The purpose of this paper is to discuss the role and efficacy of dextran in vascular procedures using evidence-based data from the review of surgical literature. A MEDLINE search using “dextran,””vascular surgery,” and “antiplatelet therapy” as keywords was performed for English-language articles. Further references were obtained through cross-referencing the bibliography cited in each work. Dextran is commonly used in carotid endarterectomy (CEA) patients where the embolic rate is reduced by 46%, resulting in fewer procedure-related strokes. As a prophylactic agent against thrombosis, multiple randomized studies have reported its benefit over other antithrombotic medications. Dextran is also particularly useful in “difficult” infragenicular lower extremity bypasses where artificial grafts (such as polytetrafluoroethylene [PTFE] or umbilical vein) are used in the setting of poor outflow vessels, or those with composite grafts and small-caliber venous conduits. Distal bypasses with adjunctive procedures (eg, arteriovenous fistula or anastomotic cuffs) also have a better outcome with the addition of dextran. Dextran has numerous important implications in vascular surgery, in particular with CEA patients or “difficult” infragenicular bypasses. Its effectiveness with endovascular stents remains unknown.
Introduction
Dextran is a macromolecule crystalline polymer with numerous functions. Inhibition of platelet aggregation and adhesiveness, with prolongation of bleeding time, is its most important feature. Over the past 60 years, dextran has been widely used in vascular surgical procedures as well as other subspecialties such as plastics, orthopedics, and trauma. In this paper, we review the properties of this molecule and its role in specific procedures and conditions that may be optimized with the addition of dextran. A MEDLINE search using “dextran,””vascular surgery,” and “antiplatelet therapy” as keywords was performed for English-language articles. Further references were obtained through cross-referencing the bibliography cited in each work.
Structure
Dextran sulfate is a biopolymer macromolecule composed of repeating glucose subunits (Figure 1). The white crystalline form of dextran is solid and odorless with moderate solubility. It is synthesized by the action of the bacterium Leuconostoc mesenteroides on sucrose. It is a polysaccharide and so it is composed of polymers with variable molecular weights. There are 2 commercially available preparations-dextran-40 (molecular weight [MW] ranging between 10,000 and 75,000) and dextran-70 (MW ranging between 20,000 and 115,000). This difference in MW leads to a difference in the renal clearance of the 2 molecules. Renal clearance of dextran is inversely proportional to its MW. Dextran-40 contains molecules of varying sizes that are cleared at various time points. For example, molecules with MWs ranging from 18,000 to 23,000, 28,000-36,000, 44,000-55,000, and 55,000-69,000 have a halflife of 20 minutes, 30 minutes, 7.5 hours, and 12 hours, respectively. In contrast, 50% of dextran70 will be recovered in the urine within 48 hours. Molecules with weight > 50,000 daltons are first catabolized by dextranases located in liver, spleen, lung, and kidney before being eliminated.
Figure 1. Chemical structure of dextrans.
Table I. Function of dextran.
Mechanism of Action
Dextran acts via various mechanisms (Table I). It has effects on primary and secondary hemostasis. It also has antiplatelet activity, interferes with fibrin polymerization, inhibits erythrocyte aggregation, decreases blood viscosity, and is an osmotic agent.
In 1994, Erdtmann et al1 showed that Dextran-40-coated cellulose decreased platelet adhesion to 80% and dextran sulfate-coated cellulose with an MW of 500,000 decreased platelet adhesion to 30% when compared to subendothelial matrix. It has been reported that lowmolecular-weight dextran sulfate dose dependently decreased ristocetin-induced platelet aggregation.2 However, the exact mechanism could not be elucidated, but it was postulated that either direct binding of dextran to platelet or binding of dextran to von Willebrand factor or decreasing factor VIII levels may be the possible mechanism of action.
Early experiments showed that dextran, regardless of MW (10,000- 776,000) interfered with the formation of fibrin clot, when purified fibrinogen was clotted with thrombin.3 Dextran was shown to modify all 3 phases of clot formation-diminishing the induction phase and the second phase while accelerating the equilibration phase. It was speculated that this alteration of clot morphology would lead to changes in biophysical properties of the clot, such as clot porosity and mechanical strength. This was later confirmed when it was shown that dextran modified fibrin polymerization, resulting in thicker fibers.4 The resulting fibers had different biochemical properties. The addition of dextran to normal plasma or plasma from patients with Dusart syndrome (a form of congenital dysfibrinogenemia) shortened the clot lysis time when recombinant tissue-type plasminogen activator (rt-PA) was added to the plasma.5
Dextran molecules have been shown to interact with erythrocytes and change the velocity of rouleaux formation, subsequently increasing the propensity to form clot. At low concentration, the velocity of rouleaux formation increases. Interestingly, beyond a critical concentration, the velocity of rouleaux formation decreases. The exact mechanism for the change in the velocity of rouleaux formation is unclear, but conformational change in the dextran macromolecule has been implicated. The critical concentration for dextran70 was calculated to be 3 g/dL.6
Owing to its large MW, dextran exerts an osmotic force similar to other intravascular proteins such as albumin and globulin. This leads to a decrease in the permeability of blood vessels. With use of a modified Landis microocclusion technique, the addition of dextran-70 to both hypertonic and isotonic saline decreased single microvessel (20-30 m in diameter) permeability.7
Complications
Several notable side effects of dextran have been described in literature. These are summarized in Table II.
Hemorrhage
As described above, dextran has various effects on primary and secondary hemostasis. As a result, hemorrhage can occur secondary to the use of dextran. Epidural hematoma at the injection site was described recently in a patient undergoing a peripheral vascular bypass.8 A retrospective review showed that 26/32 patients treated with 400 mL of dextran-70 developed bleeding from skin and had prolonged coagulation times, and 12/32 developed thrombocytopenia.9 A study of uncontrolled hemorrhage in dogs showed that infusion of dextran resulted in an increased cumulative blood loss.10
Table II. Complications with dextran use.
Pulmonary Edema
The cause of dextran-mediated pulmonary edema is controversial. Several studies have cited the osmotic effects of dextran as a cause for plasma volume expansion leading to cardiogenic pulmonary edema. Elderly patients with cardiac failure are at high risk of developing dextran-induced pulmonary edema. This risk is reduced when the volume of dextran infused is limited to less than 10% of the patient’s blood volume daily. Major complications, such as volume overload and hemorrhage, are more frequent with dextran-70 than with dextran-40.11
The “dextran syndrome” is characterized by acute hypotension, hypoxia, coagulopathy, and anemia. Its mechanism remains unknown. A case report describes this syndrome in a healthy 26-year-old woman who underwent hysteroscopy for intrauterine adhesions. Her uterus was instilled with 300 cc of 32% dextran-70 in an equal volume of normal saline for better visualization. Postoperatively she developed noncardiogenic pulmonary edema with low filling pressures. The authors speculated that the mechanism for the pulmonary edema was related to pulmonary microvascular damage leading to flooding of alveoli with proteins, as has been show in canines.12
Renal Failure
Currently 60 cases of dextran-induced acute renal failure have been reported in the literature. However, a review study reported that 4.7% (10/211) of patients with acute ischemie stroke developed acute renal failure when they were treated with dextran-40 (50-100 g/ day) for 3-6 days.13 The incidence of renal failure increased dramatically among patients who had a glomerular flow rate of less than 30 cc/minute. The mechanism by which dextran induces renal failure is unclear. Some have implicated the direct toxic effect of dextran on kidneys as the cause for renal failure. Some groups have reported that dextran induced extensive swelling and vacuolization of the proximal tubules.14 Others have found that administration of dextran can cause acute interstitial nephritis. Siegel15 implicated the precipitation of dextran in the renal tubules leading to plug formation and subsequent renal failure. Damage of tubular cells, leading to leakage, of dextran into the renal parenchyma and resulting in osmotic nephrosis, has also been postulated as a potential mechanism for acute renal failure. Dextran is not removed by hemodialysis, and hence, plasmapheresis is the current established treatment of choice for dextran-induced renal failure.
Allergic and Anaphylactic Reactions
Allergic reactions (1%) and anaphylactic shock dire\ctly related to dextran infusion have been reported (
Table III. Role of dextran in vascular surgery.
The incidence of anaphylactoid reactions can be decreased by premedicating the patients with a monovalent hapten dextran- Promiten (20 mL dextran 1, 15%, Mw 1,000 dalton). This is usually given before dextran infusion, and it binds the antigen sites on the dextran-binding antibodies. Binding of these antibodies with the monovalent dextran will prevent the binding of the antibodies to larger dextran molecules that are polyvalent and will prevent the formation of large immune complexes. In 1 Swedish study, patients who received dextran-70 or 40 and had prophylactic intravenous injection of 20 mL dextran 1 hour before the infusion experienced a significantly lower (p = 0.01) dextran-induced anaphylactic reaction.17 However, other authors have demonstrated that only 40% of iron dextran-related anaphylactic-like reactions occur in response to the initial test dose.18 Therefore, subsequent doses of iron dextran may still pose a risk.
Hemodilution
The dextran-related hemodilutional phenomenon19 was described when dextran-40 was given after coronary stent placement. The hematocrit decrease often returns to near-baseline levels within 48 hours of stopping dextran.
Contraindications
Contraindications to the use of dextran include those patients with severe biventricular failure, pulmonary edema, or severe congestive heart failure. These patients are prone to worsening of their cardiac failure when given dextran because of its high osmotic properties. Prior anaphylaxis to dextran and severe bleeding diathesis with platelet dysfunction or hemostatic defects are other contraindications. It should also be used cautiously in people with renal disease. Patients with renal insufficiency may not be able to handle the osmotic load and subsequent volume expansion caused by dextran. In addition, the administration of dextran may induce electrolyte abnormalities, particularly hyperkalemia, in this patient population. Adequate hydration with crystalloids is needed in this population to prevent acute renal failure.
Role in Vascular Surgery
Volume Expansion
Dextran was used as blood-plasma volume expanders in the early 1940s, and over the past 60 years, its antithrombotic properties have been better defined. It is both osmotically active and too large to pass through the uninjured vessel. These characteristics, combined with its high oncotic properties, make this agent an ideal plasma expander, and it has been previously used in hypovolemic shock (Table III). However, the data regarding the use of 6% dextran- 70 in combination with 7.5% NaCl (HSD) are conflicting. HSD is a hypertonic-hyperosmotic solution that has been used as a plasma expander in the treatment of hemorrhagic hypotension. In animal models of controlled hemorrhage there is enough evidence to prove the superiority of HSD compared to crystalloids in equal volumes.20 However, its benefits in human studies have not been clearly demonstrated. Recently, a randomized, double-blinded study demonstrated improved survival in patients with penetrating trauma to the torso who received initial fluid resuscitation with HSD as compared to normal saline.21 In contrast to controlled hemorrhage, in animal models of uncontrolled hemorrhage HSD has been shown to increase and or accelerate mortality. Its role in uncontrolled hemorrhage remains controversial.10
Antithrombotic
Dextran has been used prophylactically to prevent venous and arterial thrombosis. Several randomized clinical trials have demonstrated reductions in deep venous thrombosis (DVTs) (15.6% with dextran versus 24.2% in controls), and pulmonary emboli (PE) (1.2% with dextran versus 2.8% in controls).22 Dextran has provided effective DVT prophylaxis in patients undergoing hip surgery.23 In an international multicenter prospective study of general surgical, urological, gynecological, and orthopedic patients undergoing elective operations lasting at least 30 minutes, prophylaxis with dextran-70 (given as 3 500-mL doses with the first dose given during surgery) was compared with low-dose subcutaneous heparin (5,000 units given every 8 hours, starting 2 hours before surgery and continuing for 6 days or until full mobility). There was no difference in the incidence of fatal pulmonary embolism in the 2 groups.24 An equal number of bleeding complications occurred with both regimens, and serious allergic reactions occurred in 1.1% of patients with dextran.24
Dextran has been widely used as an alternative to heparin anticoagulation and antiplatelet agents. Its ability to inhibit factor VIII activity, lyse clot, and inhibit platelet aggregation in response to collagen made this an ideal agent in combating the postoperative hypercoagulable state.25-27 Data in rabbits from Matthiasson et al28 suggest that there might be a potential additive effect of using heparin and dextran without increasing the risk of bleeding complications. However, there are not sufficient data from clinical trials on the additive effect of using a combination of dextran and other anticoagulants. Clinical trials on the use of this combination therapy are needed.
Antiplatelet and Antifibrin (Graft Patency)
Dextran-40, also known as low-molecular-weight dextran (LMD), has been shown to reduce the platelet deposition onto prosthetic materials.29 It does not improve the early patency of autogenous infrainguinal bypass grafts.30 However, there may be subsets of patients who might benefit from dextran administration, in particular, those with veins of poor quality, those with poor outflow, and those undergoing prosthetic bypass grafting. Dextran- 40 is beneficial in any scenario in which the risk of early thrombosis is high, but its routine use as an adjunct to lower extremity revascularization performed with autologous vein is not recommended.30
Randomized animal studies have documented the efficacy of dextran in decreasing both platelet and fibrin deposition in arterial grafts.31 Intravenous dextran-40 continues to be used in microsurgical anastomosis. Dextran-70 in an ordinary dose exerts such a profound antithrombotic effect in small traumatized arteries that the addition of a high dose of low-molecular-weight heparin (LMWH) would not be beneficial.32 Dextran, however, significantly prolongs bleeding times and improves early patency rate in both arterial and venous reconstructions. It does not improve the patency beyond 1 week, and it has little effect on long-term patency.33 It has been demonstrated that dextran mixed with hypertonic normal saline solution has a significant flow-promoting action in several vascular beds and potential beneficial effects on the patency of small-diameter polytetrafluoroethylene (PTFE) grafts.34
Dextran has also been investigated as an intravenous infusion given perioperatively and for 3 days after peripheral bypass surgery. Graft patencies at 3 days and 1 week have been shown to be improved by dextran-40 in comparison to an untreated control group or in addition to standard perioperative treatment with heparin.25,34 These benefits were evident only in grafts to the tibial or peroneal vessels and were not seen in autogenous vein grafts.35 This study randomized 200 patients, and with initial 1- month follow-up, there was a 6.9% occlusion rate in the dextran group compared to 20.5% in the group that did not receive dextran. However, long-term follow-up on the same patient population confirmed no beneficial long-term patency with dextran.36 A more recent single-center study in reversed vein grafts found that there was no benefit at 30 days in terms of graft patency or in the number of patients alive with a patent bypass with dextran therapy.29 A nonrandomized comparison of dextran with the combination of dextran and warfarin suggested that the combination gave better results on clinical endpoints.37 This has also been shown in case reports.38
Infusions of dextran-40 have been shown to significantly reduce the early postoperative thrombosis in difficult distal bypasses. Rutherford and associates,25 in a multicenter, randomized trial, showed significantly improved 1-week patency rates after 156 difficult distal bypasses (6.8% vs 20.5%). In a subsequent analysis including additional cases (n = 195), a statistically significant advantage was also demonstrated after 1 month.25 Significantly greater benefit was demonstrated in the dextran group for 2 subsets of patients. The first group of patients underwent peroneal and tibial bypasses (0% vs 31.1%). The second group of patients were those who were undergoing femorodistal bypasses in which grafts other than saphenous vein grafts were used (10% vs 36.4%), such as umbilical vein or PTFE.
Shoenfel\d et al28 have demonstrated, in an ex vivo baboon shunt preparation in which its flow and dilutional effects were controlled, that dextran-40 infusions significantly reduced the rate of platelet deposition in both PTFE and Dacron grafts. This effect occurred at an infusion rate equivalent to 25 mL/kg. The regimen effective in the clinical trial employed an alternative infusion rate of 100 mL/hr (1 unit) and postoperative infusion rates of 75 mL/ hr (1 unit per day). This 4-day, 5-bottle regimen was designed to increase flow as well as to decrease thrombogenicity. The latter effect is probably more important and is multifactorial in clinical settings. Low-molecular-weight dextran coats both platelets and vascular endothelial cells, increases their electronegativity,40 and produces a decrease in factor VIII-related antigen out of proportion to what would be expected by dilutional effects alone.26,39 Also, dextran acts as a plasminogen activator and inhibits alpha-2- antiplasmin, thereby accelerating plasma clot lysis.41 Lower infusion rates of 25 mL/hr rather than larger doses are recommended in those with acute renal dysfunction and congestive heart failure. Similar lower dosage is appropriate if other means of increasing flow have been employed such as distal arteriovenous fistula or sympathetic blockade.
Antiembolic
Carotid endarterectomy (CEA) is complicated by thrombosis in approximately 3% of cases, and commonly presents in the first 6 hours postoperatively.42 The majority of perioperative strokes are secondary to thromboembolic complications occurring during carotid dissection or in the immediate postoperative period. Numerous methods have been used in an attempt to decrease the incidence of thromboembolic complications associated with CEA. These include the administration of perioperative aspirin and the intraoperative use of unfractionated heparin. In addition, some investigators have advocated the use of dextran-40 postoperatively to decrease the stroke rate.43,46
In 1 Australian study, dextran was shown to reduce the embolie signals after carotid endarterectomy42; 150 patients undergoing CEA were randomized to dextran-40 and placebo. Transcranial Doppler monitoring of the ipsilateral middle cerebral artery was performed in all the patients. The overall embolic signal counts were 46% less for the dextran group after 0-1 hour postoperatively (p = 0.052) and also 64% less again in the dextran group after 2-3 hours postoperatively (p = 0.040). Concluding results indicate that dextran reduces embolic signals within 3 hours of CEA.
Hayes et al44 conducted a prospective study on 600 consecutive CEAs using transcranial Doppler-directed dextran-40 therapy. Patients were monitored with transcranial Doppler for 6 hours postoperatively following CEA. Patients who showed evidence of postoperative thromboembolism by transcranial Doppler were started on dextran-40 at 20 mL/hr. There were no complications associated with the use of dextran in this study. The authors concluded that the use of transcranial Doppler-directed dextran-40 therapy can significantly reduce the stroke rate associated with CEA in centers performing more than 50 CEAs per year.44
Naylor et al45 performed a prospective study on 500 consecutive patients undergoing CEA. Transcranial Doppler monitoring was started after the induction of anesthesia and continued for 3 hours postoperatively. Dextran-40 was started in any patient who showed evidence of thromboembolism by transcranial Doppler. Twenty-two of 500 patients (4.4%) required dextran therapy. Dextran therapy decreased the median embolus count within the first 3 hours. The postoperative stroke rate was decreased by 60% (from 4% to 0.2%) in this study.
Lennard et al46 did a prospective study in 166 patients undergoing CEA and found that monitoring patients with transcranial Doppler-directed dextran therapy for 3 hours postoperatively was as effective as 6-hour monitoring in the prevention of postoperative carotid thrombosis. Patients who had more than 25 emboli detected in any 10-minute period or had emboli that distorted the arterial waveform were started on dextran-40. Nine of 166 patients (5.4%) required dextran therapy. Dextran therapy significantly reduced the number of emboli detected by transcranial Doppler. Emboli stopped in all patients on dextran therapy. Of the 166 patients in this study, 97% required monitoring for 3 hours, 2% for 4 hours, and 1% for more than 4 hours.
Stroke is a major cause of morbidity and mortality following CEA. Thromboembolism accounts for a significant percentage of perioperative neurologic complications from CEA. Platelet activation, adhesion, and aggregation are triggered by the surface of the endarteriomized carotid wall following CEA, leading to embolism and carotid occlusion. Dextran, owing to its antiplatelet properties, is useful in reducing the perioperative stroke rate in patients undergoing CEA.
Conclusion
Based on the current data available, we recommend that patients undergoing CEA be placed on dextran-40 at 20 cc/hr and that the infusion be started after a Promit test-dose. The infusion should continue for overnight hospital stay, and be stopped if signs of congestive heart failure or bleeding occur.
If cryopreserved, umbilical veins or PTFE grafts are used for lower extremity bypasses, in particular, those infragenicular groups, dextran40 should be used postoperatively in conjunction with systemic and oral anticoagulation. We also recommend its use in difficult bypasses: poor outflow, composite grafts, or small- caliber vein grafts, and in adjunctive procedures such as arteriovenous fistula or distal vein cuffs. In certain patients with a history of HIT (heparin-induced thrombocytopenia), dextran has been effectively used. Further prospective, randomized studies are essential to better study the effects and potential uses of dextran in vascular surgery.
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Farshad Abir, MD, Siamak Barkhordarian, MD, and Bauer E. Sumpio, MD, PhD, New Haven, CT
Vasc Endovasc Surg 38:483-491, 2004
From the Yale University School of Medicine, section of Vascular Surgery, New Haven, CT
Correspondence: Bauer E. Sumpio, MD, PhD, Yale University School of Medicine, section of Vascular Surgery, 333 Cedar St., FMB 137, New Haven, CT 06520-8062
E-mail: [email protected]
2004 Westminster Publications, Inc, 708 Glen Cove Avenue, Glen Head, NY 11545, USA
Copyright Westminster Publications, Inc. Nov/Dec 2004
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