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 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

Molecular weight distrubutionsfor 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

Albumin HES Gelatin

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 leucocytes flush, shock,

complement bronchospasm coagulation etc

Classification of DIARGrade 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 arrestV Fatal 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 40 000

Hapten inhibition 1

Hapten inhibition 2

Dextran 1 molecular distribution

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)

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)

Reactions to dextran 1

Type Symptoms No.A Skin symptoms (flush, 22

erythema, urticaria)B Bradycardia ± hypotension 6C Hypotension 10Misc. Dizziness, nausea etc 8

Total 46Incidence: 1 in 100 000 doses

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)

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

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.