Prevention of adverse reactions to dextran

1. Prevention of adverse reactions to dextran • Karl-Gösta Ljungström • M.D., Ph.D., Associate professor, Karolinska Institute • Department of Surgery • Danderyd Hospital • Stockholm • Sweden

2. Björn Ingelman - originator of dextran in 1942

3. Dextrans are made from (1-6 ) linked glucose units

4. Dextran In clinical use since 1947. Manufacturing process: Sucrose is converted by Leuconostoc mesenteroides to native dextran, which is hydrolysed and fractionated. Since 1955 the B512 strain of Leuconostoc is used, producing a dextran molecule with few sidebranches

5. Molecular weight distrubutions for different colloids

6. Dextran 1947 and 2005 are not the same!

7. Dextran - >50 years in clinical use Replacement of blood loss Plasma replacement Thrombosis prophylaxis Volume expansion Rheological improvement Optic medium in surgery Pharmacological agent

8. Adverse effects of colloids Fluid overload Renal function impairment Dilution of coagulation factors Loading of the RES and storage in the body Allergic reactions

9. Severe anaphylactic reaction to a colloid (gelatin)

10. Anaphylactoid or anaphylactic reactions to colloids? Anaphylactoid - an adverse reaction with allergic symptoms but NOT involving preformed antibodies. The mechanisms involved may be quite different in seemingly similar reactions. Anaphylactic- an allergic reaction involving either reaginic antibodies (IgE), e.g. some reactions to gelatin, or antibodies of other classes (IgG, IgM, IgA), e.g. dextran reactions.

11. Allergic reactions to colloids - look the same but different mechanisms Albumin HES Gelatin

12. Dextran-induced anaphylactic reaction (DIAR)

13. Allergic reactions to dextran DIAR = Dextran induced anaphylactoid/anaphylactic reactions DRA = Dextran reactive antibodies

14. DIAR have dual pathomechanisms Mild dextran reactions are anaphylactoid and many of these patients have a history of allergy. Severe DIAR are anaphylactic and are caused by preformed DRA, predominantly of IgG-class, causing a type III or immune complex anaphylaxis. Elevated IgE-levels and histamine liberation has not been found in DIAR

15. Titre of DRA

16. Immune complex anaphylaxis

17. Pathomechanism for severe DIAR DRA + Clinical dextran Immune complexes Activation of vasoactive platelets mediators causing leucocytes flush, shock, complement bronchospasm coagulation etc

18. Classification of DIAR Grade of Characteristic symptoms severity I Skin manifestations(flush, erythema, urticaria) Lumbar pain II Mild to moderate hypotension Gastrointestinal disturbances Respiratory distress III Severe hypotension, shock Bronchospasm IV Cardiac and/or respiratory arrest V Fatal reaction

19. Potential antigenic stimuli for DRA production Native dextran Dental plaques Food additive Contaminant of sucrose Cross-reactive polysaccharides Pneumococci Streptococci Salmonella Klebsiella

20. Harriet Hedin and Wolfgang Richter - immunologists

21. Hapten An incomplete antigen, unable to induce the formation of antibodies but still able to bind to specific antibodies The name (from greek hapto = to seize) was introduced by Karl Landsteiner 1921

22. Dextran molecule, Mw 40 000

23. Hapten inhibition 1

24. Hapten inhibition 2

25. Dextran 1 molecular distribution

26. Scandinavian studies with dextran 1, 1978-1982 N. pat N. severe DIAR 1.5 g dx 1 preinj. 29 252 7 p=0,010 3 g dx 1 preinj. 41 099 1 (combined)

27. DIAR in Sweden before and after introduction of Promit® DIAR, grades of severity • I II III IV V Total • 1975- Without • 1979 dextran 1 61 94 78 44 23 300 • (0.3 milj. patients) • 145 • (1/2 000 patients) • 1983- With • 1992 dextran 1 78 44 12 4 1 139 • (1.2 milj. patients) • 17 • (1/70 000 patients)

28. Reactions to dextran 1 Type Symptoms No. A Skin symptoms (flush, 22 erythema, urticaria) B Bradycardia ± hypotension 6 C Hypotension 10 Misc. Dizziness, nausea etc 8 Total46 Incidence: 1 in 100 000 doses

29. DIAR in Sweden 1993-2004 DIAR, grades of severity • I II III IV V Total • 1975- Without • 1979 dextran 1 61 94 78 44 23 300 • (0.3 mil. patients) • 145 • (1/2 000 patients) • 1993- With • 2004 dextran 1 18 26 13 2 0 62 • (≈1 mil. patients) • 15 • (1/67 000 patients)

30. DRA-titers in some examples of mitigated severe DIAR Reg.no. Grade DRA-titer 86-P-Mac-27 II 2 000 000 88-P-Mac- 1 III 32 768 91-P-Mac-2 III 33 000 000 92 30315 III 134 000 000

31. References Hedin H, Richter W: Pathomechanisms of dextran-induced anaphylactoid/anaphylactic reactions in man. Int Arch Allergy Appl Immunol 1982; 68: 122-6. Ljungström K-G. Safety of dextran in relation to other colloids - Ten years experience with hapten inhibition. Infusionsther Transfusionsmed 1993; 20: 206-10. Ljungström K-G. Colloid safety - fact or fiction. In: Baillière’s Clinical Anaesthesiology, 1997, vol.11: 163-177.