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Prevention of adverse reactions to dextran Karl-Gösta Ljungström M.D., Ph.D., Associate professor, Karolinska Institute Department of Surgery Danderyd Hospital Stockholm Sweden
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Björn Ingelman - originator of dextran in 1942
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Dextrans are made from (1-6 ) linked glucose units
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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
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Molecular weight distrubutions for different colloids
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Dextran 1947 and 2005 are not the same!
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Dextran - >50 years in clinical use Replacement of blood loss Plasma replacement Thrombosis prophylaxis Volume expansion Rheological improvement Optic medium in surgery Pharmacological agent
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Adverse effects of colloids Fluid overload Renal function impairment Dilution of coagulation factors Loading of the RES and storage in the body Allergic reactions
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Severe anaphylactic reaction to a colloid (gelatin)
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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.
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Allergic reactions to colloids - look the same but different mechanisms AlbuminHESGelatin
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Dextran-induced anaphylactic reaction (DIAR)
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Allergic reactions to dextran DIAR = Dextran induced anaphylactoid/anaphylactic reactions DRA = Dextran reactive antibodies
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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
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Titre of DRA
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Immune complex anaphylaxis
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Pathomechanism for severe DIAR DRA + Clinical dextran Immune complexes Activation of vasoactive platelets mediators causing leucocytesflush, shock, complementbronchospasm coagulationetc
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Classification of DIAR Grade of Characteristic symptoms severity ISkin manifestations(flush, erythema, urticaria) Lumbar pain IIMild to moderate hypotension Gastrointestinal disturbances Respiratory distress IIISevere hypotension, shock Bronchospasm IVCardiac and/or respiratory arrest VFatal reaction
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Potential antigenic stimuli for DRA production Native dextran Dental plaques Food additive Contaminant of sucrose Cross-reactive polysaccharides Pneumococci Streptococci Salmonella Klebsiella
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Harriet Hedin and Wolfgang Richter - immunologists
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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
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Dextran molecule, Mw 40 000
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Hapten inhibition 1
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Hapten inhibition 2
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Dextran 1 molecular distribution
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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)
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DIAR in Sweden before and after introduction of Promit ® DIAR, grades of severity I II III IV V Total 1975- Without 1979 dextran 1 61947844 23 300 (0.3 milj. patients) 145 (1/2 000 patients) 1983- With 1992 dextran 1 78 44124 1 139 (1.2 milj. patients) 17 (1/70 000 patients)
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Reactions to dextran 1 TypeSymptomsNo. ASkin symptoms (flush, 22 erythema, urticaria) BBradycardia ± hypotension6 CHypotension10 Misc.Dizziness, nausea etc8 Total46 Incidence: 1 in 100 000 doses
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DIAR in Sweden 1993-2004 DIAR, grades of severity I II III IV V Total 1975- Without 1979 dextran 1 61947844 23 300 (0.3 mil. patients) 145 (1/2 000 patients) 1993- With 2004 dextran 1 18 26132 0 62 (≈1 mil. patients) 15 (1/67 000 patients)
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DRA-titers in some examples of mitigated severe DIAR Reg.no.GradeDRA-titer 86-P-Mac-27II2 000 000 88-P-Mac- 1III32 768 91-P-Mac-2III33 000 000 92 30315III134 000 000
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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.
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