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

Björn Ingelman - originator of dextran in 1942

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

Dextran In clinical use since 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

Molecular weight distrubutions for different colloids

Dextran 1947 and 2005 are not the same!

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

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

Severe anaphylactic reaction to a colloid (gelatin)

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.

Allergic reactions to colloids - look the same but different mechanisms AlbuminHESGelatin

Dextran-induced anaphylactic reaction (DIAR)

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

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

Titre of DRA

Immune complex anaphylaxis

Pathomechanism for severe DIAR DRA + Clinical dextran Immune complexes Activation of vasoactive platelets mediators causing leucocytesflush, shock, complementbronchospasm coagulationetc

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

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

Harriet Hedin and Wolfgang Richter - immunologists

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

Dextran molecule, Mw

Hapten inhibition 1

Hapten inhibition 2

Dextran 1 molecular distribution

Scandinavian studies with dextran 1, N. pat N. severe DIAR 1.5 g dx 1 preinj p=0,010 3 g dx 1 preinj (combined)

DIAR in Sweden before and after introduction of Promit ® DIAR, grades of severity I II III IV V Total Without 1979 dextran (0.3 milj. patients) 145 (1/2 000 patients) With 1992 dextran (1.2 milj. patients) 17 (1/ patients)

Reactions to dextran 1 TypeSymptomsNo. ASkin symptoms (flush, 22 erythema, urticaria) BBradycardia ± hypotension6 CHypotension10 Misc.Dizziness, nausea etc8 Total46 Incidence: 1 in doses

DIAR in Sweden DIAR, grades of severity I II III IV V Total Without 1979 dextran (0.3 mil. patients) 145 (1/2 000 patients) With 2004 dextran (≈1 mil. patients) 15 (1/ patients)

DRA-titers in some examples of mitigated severe DIAR Reg.no.GradeDRA-titer 86-P-Mac-27II P-Mac- 1III P-Mac-2III III

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