Journal of Vascular Surgery
Volume 43, Issue 5 , Pages 1070-1072, May 2006

Invited commentary: Pretreatment with dextran 1 makes dextran 40 therapy safer

  • Karl-Gösta Ljungström, MD, PhD

      Affiliations

    • Corresponding Author InformationReprint requests: Karl-Gösta Ljungström, MD, PhD, Department of Surgery, Danderyd Hospital, S-182 88 Stockholm, Sweden

Department of Surgery, Danderyd Hospital, Stockholm, Sweden

Received 9 September 2005; accepted 23 November 2005.

Article Outline

 

At a meeting held in July 2005, the Blood Products Advisory Committee of the US Food and Drug Administration (FDA) addressed the problem of serious and life-threatening anaphylactoid reactions induced by intravenous dextran solutions (dextran-induced anaphylactoid[ic] reactions, DIAR). The FDA has recently become aware that pretreatment with dextran 1 to reduce the risk of DIAR is rarely being followed by surgeons and anesthesiologists, especially those just out of training, because the package inserts of clinical dextrans sold in the United States today do not contain any information on the clinical benefit of dextran 1. The purpose of this editorial is to review hapten inhibition by dextran 1, a routine that has resulted in a dramatic 35-fold reduction of severe DIAR in other countries.

Dextrans are composed of long chains of glucose molecules linked by α1-6 bonds. These solutions have been licensed for almost 60 years, and although many newer colloids have been introduced, dextrans still hold a place for routine use in vascular and plastic surgery. The reason is that dextrans have advantageous rheologic properties—they moderate platelet function and are antithrombotic—that other colloids do not possess. Today, dextran solutions are utilized by vascular surgeons to reduce the risk of postoperative stroke in carotid endarterectomy patients1 and by plastic and reconstructive surgeons to reduce the risk of occlusion of microvascular anastomoses.2

Allergic reactions are seen with both naturally occurring and artificial colloids administered intravenously. The early dextrans of the 1940s frequently caused allergic reactions. Despite introduction in the 1950s of less-branched dextran molecules and a much lower incidence of adverse reactions, this view continues to prevail in some countries.

Two different mechanisms in DIAR have been demonstrated: mild, anaphylactoid, non-antibody-dependent reactions, and severe anaphylactic reactions in patients with high titers of preformed dextran-reactive antibodies (DRA).3 These severe reactions can be triggered by small or even minute (0.5 to 1.0 mL) volumes of dextran and are caused by large immune complexes formed from dextran molecules and DRA, predominantly immunoglobulin (Ig) G.4 These reactions activate platelets, as well the coagulation and complement systems, resulting in allergic symptoms. Respiratory and circulatory derangement is also seen with increasing grades of severity, as summarized in Table I. It should be pointed out that IgE, mast cells, and histamine, among others, are not involved in these type III anaphylaxis reactions. Clinical dextrans are nonimmunogenic, and previous exposure to dextrans is not a risk factor. Rather, DRA are thought to represent cross-reactive antibodies against polysaccharides in encapsulated bacteria7 or antibodies against native, “wild” dextran, such as in cane sugar.

Table I. Dextran-induced anaphylactoid(ic) reaction in Sweden, 1975 to 1979, and during postmarketing surveillance, 1983 to 1992

DIAR, Dextran-induced anaphylactoid(ic) reaction.

⁎ During 1975-1979, 647,756 units of clinical dextrans were sold to hospital clinics in Sweden, corresponding to 0.3 million dextran-treated patients.5

† During 1983-1992, 1.2 million units of dextran 1 were sold, corresponding to the same number of dextran-treated patients, since dextran 1 is only given before the first unit of clinical dextran.6

Reports of adverse drug effects in national pharmacovigilance databases may underestimate the true incidence of side effects. The incidence of adverse effects following colloid administration, even in prospective trials, may be misleading if the incidence is only calculated in relation to the number of units of colloids administered. This is because adverse reactions are generally seen only when the first unit is given, and it is common to give several units to each patient.

In Sweden, reporting of adverse reactions to drugs was made mandatory in 1974. This caused a considerable increase in the total number of adverse events reported but no increase in the number of reports on fatal adverse events, indicating that these were already being reported to a high degree. In a study of adverse reactions to dextrans in Sweden for 1970 to 1979, reports sent to regulatory bodies, insurance companies, and the manufacturer were collected and analysed. Complete hospital records were available in 90% of the cases. For the period 1975 to 1979, the calculated incidence of severe DIAR was one in 2000.5

The idea to use hapten inhibition was suggested early on by Kabat et al,8 who demonstrated in vitro that the combining site of DRA would bind to approximately five glucose molecules of the dextran chain. It was later shown in animal experiments that by injecting small fragments of dextran (ie, dextran 1), the combining sites of DRA could be blocked without eliciting a reaction.9 Demonstrating the efficacy of this method in humans was a formidable task, given an incidence of only one reaction in 2000 treated patients. Between 1978 and1982, a series of multicenter studies comprising 130,000 patients were conducted in three Scandinavian countries, Germany, and Switzerland. The 1.5-g dose of dextran 1 used in the beginning proved too small; however, doubling the dose significantly reduced the incidence of severe DIAR compared with the first dose. Reactions to dextran 1 itself were of low frequency, mainly isolated mild skin reactions or short-lasting episodes of bradycardia with or without hypotension.10, 11, 12, 13

Shortly thereafter, dextran 1 was approved in 15 countries, including the United States, where it was introduced in 1984. Postmarketing surveillance has continued during the 22 years since approval both in Sweden and worldwide, and the results have been published twice.6, 14 Overall, the same protective effect achieved in the prospective studies has been observed in clinical practice—a 35-fold reduction in severe DIAR (an incidence of 1 in 70,000 exposures) compared with the 1975 to 1979 historical control data (Table I). With >8 million doses of dextran 1 distributed worldwide, only two fatal cases of DIAR have been reported after clinical dextran administration in patients pretreated with dextran 1, a 90-fold reduction!

The basic principles for administering dextran 1 are summarized in Table II. Of note, pretreatment with 3 g of dextran 1 cannot completely eliminate the risk for severe DIAR, since occasional patients with extremely high titres of DRA still react, although the reactions in most of these cases are attenuated. In addition, pretreatment with dextran 1 does not prevent mild, anaphylactoid, nonantibody-dependent reactions. Still, with dextran 1 pretreatment, the incidence of severe adverse reactions to dextran in Sweden today is lower than the corresponding incidence reported for human serum albumin in the only two existing prospective studies on adverse reactions to intravenous colloids.15, 16

Table II. Principles for the administration of dextran 1
•Dextran 1 is injected intravenously 1-2 minutes before the start of an infusion of clinical dextran (dextran 40 or 70).
•The dose is 20 mL for adults and 0.3 mL/kg body weight for children.
•The time interval between the administration of dextran 1 and clinical dextran should not exceed 15 minutes; if a longer period has elapsed, another dose of dextran 1 should be given.
•If another infusion of clinical dextran is to be given, it is only necessary to repeat the dextran 1 injection if >48 hours have elapsed since the last dextran infusion.
•Be sure not to inject dextran 1 through intravenous lines (etc) that already contain clinical dextran solution.

Use of hypertonic saline/dextran to resuscitate trauma patients in the field and in-hospital is a fascinating new therapy. This solution has been widely used in Europe (20,000 units sold) without any reports of DIAR, even though dextran 1 is rarely preinjected. Some have proposed that absence of reports of DIAR in patients with hemorrhagic shock is due to the excessive release of endogenous catecholamines, although there is no scientific evidence for this. In any event, in the emergency setting, the risk of severe DIAR (1/2000) is insignificant compared with the risk of increased mortality from prolonged shock.

In summary, severe DIAR is a condition that can be virtually prevented by the safe and simple principle of hapten inhibition with dextran 1 pretreatment. This method has been used in northern Europe for >20 years with >8 million exposures and has resulted in a 35-fold reduction of severe DIAR and a 90-fold reduction of fatal reactions, making dextran at least as safe as albumin and starches.

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References 

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 Competition of interest: none.

PII: S0741-5214(05)02096-3

doi:10.1016/j.jvs.2005.11.056

Journal of Vascular Surgery
Volume 43, Issue 5 , Pages 1070-1072, May 2006

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