Symposium on a Physiologic Approach to Critical Care

Dextran and the Prevention of Postoperative Thromboembolic Complications PD Dr. Ulrich F. Gruber*

That the induction of limited normovolemic hemodilution is a reasonable concept in clinical care has been extensively documented. 3O-32 . 48 Hemodilution and volume replacement in general can be carried out by infusing large amounts of pure electrolyte solutions (not containing any colloidal substance) such as Ringer's lactate, but it has never been documented that such a procedure in man shows any advantages whatsoever over a fluid regimen which includes the administration of a colloid. However, there are good reasons to believe that the administration of large amounts of pure electrolyte solutions is not without danger.33 On the other hand, it is important to realize that plasma oncotic pressure (synonymous with plasma colloid osmotic pressure) is the only force which can draw water into the circulation. This colloid osmotic pressure is therefore of paramount importance for the maintenance of a normal nutritive flow in the microcirculation. Nobody has ever shown that nutritive flow is better when the physiologic colloid osmotic pressure is lowered (as it occurs after infusion of several liters of Ringer's lactate into a shocked individual) as compared to keeping it normal by giving colloids. If we therefore feel that it is reasonable to replace blood and plasma losses by colloidal infusion solutions and thus try to maintain a normal intravascular oncotic pressure, we have to choose among several different colloids available.

Blood Due to the risk of transmitting viral hepatitis, whole blood should be administered only if the hematocrit threatens to fall below 30 per cent (or the hemoglobin below 10 gm per cent). Whenever and wherever possible, repeatedly washed deep frozen erythrocytes are preferred; the hepatitis risk is thus reduced. 'Department of Surgery of the University of Basle, Division for General Surgery, Kantonsspital, Basel, Switzerland Surgical Clinics of North America- Vol. 55, No.3, June 1975

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The following three colloidal solutions may be used for initial volume replacement intraoperatively or in shocked patients: 1. Albumin 2. Pasteurized plasma protein solution (PPS) 3. Dextran

Quite apart from their excessive cost, neither albumin nor PPS is everywhere and always available in sufficient quantities. In fact, these important proteins are imported into the western world from countries where many people definitely would need more proteins! All other forms of plasma preparations (fresh plasma, dried plasma) should no longer be used, since they all carry the risk of transmitting hepatitis. It is therefore essential to employ an artificial colloid which behaves in the human body essentially in the same manner as a safe plasma preparation. The only colloid available today which fulfils these requirements is dextran.28

DEXTRAN It is quite evident that for some surgeons dextran has become some sort of a "dirty word," because they have seen complications with its use or because they have read about side effects. The pity is that these people do not realize that in this field too, things have changed so tremendously, as for example in the field of antibiotics, that it would be silly to compare results obtained with certain dextran preparations during the Korean war with data obtained with the much refined dextran preparations presently available. Therefore, the following preliminary remarks for evaluating literature on dextran seem to be necessary. In evaluating the results of research on dextran, great difficulty arises because various dextran preparations are manufactured in several countries by differing methods and with different properties. Unfortunately, very few investigators indicate the characteristics of the dextran they use, and the manufacturer's data (lot number) are mentioned only in the rarest instances. Even worse, many authors of review articles do not place sufficient importance on these facts and use the results which were obtained with one particular preparation to draw conclusions about all other dextran preparations. The situation is further complicated in that the oldest and most often used preparation, Macrodex, has likewise gone through certain changes over the years. The most important of these concerns an alteration of the Leuconostoc strain used in manufacturing dextran and the repeated reduction of the average molecular weight by narrowing the molecular weight distribution. As a rule, the older preparations have higher average molecular weights and higher top fractions. The physicochemical and biologic properties of a dextran solution depend upon the following factors: average molecular weight, molecular weight distribution, concentration, and molecular structure. These factors are responsible for some of the previously observed side-effects of dextran, such as influence on blood coagulation and blood group determination. As a simplification, one can say that the complications

681

DEXTRAN AND POSTOPERATIVE THROMBOEMBOLIC COMPLICATIONS

increase with higher average molecular weight, broader molecular weight distribution, and more pronounced degree of branching of the molecule. In the dextran literature, the following simple terminology has become standard: dextran 70 signifies a dextran with an average Mw of about 70,000, dextran 40 a dextran with an Mw of about 40,000, etc. Please note: Dextran is not just dextran! One must know with which preparation a result has been obtained in what year before reaching conclusions.

Dextran Preparations The two most· important of the preparations currently used are described here because all necessary data on these products are available. Macrodex (trade mark by Pharmacia, Uppsala/Sweden): Dextran DRI (quality code for dextran 70) in 0.9 per cent NaCI or 5 per cent glucose solution.

Cone. 6 per cent 6 per cent

Na CI mEq perl

mosm perl

154 154 Glucose 50 gm per I

Mw = approx. 70,000

cal per I Almost 0

308 277

200

In normal saline In glucose

Mn = approx. 39,000

Molecular weight distribution Mw for more than 90 per cent of the molecules is between 25,000 and 125,000. Rheomacrodex (Pharmacia; synonyms: LMWD = low molecular weight dextran, L VD = low viscosity dextran): Dextran RMI (quality code for dextran 40) in 0.9 per cent NaCI or 5 per cent glucose solution Cone. 10 per cent

CI Na mEq perl 154 154

mosm perl 308

10 per cent

glucose 50 gm per I

277

Mw = approx. 40,000;

cal per I Almost 0

200

Mn = approx. 25,000

Molecular weight distribution: Mw for more than 90 per cent of the molecules is between 10,000 and 80,000.

Clinical Use of Dextran The following well established facts regarding the use of dextran in clinical practice (extensive list of references in Gruber28 ) might be of interest: 1. Dextrans are polysaccharides built up of glucose molecules. 2. The colloid-osmotic effectivity of dextran is based on the fact that every intravascular gram of dextran binds about 20 to 25 ml H 2 0. 3. A 3.5 per cent solution of dextran 70 and a 2.5 per cent solution of dex-

682

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4. 5. 6.

7. 8. 9. 10.

11. 12.

13.

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tran 40 are approximately blood iso-oncotic. A 6 per cent solution of dextran 70 accordingly exerts immediately after rapid infusion a higher colloid osmotic pressure than blood does. This makes up for the quickly eliminated low molecular fractions. The colloid osmotic pressure of 10 per cent dextran 40 corresponds in vitro to that of an approximately 17 per cent albumin solution. Small dextran molecules are quickly excreted. Thus the colloid osmotic effect produced by Rheomacrodex in vivo drops more quickly than that of a corresponding albumin solution. The permeability of the membranes in the glomeruli is most important for this effect. For dextran the renal threshold is about MW = 50,000. In the human organism, dextran is completely broken down or excreted at a rate of approximately 70 mg per kg of body weight per 24 hours. In humans the dextran-plasma concentration after infusions of 0.5 to 1.5 liter is approximately 0.5 to 1.5 gm per cent. There is no basis for believing that dextran infusions impair renal function. When infusing large amounts of dextran 40, one must assure normal conditions of water and electrolyte balance, since this highly colloidosmotically-active solution displaces interstitial fluid into the vascular system. Changes in the renal tubuli in the sense of "osmotic nephrosis" have been described after infusion of dextran. These are of a functional and temporary nature and do not impair renal function. The dextran preparations (Macrodex and Rheomacrodex) now in clinical use have no antigenic effect. Allergic side-effects, so-called anaphylactoid reactions, however, do occur. Increased blood viscosity can be reduced by infusion of dextran. Under standard conditions dextran 40 and 70 do not influence blood group determination in any way. With the molecular weight distributions of present dextran 40 and 70, no changes in the coagulation parameters can be measured when dosages of 1.5 or 1 gm per kg of body weight respectively are used in humans. Dextrans definitely reduce platelet adhesiveness. This contributes to the antithrombotic effect of dextran (see below). Dextran solutions can be stored safely for 10 years under constant storage conditions. Defects in the containers limit storage capabilities. Dextran substance can be stored indefinitely. The volume effect of a dextran 70 infusion in hypovolemic individuals is initially somewhat more than the amount infused. After replacement of a given loss with the same amount of dextran 70, the blood volume remains normal until the body's own regulation mechanisms have completely replaced the blood or plasma loss. The initial volume effect of dextran 40 is almost twice the amount infused, but it does not last as long. About 3 to 4 hours after infusion, the volume effect is still about the same as the amount infused. In hypovolemic persons, infusions of dextran 40 or 70 bring about normalization of blood pressure, increase in cardiac output and venous return, reduction of peripheral resistance, decrease in circulation time, and improved nutritive flow. A large number of experimental and clinical studies confirm that the effect of dextran solutions is at least as good as that of the best plasma preparations. Several million bottles of dextran 70 and dextran 40 have been administered to date. Because of availability and cost, dextran solutions are preferred to pasteurized plasma protein solution and albumin for initial volume replacement in shocked patients and during surgical operations. An important additional reason is that dextrans have well documented antithrombotic effects. Thus, with the same agent it is possible to increase blood volume and flow and to prevent the complications which commonly occur in patients requiring volume substitution.

DEXTRAN AND POSTOPERATIVE THROMBOEMBOLIC COMPLICATIONS

683

In the following table are seen the advantages and disadvantages of pasteurized plasma protein solution (or albumin) and dextran in clinical shock therapy: PPS or Albumin

Dextran

Allergic reactions Influence on blood group determination Influence on blood coagulation

Rare None

Rare None

None

Influence on laboratory investigations Production Price Antithrombotic effect

None

Slight in doses over 1 gm per kg bw In certain cases

Limited Expensive Absent

Unlimited Inexpensive Present

Dextran for the Prevention of Thromboembolic Complications By means of newer diagnostic methods such as phlebography7 and the radioactive iodine fibrinogen test,6.45 it has been shown that postoperative deep venous thrombosis (DVT) occurs much more frequently than was known until now. 26 . 53 About 30 per cent of all patients on a general surgical ward develop postoperatively a DVT.7. 15. 21. 29. 46. 64 In certain patients, such as those with fractures of the neck of the femur, a frequency of up to 80 per cent has been found. 13 . 24. 34. 51. 55. 58. 60 Therefore, there must be a great interest in prophylactic measures which lower the rate of postoperative thromboembolic complications (TEC). Sevitt and Gallagher59 show that half of all lethal pulmonary embolism (PE) occurs without preceding clinical signs. It is likely that there are much more non lethal PE than was hitherto assumed. 15 In lethal PE, death occurs in 50 per cent of the patients within 15 minutes after the acute event; in another 10 per cent, within 60 minutes. 2o This means that in massive PE therapy starts usually too late and prophylaxis should be given to all patients undergoing surgery. Such a prophylaxis should be easy to apply, have few contraindications, cause only few complications, and already be active during operation. PHYSICAL METHODS FOR PREVENTION .OF TEC. Contrary to common belief, it is known today that postoperative early ambulation and intensive physiotherapy alone, i.e., without additional application of drugs, do not lead to the expected reduction in TEC.27 Also elevation of the legs during operation does not lead to a reduction of TEC; the same is true for wearing elastic stockings. 16 . 23 There are two mechanical methods which are said to lower DVT frequency: intraoperative electrical stimulation 14 . 41 and intermittent compression38 of the calf muscles. Both these forms of prophylaxis are rather unpractical and it is unlikely that they will ever be introduced on a large scale. DRUGS FOR THE PREVENTION OF TEC. Three drugs are used mainly: coumarin and its derivatives, dextran, and heparin. Coumarin* adminis'Sodium warfarin (coumadin) is an example of this type of anticoagulant

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tration (13 studies) has been practiced for decades. As we have recently shown,65 there is, however, little objective evidence which could justify its use in all surgical specialties. Subcutaneous application of small doses of heparin (13 studies) is the latest form of prophylaxis and is effective in reducing the DVT incidence in general surgery. There are yet insufficient data regarding its effectiveness in orthopedic surgery, urology, and gynecology, as well as against lethal PE. For other drugs, such as aspirinlo and hydroxychloroquine,t9 there are so far insufficient results available which would support their use in patients operated upon. In the following the results obtained with dextran for prevention of TEC in surgery are reviewed. We analyze those studies only which fulfill the following criteria: (1) Objective, diagnostic methods (such as 125iodine fibrinogen test, phlebography, or autopsy) have to be used for detecting DVT or PE. (2) The treated group has to be compared to a control group or to another group of patients which gets prophylaxis of known effectiveness. (3) The study has to be prospective. (4) The patients have to be randomly allocated to the control or treatment group. (5) The groups have to be observed during the same period of time. (6) The populations have to be identical, except the type of prophylaxis. (7) Statistical evaluation must be possible. Results. Dextran 70: 20 prospective controlled clinical trials tested the effectiveness of dextran 70 prophylaxis for prevention of thromboembolic complications in orthopedic patients as well as in general surgery, gynecology, and urology (Table 1). It is evident that dextran 70 is effective for reducing DVT in orthopedic surgery (Table 2). No definite conclusions can be drawn from studies regarding gynecologic surgery (Table 3). Results in general surgery are conflicting (Table 4). The DVT incidence in Carter'slB and Kline's44 control groups are as low or lower than in other authors' treatment groups. These studies are therefore difficult to interpret. Stephenson64 could not show a significant effect. He has started dextran prophylaxis after operation only. After all we know on the etiology of postoperative DVT, dextran has no chance to show any effect when given postoperatively only. Becker7 finds no significant effect when the results of the fibrinogen test alone are considered. If, however, the phlebographic results, obtained 3 to 14 days later, are evaluated, one third of the thrombi formed in the dextran group could no longer be found. This discrepancy was especially marked in females where the DVT frequency dropped from 20.8 to 9.5 per cent. We too are comparing phlebographies taken immediately after a thrombus is diagnosed by means of the fibrinogen test with films obtained 14 days later; the number of patients studied so far does not yet allow any definite conclusion. Facilitated lysis of the coarse fibrin network in a thrombus formed in the presence of dextran is probably the reason for the disappearance of such thrombi (Fig. 1). Direct support for this assumption was recently presented. I • 49 In this connection, it is of great interest to note that the best results for reducing the DVT frequency by means of dextran infusions are obtained by authors using phlebography as the diagnostic criterion. From the authors men-

DEXTRAN AND POSTOPERATIVE THROMBOEMBOLIC COMPLICATIONS

685

Table 1. Review of Prospective Randomized Studies on the Value of Dextran 70 in the Prevention of Deep Vein Thrombosis'~ AUTHOR

DIAGNOSIS

Ahlberg Ahlberg Becker

1968 1969 1973

Bergqvist Bergqvist Bonnar

1972 1973 1972

Bronge Carter Daniel Davidson Harper Hedlund Johnson Kline

1971 1973 1972 1972 1973 1974 1968 1974

Korvald Lambie Myhre Myrvold Ruckley Stephenson

1973 1970 1969 1973 1974 1973

Phlebography Phlebography Phlebography and fibrinogen test Phlebography Fibrinogen test Phlebography and fibrinogen test Phlebography Fibrinogen test Fibrinogen test Fibrinogen test Phlebography Fibrinogen test Phlebography Fibrinogen test and phlebography Phlebography Fibrinogen test Phlebography Fibrinogen testt Fibrinogen test Fibrinogen test

SURGERY

Orthopedic Orthopedic General Orthopedic Orthopedic Gynecologic Orthopedic General Orthopedic Gynecologic Leg amputation Urological Orthopedic General Orthopedic Gynecologic Orthopedic Orthopedic General/gynecologic General

"The papers included are those in which objective diagnostic methods were used. tFifty-three of the 94 patients were controlled by means of fibrinogen test and phlebography.

tioned in Table 2 regarding dextran and orthopedic surgery, all except two'" 21 have used phlebography. These two find the highest DVT incidence in the dextran group. In gynecologic surgery, only Bonnar 1 has used phlebography and documents an excellent result; the other three authors were applying the fibrinogen test. For general surgery, we have already stressed the marked difference in Becker's7 results (see above). Only Kline44 has also used phlebography, but no mention is made that phlebographies were repeated later on. From the single study dealing with urological patients, no final conclusions can be drawn (Table 5). The finding that thrombi formed in the presence of dextran are more rapidly dissoluted by the body's own fibrinolytic system7 might well be responsible for the fact that dextran prophylaxis is effective in reducing the number of pulmonary emboli (Table 6). Dextran 40 too has antithrombotic properties. Results of such studies are summarized in Table 7. Again, Evarts'25 study is a phlebographic one, whereas our preliminary data presented here were obtained with the fibrinogen test. The antithrombotic effect of dextran is due to: reduced platelet activity,t7 change of fibrin structure (see Fig. 1),50.66 change of mechanical properties of fibrin clot,66 facilitated lysis of fibrin,66 blood flow improvement.28

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Table 2.

Review of Studies Documenting the Value of Dextran 70 in the Prevention of Deep Venous Thrombosis in Orthopedic Surgery NUMBER OF PATIENTS

AUTHOR

Ahlberg Ahlberg Bergqvist Bergqvist Bronge Daniel Harper Johnson Korvald Myhre Myrvold

YEAR

Controls

1968 1969 1972 1973 1971 1972 1973 1968 1973 1969 1973

45 95

31 15 25 55

Dextran 70

39 70 75 43 74 35 12 27 43 55 55

PATIENTS WITH DVT (PER CENT)

Coumarin Heparin

Controls

35.5 42.1 63 32 61 61.3 66.6 52.0 39+ 50

40 39

Dextran 70

12.8 18.5 33.3 44.2 36.5 60t

Coumarin Heparin

p < 0.05 p < 0.05

30.2 50 34.4

None None* p= 0.3

ot 4 34.9 20 36

SIGNIFICANCE

1O.2§

18 41

None Yes p < 0.05 0.01 < p < 0.05 0.025 < p < 0.005 None

"'In the dextran-treated group there were half as many patients with major thrombi as in the coumarin group; in the coumarin group there were also significantly more patients with bilateral thrombi. tFrom the abstract it is not evident after what time interval the patients were operated upon (fractured femoral neck). This might explain the negative result, since dextran was started during operation only. t Leg amputations § Combined use of coumarins and dextran.

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Table 3. Review of Studies Documenting the Value of Dextran 70 in the Prevention of Deep Venous Thrombosis in Gynecologic Surgery NUMBER OF PATIENTS AUTHOR

YEAR

Controls

>

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PATIENTS WITH DVT (PER CENT)

Dextran Coumarin Heparin 70

Controls

Dextran 70 Coumarin Heparin

oen SIGNIFICANCE

..,

o

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Bonnar Davidson Lambie Ruckley

1972 1972 1970 1974

140

29

120 30 40 27

10.7 30 40 26

14

0.8 10 10 22

~

p < 0.01 None p < 0.01

13 30

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Table 4.

Review of Studies Documenting the Value of Dextran 70 in the Prevention of Deep Venous Thrombosis in General Surgery

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None

"The important finding in this study is that there were five fatal pulmonary emboli in the control group and none in the dextran group. Ql (Xl ~

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Figure 1. These two pictures taken by scanning electron microscopy (IlL = 11 mm) with the same degree of magnification (1 :10,000) clearly demonstrate the difference between fibrin formed in the absence (A) and presence of dextran (B). Fibrin formed in the presence of 1.8 gm dextran 70 (B) shows thicker fibers and a coarser network. This changed morphology implies changed properties of the fibrin. Its mechanical and chemical stability is changed. The effect of dextran is not related to its molecular weight. The coarser network and lower branching frequency reduce mechanical stability, which may decrease the possibility for the build-up of large thrombi and thereby the formation of large emboli. Such fibrin is more rapidly lysed by plasmin in vitro. Clinical results indicate a faster lysis of thrombi formed in the presence of dextran. (Photographs with kind permission of O. Tangen and reproduced from Tangen, 0., et aI.: Effects of dextran on the structure and plasmin-induced lysis of human fibrin. Thromb. Res., 1 :487, 1972. Used with permission.)

The fact that dextran has antithrombotic properties makes many believe that there must be an increased risk of bleeding complications. It is of course true that an improved microcirculation increases oozing. But this is not a real problem, except in special situations such as liver resection and in neurosurgery. It is, however, a fact that dextran preparations available today used in clinical dosages do not induce measurable changes in the clotting mechanism. 28

DISCUSSION There is no doubt that one of the most important factors leading to postoperative thrombus formation is the enormous tissue damage (due to trauma and surgery), with its release of tissue thrombokinase. Of importance in thrombus formation are also premedication, anesthesia, immobilization of the patient, and other conditions leading to impaired blood flow; such as blood loss and positive pressure breathing. This information regarding pathogenesis of postoperative DVT leads to the requirement of prophylaxis for thromboembolic complications in all trauma patients and in surgery in general. Such a prophylaxis has to start as soon as possible, i.e., it has to be active during operation in patients undergoing elective surgery. In injured patients the prophylaxis has to be instituted just after admission. The demand of early prophylaxis is made by the fact that most of the postoperative DVT can already be diagnosed within the first 48 hours after operation. 26 • 29. 53

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Review of Studies Documenting the Value of Dextran 70 in the Prevention of Deep Venous ~ Thrombosis in Urology NUMBER OF PATIENTS

AUTHOR

YEAR

Controls

Dextran 70

l"l

~

PATIENTS WITH DVT (PER CENT)

Heparin

Controls

Dextran 70

Heparin

SIGNIFICANCE

*

~

b:l

o

l"l

Hedlund

1974

40

37

38

45

37

27

C-D p = 0.08 C-H-p= 0.23

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o

'Fischer's exact test.

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Table 6. Review of Controlled Studies on the Value of Dextran 70 in the Prevention of Postoperative Fatal Pulmonary Embolism (FPE), Verified at Autopsy NUMBER OF PATIENTS

Controls AUTHOR

YEAR

Total

FPE

Ahlberg Ahlberg Atik Hartshorn Huttunen Jansen Koekenberg Myhre Stadil

1968 1969 1970 1969 1971 1972 1962 1969 1970

47 52 77 104 100 301 105 55 397 1238

2 2 5 2 4 4

TOTAL

2 5 27

Dextran" Total 39 32 49 99 100 304 94 55 424 1196

FPE 0 1 0

0 0

5

':'The effect of dextran 70 is highly significant (p < 0.001).

Coumarins In spite of the fact that oral anticoagulation has been known for years, it has not been accepted as a general form of prophylaxis for TEC. Obviously surgeons are afraid of bleeding complications and they rather accept a PE than run a high risk by a prophylactic measure. Apart from bleeding complications, there are other problems which make coumarin prophylaxis in surgery difficult: There are many containdications and drug interactions.54, 57, 61, 62 Also, frequent laboratory controls are necessary. This is time-consuming and costly. On the evidence available, the effectiveness of postoperative administration of coumarin and its derivatives for preventing DVT is established with certainty in hip surgery only.12,65 Coumarin seems to reduce the incidence of lethal PE in general and hip surgery. Taking all the disadvantages of coumarin prophylaxis into consideration, it is not surprising that dextran and subcutaneous heparin are the two drugs preferably used by surgeons for prevention of TEC. Heparin More patients have to be studied before the effectiveness of minidose heparin can be guaranteed in orthopedic and gynecologic surgery.5 However, it is well documented in general surgery and it is likely that it can be shown to be effective in reducing the number of lethal postoperative PE. No conclusions are possible regarding the ideal dose. It seems that 3 x 5000 IV per day are more effective and 2 x 5000 IV may not be sufficient for significantly lowering the incidence of lethal PE in all types of surgical patients. As for coumarin and dextran, little is known regarding prevention of TEC in urology. More trials are needed. In our personal clinical study we see resistance on the part of patients, nurses, and surgeons to the use of subcutaneous heparin. Patients do not like the 8-hourly injections during days, nurses do not like the additional work, and surgeons are worrying about bleeding compli-

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Table 7. Dextran 40 and DVT Incidence in Orthopedic or General Surgery and Urology* PATIENTS WITH DVT (PER CENT)

NUMBER OF PATIENTS AUTHOR

YEAR

Controls

Dextran 40

1971 1974

36 95

31 83

t>1

Heparin

Controls

Dextran 40

83

55.6 35.8

6.4 20.5

Heparin

SIGNIFICANCE

13.2

p < 0.001 p < 0.05 p < 0.001

~ ~

CO

Evarts Gruber

'Gruber, own results.

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cations in these patients, which do occur in contrast to those having dextran. It may be that many surgeons do not care so much if the DVT rate is lowered to 2/7 (by heparin) or to 3/7 of the controls (by dextran), but they definitely do not want to have postoperative bleeding problems. These practical problems seem to us to be the most important drawback of the heparin regimen; we do not doubt its effectiveness for reducing DVT in general surgery. Dextran Whereas the efficacy of dextran 70 for the prevenion of DVT in orthopedic surgery is well established and most probably for gynecology, the situation is less clear in general surgery. One of the main reasons why dextran's effectiveness in this important area is not yet as well documented might be the lack of studies using phlebography as the diagnostic criterion. It seems, however, reasonable to assume that the antithrombotic effect of dextran in general surgery exists here as well as in hip surgery, since it is well known that patients with a fractured femoral neck run a specially high risk of developing DVT and here dextran 70 has been shown to be extremely potent in lowering the DVT incidence. Dextran 40 is extremely effective in orthopedic surgery25 and in females in general surgery. This peculiarity of dextran certainly needs to be investigated further. The fact that fractures of the neck of the femur occur more often in women might explain the excellent results obtained with dextran in hip surgery. On all the evidence available it seems to be clear that dextran administration lowers the incidence of postoperative lethal PE, which certainly is one of the most important goals of any method for the prevention of TEe. The main disadvantage of dextran prophylaxis is the fact that it can be given by infusion only. This is no problem for the day of operation and the first postoperative day. It is neither a problem in major abdominal surgery, where patients are usually on intravenous feeding for several days. However, for those who can drink and eat early, additional infusions are boring. The advantages of dextran prophylaxis in surgery are that there is simultaneous volume replacement including hemodilution, the procedure is simple, no laboratory determinations are necessary, there are few complications, and the costs are low. Reviewing the literature, the following recommendations for the use of dextran can be made: Shock patients receiving dextran 40 or 70 for initial volume replacement should receive additional 500 ml on the first day after trauma and every other day thereafter if they cannot be mobilized. It is reasonable to institute oral anticoagulation with coumarin if it is clear that bed rest is prolonged. In elective surgery, 500 ml should be started shortly after induction of anesthesia. The reasons for this are the so-called anaphylactoid reactions, which may occur with a very low incidence after infusion of a few drops of dextran. For unknown reasons these reactions are extremely rare in shocked and anesthetized patients, but have been seen when the first dextran bottle was

DEXTRAN AND POSTOPERATIVE THROMBOEMBOLIC COMPLICATIONS

693

given to awake normovolemic individuals. Treatment of such reactions consists in rapid volume intravenous administration of steroids (250 mg hydrocortisone), antihistamines, and adrenalin (0.1 to 0.5 ml epinephrine hydrochloride 1: 1000). At the present state of knowledge, it can be said that it is a matter of taste if heparin or dextran prophylaxis is used in surgical patients; the most important is that one be used.

SUMMARY 1. The purpose of fluid administration is not only the restoration of blood volume but also the normalization of impaired nutritive flow. 2. Plasma oncotic (colloid osmotic) pressure is the only force which can draw water into the circulation. In shock the infusion of colloid solutions is able to normalize nutritive flow and peripheral resistance almost at once. 3. Five per cent solutions of pasteurized plasma protein or albumin and 6 per cent dextran 70 yield a volume expansion corresponding to the amount infused. 4. The decrease in hematocrit produced by the infusion of these three colloidal solutions is accompanied by a decrease in whole blood viscosity resulting in a rise in cardiac output as well as in nutritional tissue flow. 5. Hemodilution improves oxygen supply as long as the hematocrit does not fall below 30 per cent, although normovolemia is the critical requirement. 6. Transmission of viral hepatitis is still the greatest danger of blood transfusion. 7. The use of large amounts of Ringer's lactate is not advised, as this solution does not reduce the total number of units of blood which need to be given. Pulmonary edema may become a problem. 8. Dextrans are best suited to initial volume replacement in shock. They increase plasma volume, improve blood flow, have antithrombotic properties, and are easily available and relatively cheap. Anaphylactoid reactions are rare. 9. Every third patient undergoing general surgery and every other patient having hip surgery develops a deep venous thrombosis. Widespread prophylaxis to prevent thromboembolic complications is mandatory. 10. The antithrombotic properties of dextran are due to a reduction in platelet adhesiveness, a change in fibrin clot structure, and the increased lysability of thrombi and the improvement of blood flow. 11. In a personal controlled, prospective, randomized trial comparing subcu~ taneous heparin and intravenous dextran 40, 35.8 per cent of the controls (n = 95), 13.2 per cent of the 83 patients in the heparin group, and 20.5 per cent in the dextran group (n = 83) developed deep venous thrombosis. The difference between dextran and heparin is not significant; however, both treatment groups show a statistically significant effect compared to the controls.

REFERENCES 1. Aberg, M., Bergentz, S. E., Hedner, U., and Nilsson, I. M.: The mechanism of action for the antithrombotic effect of dextran. Europ. Surg. Res., 6(Supp!. 1):29, 1974. 2. Ahlberg, A., Goran, N., Robertson, B., Cronberg, S., and Nilsson, I.: Dextran in prophylaxis of thrombosis in fractures of the hip. Acta Chir. Scand., Supp!. 387:83, 1968. 3. Ahlberg, A.: Trombosprofylax med macrodex i ett collumfrakturmateria!. Studentlitteratur Lund, 89, 1969.

694

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