood or cell aggregates can withstand finite forces without flowing. But if red cell aggregates, for example, at high hematocrits are able to reversibly turn into a `functional solid' without being truly clotted, then this might explain your observation on a rheological basis. Also, the reliefs of this redistribution by herodilution with Rheomacrodex can be explained on all the same basis. It ist — after — well known that Rheomacrodex has a whole number of specific and unspecific rheological effects. One, of course, is that with the infusion given to your patients substantially you reduce the stability of red cell aggregates. Unfortunately, we did not have the chance to measure this objectively after we developed the tools to measure shear resistance or the mechanical integrity of red cell aggregates. From in vitro experiments I would suggest that the mechanical integrity of red cells after the infusion of only one bottle of Rheomacrodex is reduced by 50°/0. The second mechanism operational is, of course, that the mechanical integrity of red cell aggregates very strongly depends on the hematocrit value which you also reduce. In other words: the reduction of the hematocrit from 45 to somewhere around 38°/o would greatly reduce the mechanical integrity of the full static plug that might block flow in a collateral. Another mechanism of Rheomacrodex which we have reported first to this meeting 3 years ago, and which has since been substantiated in many studies in our own labo-
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ratory and also by Dr. CHIEN and by Dr. EHRLY, is the facilitation of red cell deformation. The increase in plasma viscosity that one obtains with Rheomacrodex enables or facilitates cell alignment and deformation even under conditions of relatively slow flow. This has two consequences: (1) One can reduce the shear stresses much more before the cell becomes immobilized into a red cell aggregate, at which moment it gives up its fluidity and then is part of an elastic, three-dimensional cell structure. (2) The second consequence is that the cells, when flowing, are much more readily deformed which, for example, also has an influence on the velocity profile in the sense that there would be a smaller core of no shear than before addition of Rheomacrodex. Last not least, one improves the flow conditions because one keeps the blood circulating, and as we know the best way to keep blood liquid is to keep it flowing rapidly. L. Ε. GELIN: I agree especially on that last aspect: as long as we can keep blood flowing, no thrombi will form. So I think that is exactly what these flow data show: it is possible to keep the deep venous system open for flow with this method. And, of course, even if plasma viscosity itself increases with the infusion of Rheomacrodex immediately, that will include very small changes. Almost identical data of the effect of dextran infusion on plasma viscosity were found. But it will because of its hemodiluting or hematocrit-decreasing effect also provide a lower blood viscosity, especially at the low shear rate. And I think that has the important bearing for the venous off-flow system. It is on these low shear rates that it has its most marked effect. K. MESSIER: In addressing the same problem I would like to stress the point that according to your interpretation of these data and the further elucidation by H. SCΗΜΙD-SCΗ1 ΝΒΕΙN it seems that the antithrombotic effect of dextran 40 could be attributed to the flow improvement. But this is in absolute contrast to the very early findings of GRUBER and BERGENTZ [J. surg. Res. 6: 379, 1966]. L. Ε. GaLlI: No, I would not go that far, but I think it has been overemphasized. The antithrombotic property of dextran is essentially the one of the flow promotion. We don't have to forget about that. And there is — not statistically, however — a difference between dextran 40 and dextran 70. If it had been so, I should have been on safer ground in this statement. K. MESSIER: Dr. BERGENTZ, would you please comment. You have demonstrated that the identical degree of dilution obtained with albumin and dextran was associated with an antithrombotic effect in the dextran- but not so in the albumin-treated animals. Would this mean that there was only a difference in plasma viscosity, which certainly was lower in the albumin-treated group? S. Ε. BERGEITZ: You put me in a difficult situation. I think, we have to agree that there are two factors. I will remind you of the study by BECKER and Scnλµrτ indicating that when using dextran they do actually not see a decrease in the immediate incidence of postoperative thrombi as diagnosed with 125 Ι; but several days later when performing a phlebography, they find a decreased incidence of thrombi with dextran, indicating that thrombi do actually form but disappear more rapidly when dextran has been given. This study suggests that there is actually a specific antithrombotic property which also plays an important role.
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H. Scmνπο-Sc öΝsετκ: There are so many physiochemical factors of the blood affected by dextran. Here is another one: red cell charge, which is increased after Rheomacrodex infusion. The role of surface charge in platelet behavior has been greatly stressed by SAWYER'S group. Dextran effects remain to be elucidated. L. E. GE UN: Yes, and not only on the cell membrane, but also on the endothelial layer which might be even more important for the thrombus formation. D. H. LEWIS: I just wanted to reemphasize what Dr. GELIN said. You cannot say from the data available, which is the more important factor. It may well be that dextran's effect on platelets, on the strength of the fibrin clot and on the blood flow is of equal importance. We were able to demonstrate patients who were operated upon and not given dextran, and there appeared a closing off of the deep venous system of the calf. Dextran administration could keep this system open. We wanted to emphasize that this was one factor that could be important in thrombus preventíοn and, as I said, perhaps equally important as platelet aggregation, fibrin formation and clot solubility. K. MESSIER: Dr. LEWIS, have you carried out comparative studies using albumin to get the same degree of dilution and then applying the isotope transit time technique? D. H. LEWIS: No, not as yet. K. MESSIER: I certainly would like to see the results of such a study at identical hematocrit values. D. H. LEWIS: So would I! E. Lowuxsτmν: As I recall, there were four deaths from thromboembolism out of the 19 deaths. Is the dextran associated with a statistically significant decline in the death rate, if you exclude those four deaths? I would think, if this was really the case, this would obviously be very important and should be recognized. L. Ε. GaLmm: Sure. It is a statistically relevant difference between the 19 and the 10 deaths in the two groups, but if we remove the 4 embolic cases, this statistical difference disappears. L. DINTENFASS: One more comment on the effect of course of dextran and other proteins on the deformability of red cells. In principle, it does not make any difference if the plasma viscosity is due to globulin, macroglobulin or dextran of different molecular weight. The basic fundamental point is the ratio of internal viscosity of the red cells to the viscosity of plasma. This has a powerful effect on the concept of the critical radius of the inversion phenomenon, because a very slight change in the deformability of red cells is greatly amplified due to this phenomenon and even a slight increase in the deformability of red cells or a slight decrease in the internal viscosity of red cells will improve flow manyfold, completely out of proportion to the gross viscosity changes or to the viscosity changes in the whole blood. Ιn respect of the effect of dextran on platelet properties: unfortunately I do not know the effect of dextran but we were studying effects of macroglobulins on platelets and we found out that macroglobulins are coating platelets and prevent formation of white thrombi. Perhaps there is an analogous mechanism in the presence of dextran. H. Scss µm-Ser-ιöwsrnν: I would like to modify this statement, if I may. Ι fully agree with you that the cause of the increase in plasma viscosity is irrelevant. However, in nature the only proteins which effectively increase the plasma viscosity un-
2 46
GELIN/.IANSEN
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fortunately at the same time are rather large molecules. They are fibrinogen, α2 macroglobulin, IgM-globulins. They can also increase the mechanical integrity of the cell aggregates. It is in this respect that Rheomacrodex is unique: it is the only colloid I know, which in concentrations that can be achieved in vivo increases plasma viscosity, thereby increases effective cell deformation for any given shear stress, without at the same time exaggerating red cell aggregation. L. DINTENFASS: Well, in general, I agree with you. But there are certain exceptions. It is quite true that dextran, and especially the LMWD in general, will in some occasions decrease the degree of aggregation of red cells. This slightly depends on the type of red cells and on the individual. For sake of argument, if you administer LMWD to a very healthy person, you might increase aggregation of red cells; on the other hand, if you give LMWD to a patient who suffers from disorders which lead to intervention, in most cases it would disaggregate the red cells. So I would quite agree in this aspect that dextran can have quite a number of properties. What I was mentioning before is that it is the principle of the fact that the fluidity of red cells depends on the viscosity of plasma, decisively of the way the plasma viscosity is made up. H. SCIJMID-SCHÖNBEIN: I'm now coming back to yesterday's discussion and may be, in Sweden, people are more willing to tell us about the hematocrit values or ether hematological parameters. If in fact we accept `stasis' as an important factor in red thrombus formation, then we should look at all parameters that interfere with the normal flow of the blood. Under low flow conditions, the hematocrit is very important and it would be interesting to know, if possible, if there is a higher incidence of thromboembolic complications in patients with a moderately increased hematocrit. I am aware of the fact that genuine polycythemia is associated with high incidence of thromboembolic complications. But how about the range of 45-550/ο? The second point relates to what Dr. DINTENFASS said: the intrinsic aggregability of the blood, which is enormously variable in different subjects, has been hidden from the medical public due to the Westergren method to measure red cell aggregation. This works clinically so well because it obviously very nicely separates between normal and abnormal. This is due to the fact that it is associated with very strong in vitro hemodilution. This strong plasma dilution produced by adding 1 ml of sodium citrate to 4 ml of blood first of all is not really controlled, because unless you know the hematocrit of the patient beforehand, the extent of dilution is unknown. Therefore, it is mandatory that the future studies on red cell aggregation should be done without plasma dilution. This would then bring to light the strong tendency to aggregation in the blood of many patients which run a normal sedimentation rate after their plasma has been diluted modo Westergren. Furthermore, one should now look into the immense variability of the mechanical integrity of these aggregates, on their rheological behavior in flow fields. This can be quite different between an aggregation caused by increased fibrinogen concentration or by high amounts of O2macroglobulins. Some of these differences have been published by our group [Biorheology. 1973). L. DτxτεPFASS: 1 will add one sentence. I consider that clinicians do collect data on the ABO blood groups of patients, because we did find out that the addition of different plasma expanders affects aggregation of red cells of different patients dif-
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ferently. And to a high degree, the patients of blood group A would behave differently from patients with blood group Ο. This is as true for aggregation of red cells, thrombus viscosity, as for thrombus degradation. L. E. Guth% I agree with you, especially on the blood group A; but this is such a heterogeneous group, as we have seen during the evaluation of selection of donors for transplantation. The A group behaves very differently. I will come back a little to the specific effect. Let me state first that any hemodilution will have a prophylactic effect on venous thrombus formation. Albumin decreases thrombus formation in the experimental model but not in the same extent as dextran 40. But it is possible to induce venous thrombi with dextran if you do increase the molecular size. This is an experiment in rabbits with ligated femoral veins. It normally does not lead to any thrombi, but if you induce coagulation by thrombin in your rabbit, or if you inject fibrinogen, so an increased high plasma viscosity occurs, as we interpret it, or dextran as such will do if the molecule is about 1 X 106 in size. That is of course a very high viscous solution which leads to stasis itself. Then we know that these high molecular proteins or dextrans or any large asymmetric molecules will initiate intravascular coagulation. Η. SCnMm-SCHbNBEIN: I am afraid that the influence of enhanced aggregation on apparent blood viscosity is a very complicated matter. The macromolecules that induce this aggregation always increase the viscosity of the plasma as well. Therefore, if one computes the relative apparent viscosity, at high rates of shear this value actually is lower than in normal controls of equivalent hematocrit value, whereas at low shear rates the measurements are equivocal. This is due to the fact that very rapid phase separation occurs. As a consequence, the influence of the pathological cell aggregates on blood viscosity is most probably missed by the slowly reacting mechanical viscometers used to date. I suspect that the effect of these high molecular weight colloids in vivo is much more pronounced. It has been shown, for example, that the infusion of high molecular weight dextran not only promotes deep venous thrombosis, but also initiates generalized and disseminated intravascular coagulation [Κuην et al.]. L. Ε. GaLm: I would like to emphasize a little bit what Dr. DINTENFASS tried to get included, namely the rigidity of the red cell. Here, clinically, the most promoting effect for stagnation is dehydration. I mean that dehydration not only includes an increased rigidity of the cell, but also an increased number of cells per unit volume which increase the possibility for stagnation. That suggests that the number, not only the volume, will contribute to the stasis phenomenon. Therefore, it is important to remember, even when you try with dextran 40 as a prophylactic measure, that flow is needed, otherwise it does not work.
Moderate Preoperative Hemodilution, Mortality and Thrombus Formation in General Surgery LARS-ERIK GELIN and HJALMAR JANSEN Department of Surgery I, University of Gothenburg, Gothenburg
Introduction
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Tissue injury is regularly followed by an increased aggregability of the formed elements of blood and increased viscosity of blood, which impair the perfusion and produce stasis. This circulatory insufficiency is compensated for by an anemia of injury which in severity parallels the degree of the injury. This anemia is brought about by hemolysis of aggregated and stagnated cells. This anemia is to be regarded as a normal response to injury to compensate for increased viscosity of the blood in order to maintain tissue perfusion [1, 2, 5]. Thus, Nature uses hemolysis to produce hemodilution for flow purposes. Here I should like to stress Nature's wisdom to induce this degree of anemia with a hematocrit of about 30-270/0. This is the volume of cells which can be suspended in plasma with highly increased viscosity without increasing the whole blood viscosity above normal levels [4]. This degree of anemia fits very well with the data obtained by MESSIER and his group regarding the optimal total oxygen carrying capacity during experimental hemodilution [8]. It thus seems clear that the anemia of injury is a purposeful reaction of the body to maintain adequate perfusion. The aim of the following clincial investigation was to observe favorable and nonfavorable reactions from moderate preoperative hemodilution in general surgery.
GELIN/JANSEN
240
Table 1 Number of Mean Preoperative Hemodílution Number of Mortality, Lethal hemoglobin, agent deaths % emboli patients age, years g/100 ml 301 304 296
65 65 64
13.2 13.1 13.1
glucose dextran 70 dextran 40
19 13 10
6.3 4.3 3.4
4 1 0
Table 11 Cases Emboli
Glucose Dextran 70 Dextran 40
301 304 296
Thromboses Thromboembolism
major
minor
5 1 0
1 3 0
total 24 14 13
30 18 13
30 10 5.9 4.4
Material and Methods Α prospective series of 901 consecutive patients above 50 years of age undergoing major surgical procedures were divided into 3 groups according to a doubleblind method. The 3 groups of patients were given 500 ml of a test solution in the following way: group I glucose, group I1 dextran 70 and group III dextran 40. There was no difference in distribution of age, sex, surgical procedure or disease between the 3 groups. The preoperative hemoglobin value was 13.1 g/100 ml blood corresponding to hematocrit 390/0. The patients were analyzed concerning duration of operation, transfusions of whole blood during operation, bleeding during operation and the occurrence of thromboembolic complications and survival.
Results Mortality
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From table I appears the total death rate and the number of lethal pulmonary emboli observed in the 3 groups of patients. Hemodílution with dextran 40 decreased the mortality rate from 6.3 to 3.30/0. This influence on postoperative mortality might be ascribed to many factors. There
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was no difference in causes of death between the groups, except for major pulmonary emboli which occurred in 4 patients in the glucose-treated group and in 1 patient in the dextran 70 group. With consideration of a preventive effect of dextran on pulmonary embolism this difference in mortality rate still favors a more general improvement than prophylaxis of thromboembolic complications from the treatment with dextran 40. We have interpreted the lowered mortality as a consequence of improved tissue perfusion. Postoperative Thromboembolism The incidence of postoperative phlebographically verified thromboembolic complications are reported for the 3 groups in table II. As apparent, both dextran 70 and dextran 40 treated patients had about 500/0 lower incidence of thromboembolic complications as compared to the glucosetreated group. This difference is statistically significant. There was no statistical difference between dextran 70 and dextran 40 in this respect. This should favor the assumption that a specific antithrombotic property of dextran was acting. A nonsignificant lower incidence of postoperative thrombosis in the dextran 40 treated group suggests, however, that another mechanism might be as important, namely the flow-promoting effect. Therefore, a special study was initiated to evaluate this mechanism of action. Venous Flow Pattern in the Lower Extremity Before and After Operation
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24 patients undergoing cholecystectomy were divided into 2 groups of which 12 patients received 500 ml dextran 40 during the operation and the other 12 glucose. The venous flow pattern in the lower leg was studied with Ι3Ι J-Hippuran injected into a dorsal vein of the hallux, with registration of the appearance time over the femoral vein in the groin and the disappearance rate over the calf [7]. From this investigation it became apparent that in the control group the appearance time of the isotope in the groin was much faster after operation than before the operation. In the dextran 40 treated group the appearance time and the disappearance rate after operation were equal to the values observed before operation. This discrepancy between the 2 groups indicates that the deeper venous
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flow was more or less shunted off from effective flow in the control group but was properly maintained in the dextran 40 treated group [7]. This effect was verified at phlebography. Therefore, the thromboprophylactic effect of dextran in the per- and postoperative period might be ascribed to a flow-promoting effect in the deep venous system of the lower leg rather than to a specific antithrombotic effect [2].
Discussion and Conclusion Both mortality and thromboembolic complications decreased with moderate peroperative hemodilution with dextran 70 and dextran 40. The more marked effect both on mortality and on the incidence of thromboembolic complications favors the assumption that hemodilution with dextran 40 provided better perfusion and venous return flow than with dextran 70 [5]. This emphasizes the rheologic concept in hemodilution. Moderate hemodilution in elective general surgical practice is not only justified but advisable. References 1 GELIN, L.-E.: Studies in anemia of injury. Acta chir. scand. Suppl. 210, (1956). 2 BORGSTRUM, S.; Gειτκ, L.-E., and ZEDERFaLDT, Β.: The formation of vein thrombi following tissue injury. An experimental study in rabbits. Acta chir. scand. suppl. 247 (1959). 3 GELIN, L.-E.: Rheological disturbances following tissue injury; in COPLEY Proc. 4th Int. Congr. on Rheology, part 4, p. 299 (Interscience, New York 1965). 4 Gειτκ, L.-E.; RUDENSTAM, C.-M., and ZEDERFELDT, Β.: The rheology of red cell suspensions. Bibl. gnat. 7: 368 (1965). 5 LUI, R. C.; KOSTRZEWSKA, E.; BERGEITZ, S.-E., and GELIN, L.-E.: Rheology of human blood following treatment with dextran 40 and dextran 70. Bibl. anat. 10: 9 (1969). 6 GELIN, L.-E.: Reaction of the body as a whole to injury. J. Trauma 10: 932 (1970). 7 JANSEN, R.: Postoperative thromboembolism and its prevention with 500 ml dextran given during operation with a special study of he venous flow pattern in the lower extremities. Acta chir. scand. Suppl. 427 (1972). 8 MESSN.ER, K.; SUNDER-PLASSMANN, L.; KLbVEKORN, W. P., and ROEPER, K.: Circulatory significance of hemodilution. Rheological changes and limitations. Adv. Microcirc. 4.• 1 (1972).
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Prof. L.-E. GELIN and Dr. H. JANSEN, Department of Surgery I, University of Gothenburg, Gothenburg (Sweden)
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Discussion Moderator: L. E. GELIN
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H. SCHMID-SCHbNBEIN: The compensation of adverse rheological properties by reduction of hematocrit is something which is obviously widely used in nature. There is, of course, an effective filter placed in the circulation, namely the spleen. There is good evidence to support the notion that it can recognize these cells which have lost their fluidity. One of the most simple ways in which the red cells can loose their remarkable rheological properties is that they stick rigidly to one another, the doublet, the two of them behave like an ordinary, more or less rigid body. Chances are higher that there is much more trapping of these in the spleen. I would now like to address myself to your very interesting results about the clearance pattern of radioactive tracers from the venous bed in the legs. I am somewhat puzzled, how do you explain this finding? L. Ε. GEL IN: It is quite apparent to us — we will ask DAVID LEWIS about that — that it is a shunting off of deep venous flow. All venous off flow passes over the superficial venous system, where you can see after an operation that the flow goes very fast, and you can visualize it also by phlebography. This occurs, unless you do something specific to protect the deep venous system. H. SCHMID-SCHbNBEIN: And you imply then, since the overall flow is about the same, that the proof of a few rapid channels suggests that the major part of the vessels is not perfused at all. Let us assume for a moment that this is true; this again would then be a situation where indeed the concept of `collateral increase in apparent viscosity', I presented in my paper, might come into play. If I remember my anatomy correctly, the veins in the legs have frequent interconnections. And, in fact, there is a possibility that a yield shear stress of blood exists. Admittedly, this quantity is difficult to measure, and therefore, at present, we do not know for sure whether or not blood or cell aggregates can withstand finite forces without flowing. But if red cell aggregates, for example, at high hematocrits are able to reversibly turn into a `functional solid' without being truly clotted, then this might explain your observation on a rheological basis. Also, the reliefs of this redistribution by herodilution with Rheomacrodex can be explained on all the same basis. It ist — after — well known that Rheomacrodex has a whole number of specific and unspecific rheological effects. One, of course, is that with the infusion given to your patients substantially you reduce the stability of red cell aggregates. Unfortunately, we did not have the chance to measure this objectively after we developed the tools to measure shear resistance or the mechanical integrity of red cell aggregates. From in vitro experiments I would suggest that the mechanical integrity of red cells after the infusion of only one bottle of Rheomacrodex is reduced by 50°/0. The second mechanism operational is, of course, that the mechanical integrity of red cell aggregates very strongly depends on the hematocrit value which you also reduce. In other words: the reduction of the hematocrit from 45 to somewhere around 38°/o would greatly reduce the mechanical integrity of the full static plug that might block flow in a collateral. Another mechanism of Rheomacrodex which we have reported first to this meeting 3 years ago, and which has since been substantiated in many studies in our own labo-
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ratory and also by Dr. CHIEN and by Dr. EHRLY, is the facilitation of red cell deformation. The increase in plasma viscosity that one obtains with Rheomacrodex enables or facilitates cell alignment and deformation even under conditions of relatively slow flow. This has two consequences: (1) One can reduce the shear stresses much more before the cell becomes immobilized into a red cell aggregate, at which moment it gives up its fluidity and then is part of an elastic, three-dimensional cell structure. (2) The second consequence is that the cells, when flowing, are much more readily deformed which, for example, also has an influence on the velocity profile in the sense that there would be a smaller core of no shear than before addition of Rheomacrodex. Last not least, one improves the flow conditions because one keeps the blood circulating, and as we know the best way to keep blood liquid is to keep it flowing rapidly. L. Ε. GELIN: I agree especially on that last aspect: as long as we can keep blood flowing, no thrombi will form. So I think that is exactly what these flow data show: it is possible to keep the deep venous system open for flow with this method. And, of course, even if plasma viscosity itself increases with the infusion of Rheomacrodex immediately, that will include very small changes. Almost identical data of the effect of dextran infusion on plasma viscosity were found. But it will because of its hemodiluting or hematocrit-decreasing effect also provide a lower blood viscosity, especially at the low shear rate. And I think that has the important bearing for the venous off-flow system. It is on these low shear rates that it has its most marked effect. K. MESSIER: In addressing the same problem I would like to stress the point that according to your interpretation of these data and the further elucidation by H. SCΗΜΙD-SCΗ1 ΝΒΕΙN it seems that the antithrombotic effect of dextran 40 could be attributed to the flow improvement. But this is in absolute contrast to the very early findings of GRUBER and BERGENTZ [J. surg. Res. 6: 379, 1966]. L. Ε. GaLlI: No, I would not go that far, but I think it has been overemphasized. The antithrombotic property of dextran is essentially the one of the flow promotion. We don't have to forget about that. And there is — not statistically, however — a difference between dextran 40 and dextran 70. If it had been so, I should have been on safer ground in this statement. K. MESSIER: Dr. BERGENTZ, would you please comment. You have demonstrated that the identical degree of dilution obtained with albumin and dextran was associated with an antithrombotic effect in the dextran- but not so in the albumin-treated animals. Would this mean that there was only a difference in plasma viscosity, which certainly was lower in the albumin-treated group? S. Ε. BERGEITZ: You put me in a difficult situation. I think, we have to agree that there are two factors. I will remind you of the study by BECKER and Scnλµrτ indicating that when using dextran they do actually not see a decrease in the immediate incidence of postoperative thrombi as diagnosed with 125 Ι; but several days later when performing a phlebography, they find a decreased incidence of thrombi with dextran, indicating that thrombi do actually form but disappear more rapidly when dextran has been given. This study suggests that there is actually a specific antithrombotic property which also plays an important role.
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H. Scmνπο-Sc öΝsετκ: There are so many physiochemical factors of the blood affected by dextran. Here is another one: red cell charge, which is increased after Rheomacrodex infusion. The role of surface charge in platelet behavior has been greatly stressed by SAWYER'S group. Dextran effects remain to be elucidated. L. E. GE UN: Yes, and not only on the cell membrane, but also on the endothelial layer which might be even more important for the thrombus formation. D. H. LEWIS: I just wanted to reemphasize what Dr. GELIN said. You cannot say from the data available, which is the more important factor. It may well be that dextran's effect on platelets, on the strength of the fibrin clot and on the blood flow is of equal importance. We were able to demonstrate patients who were operated upon and not given dextran, and there appeared a closing off of the deep venous system of the calf. Dextran administration could keep this system open. We wanted to emphasize that this was one factor that could be important in thrombus preventíοn and, as I said, perhaps equally important as platelet aggregation, fibrin formation and clot solubility. K. MESSIER: Dr. LEWIS, have you carried out comparative studies using albumin to get the same degree of dilution and then applying the isotope transit time technique? D. H. LEWIS: No, not as yet. K. MESSIER: I certainly would like to see the results of such a study at identical hematocrit values. D. H. LEWIS: So would I! E. Lowuxsτmν: As I recall, there were four deaths from thromboembolism out of the 19 deaths. Is the dextran associated with a statistically significant decline in the death rate, if you exclude those four deaths? I would think, if this was really the case, this would obviously be very important and should be recognized. L. Ε. GaLmm: Sure. It is a statistically relevant difference between the 19 and the 10 deaths in the two groups, but if we remove the 4 embolic cases, this statistical difference disappears. L. DINTENFASS: One more comment on the effect of course of dextran and other proteins on the deformability of red cells. In principle, it does not make any difference if the plasma viscosity is due to globulin, macroglobulin or dextran of different molecular weight. The basic fundamental point is the ratio of internal viscosity of the red cells to the viscosity of plasma. This has a powerful effect on the concept of the critical radius of the inversion phenomenon, because a very slight change in the deformability of red cells is greatly amplified due to this phenomenon and even a slight increase in the deformability of red cells or a slight decrease in the internal viscosity of red cells will improve flow manyfold, completely out of proportion to the gross viscosity changes or to the viscosity changes in the whole blood. Ιn respect of the effect of dextran on platelet properties: unfortunately I do not know the effect of dextran but we were studying effects of macroglobulins on platelets and we found out that macroglobulins are coating platelets and prevent formation of white thrombi. Perhaps there is an analogous mechanism in the presence of dextran. H. Scss µm-Ser-ιöwsrnν: I would like to modify this statement, if I may. Ι fully agree with you that the cause of the increase in plasma viscosity is irrelevant. However, in nature the only proteins which effectively increase the plasma viscosity un-
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fortunately at the same time are rather large molecules. They are fibrinogen, α2 macroglobulin, IgM-globulins. They can also increase the mechanical integrity of the cell aggregates. It is in this respect that Rheomacrodex is unique: it is the only colloid I know, which in concentrations that can be achieved in vivo increases plasma viscosity, thereby increases effective cell deformation for any given shear stress, without at the same time exaggerating red cell aggregation. L. DINTENFASS: Well, in general, I agree with you. But there are certain exceptions. It is quite true that dextran, and especially the LMWD in general, will in some occasions decrease the degree of aggregation of red cells. This slightly depends on the type of red cells and on the individual. For sake of argument, if you administer LMWD to a very healthy person, you might increase aggregation of red cells; on the other hand, if you give LMWD to a patient who suffers from disorders which lead to intervention, in most cases it would disaggregate the red cells. So I would quite agree in this aspect that dextran can have quite a number of properties. What I was mentioning before is that it is the principle of the fact that the fluidity of red cells depends on the viscosity of plasma, decisively of the way the plasma viscosity is made up. H. SCIJMID-SCHÖNBEIN: I'm now coming back to yesterday's discussion and may be, in Sweden, people are more willing to tell us about the hematocrit values or ether hematological parameters. If in fact we accept `stasis' as an important factor in red thrombus formation, then we should look at all parameters that interfere with the normal flow of the blood. Under low flow conditions, the hematocrit is very important and it would be interesting to know, if possible, if there is a higher incidence of thromboembolic complications in patients with a moderately increased hematocrit. I am aware of the fact that genuine polycythemia is associated with high incidence of thromboembolic complications. But how about the range of 45-550/ο? The second point relates to what Dr. DINTENFASS said: the intrinsic aggregability of the blood, which is enormously variable in different subjects, has been hidden from the medical public due to the Westergren method to measure red cell aggregation. This works clinically so well because it obviously very nicely separates between normal and abnormal. This is due to the fact that it is associated with very strong in vitro hemodilution. This strong plasma dilution produced by adding 1 ml of sodium citrate to 4 ml of blood first of all is not really controlled, because unless you know the hematocrit of the patient beforehand, the extent of dilution is unknown. Therefore, it is mandatory that the future studies on red cell aggregation should be done without plasma dilution. This would then bring to light the strong tendency to aggregation in the blood of many patients which run a normal sedimentation rate after their plasma has been diluted modo Westergren. Furthermore, one should now look into the immense variability of the mechanical integrity of these aggregates, on their rheological behavior in flow fields. This can be quite different between an aggregation caused by increased fibrinogen concentration or by high amounts of O2macroglobulins. Some of these differences have been published by our group [Biorheology. 1973). L. DτxτεPFASS: 1 will add one sentence. I consider that clinicians do collect data on the ABO blood groups of patients, because we did find out that the addition of different plasma expanders affects aggregation of red cells of different patients dif-
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ferently. And to a high degree, the patients of blood group A would behave differently from patients with blood group Ο. This is as true for aggregation of red cells, thrombus viscosity, as for thrombus degradation. L. E. Guth% I agree with you, especially on the blood group A; but this is such a heterogeneous group, as we have seen during the evaluation of selection of donors for transplantation. The A group behaves very differently. I will come back a little to the specific effect. Let me state first that any hemodilution will have a prophylactic effect on venous thrombus formation. Albumin decreases thrombus formation in the experimental model but not in the same extent as dextran 40. But it is possible to induce venous thrombi with dextran if you do increase the molecular size. This is an experiment in rabbits with ligated femoral veins. It normally does not lead to any thrombi, but if you induce coagulation by thrombin in your rabbit, or if you inject fibrinogen, so an increased high plasma viscosity occurs, as we interpret it, or dextran as such will do if the molecule is about 1 X 106 in size. That is of course a very high viscous solution which leads to stasis itself. Then we know that these high molecular proteins or dextrans or any large asymmetric molecules will initiate intravascular coagulation. Η. SCnMm-SCHbNBEIN: I am afraid that the influence of enhanced aggregation on apparent blood viscosity is a very complicated matter. The macromolecules that induce this aggregation always increase the viscosity of the plasma as well. Therefore, if one computes the relative apparent viscosity, at high rates of shear this value actually is lower than in normal controls of equivalent hematocrit value, whereas at low shear rates the measurements are equivocal. This is due to the fact that very rapid phase separation occurs. As a consequence, the influence of the pathological cell aggregates on blood viscosity is most probably missed by the slowly reacting mechanical viscometers used to date. I suspect that the effect of these high molecular weight colloids in vivo is much more pronounced. It has been shown, for example, that the infusion of high molecular weight dextran not only promotes deep venous thrombosis, but also initiates generalized and disseminated intravascular coagulation [Κuην et al.]. L. Ε. GaLm: I would like to emphasize a little bit what Dr. DINTENFASS tried to get included, namely the rigidity of the red cell. Here, clinically, the most promoting effect for stagnation is dehydration. I mean that dehydration not only includes an increased rigidity of the cell, but also an increased number of cells per unit volume which increase the possibility for stagnation. That suggests that the number, not only the volume, will contribute to the stasis phenomenon. Therefore, it is important to remember, even when you try with dextran 40 as a prophylactic measure, that flow is needed, otherwise it does not work.
