11
`
`Allergic and anaphylactic reactions foil owing
`plasma substitute infusion
`
`S. NILDEN KOX
`WOLFGANG J. KOX
`
`Adverse drug reactions are frequently encountered in medical practice
`(Editorial, 1981). Some of these are anaphylactic in nature and range in
`severity from skin manifestations to fatal reactions such as circulatory and/or
`respiratory failure. There are reports of anaphylactic and allergic reactions
`following the use of plasma substitutes containing dextran (Brisman et al,
`1968; Strebel and Siegler, 1968; Maddi et al, 1969; Carlsson et al, 1972;
`Paull, 1987), gelatin (Eberlein and Dobberstein, 1962; Meisel and Zockler,
`1971; Schmidt and Pfluger, 1971a; Lorenz et al, 1976; Freeman, 1979) and
`hydroxyethyl starch (Lorenz et al, 1974a; Ring et al, 1976; Ring and
`Messmer, 1977; Stoelting, 1983) in a variety of clinical situations. The
`increase in number of reported adverse reactions to drugs, including plasma
`substitutes, in recent years may reflect either a true increase of such
`reactions or improved reporting by clinicians (Fischer, 1975; Furhoff, 1977;
`Hottinger et al, 1979).
`
`MECHANISMS OF ANAPHYLACTIC REACTIONS
`
`There are four mechanisms that can be responsible for allergic reactions
`after administration of a drug or other intravenous substance. All result in
`the production of chemical mediators which produce the pharmacological
`effects and clinical symptoms of allergic reactions. The first, anaphylaxis
`(Type I), requires previous exposure to the drug and the production of
`antibodies. The initial exposure to the drug stimulates the patient's lympho(cid:173)
`cytes to produce IgE antibodies specific for the drug. These antibodies
`ultimately attach to receptor sites on the cell membranes of both mast cells
`and circulating basophils. Mast cells and basophils are considered to be
`sensitized and capable of participating in an anaphylactoid reaction when
`stimulated upon re-exposure to the drug. This leads to degranulation of the
`mast cells and release of vasoactive substances such as histamine, slow(cid:173)
`reacting substance (SRS-A), platelet-activating factor (PAF), heparin,
`chemotactic factors for eosinophils and neutrophils (Figure 1). In some
`species another mediator of anaphylaxis, serotonin, is also released. These
`
`Bailliere's Clinica/Anaesthesiology-Vol. 2, No. 3, September 1988
`
`667
`
`

`

`668
`
`Mast cell
`
`S. N. KOX AND W. J. KOX
`
`+lgE
`
`a
`
`+ Allergen
`0-0
`
`b
`
`Release of mediators
`(e.g. histamine) from granules------....
`
`Anaphylaxis
`Figure 1. Type I: anaphylactic hypersensitivity. Mast-cell degranulation follows interaction of
`antigen with bound homocytotropic antibodies. (a) IgE binds to mast cells through its Fe piece
`(fragment crystallizable), the portion of the molecule different to the antigen combining sites.
`(b) When antigen (allergen 0---0) cross-links two adjacent lgE molecules, an allosteric
`modification of the antibodies occurs which induces the release of mediators from the mast cell.
`
`chemical mediators produce pharmacological effects which are responsible
`for the clinical manifestations of an allergic reaction. Histamine is the most
`important chemical mediator released by degranulation and the only
`substance proven to be essential for anaphylaxis (van Arsdel, 1982).
`Activation of the complement pathway by a drug or intravenous
`substance can proceed either through interaction with circulating IgG or
`IgM antibodies (the classical pathway) or by direct interaction with the
`complement protein C3 ( the alternate pathway) . In the former pathway the
`drug-antibody (IgG or IgM) interaction initiates a sequential cascade
`process by activating the normally quiescent circulating complement protein
`Cl. The activated products of the complement pathway, such as C3a and
`C5a, are anaphylatoxins and are capable of producing mast cell degranu(cid:173)
`lation or lysis with release of chemical mediators. In the latter pathway
`activation of the complement system involves direct activation of comple(cid:173)
`ment protein C3 in the absence of specific antibodies for the allergen/
`agonist. In this situation production of the activated complement protein
`C3a also results in degranulation of mast cells and basophils with the release
`of chemical mediators.
`The third mechanism, an anaphylactoid reaction, is due to a direct effect
`of the drug on mast cells and basophils stimulating the release of histamine.
`
`

`

`ALLERGIC AND ANAPHYLACTIC REACTIONS
`
`669
`
`The manifestations of an anaphylactoid reaction are indistinguishable from
`anaphylaxis or activation of the complement system, but the release of
`histamine is not dependent on previous exposure to the drug or the presence
`of specific antibodies. Artificial plasma substitutes are more likely to elicit an
`anaphylactoid reaction rather than either an anaphylactic reaction or acti(cid:173)
`vation of the complement pathway (Isbister and Fischer, 1980).
`
`DEXTRANS
`
`Dextrans are glucose polymers with relatively few side branches; they are
`produced from sucrose by the action of an enzyme from the bacterium
`Leuconostoc mesenteroides strain B512. Clinical dextran preparations have
`well-defined molecular weight distributions and are produced by partial acid
`hydrolysis of native dextrans with molecular weights of several millions.
`Clinical dextran preparations are usually defined by their molecular weight
`(MW) or their 'number average' (Mn), since colloidal solutions are more
`accurately described by their mean osmotically active particle weight. The
`following preparations are available: Dextran-40 (MW 40000, Mn 25 000),
`available as Rheomacrodex; Dextran-70 (MW 70 000, Mn 39 000), available
`as Dextraven-70 and Macrodex; and Dextran-110 (MW 110000, Mn
`55 000), available as Dextraven-110. Dextran-60, Dextran-75 and Dextran-
`150 are also available.
`Dcxtran-induced anaphylactoid/anaphylactic reactions (DIAR) have
`been reported since the introduction of dextran therapy in 1947. These
`range from skin manifestations to circulatory shock (Ring and Messmer,
`1977) and are potentially fatal (Revenas et al, 1980). The reactions are
`graded into four categories according to severity (Table 1) (Ring and
`Messmer, 1977) . The reported incidence of DIAR varies from 0.03 to 4.7%,
`and that of severe DIAR from 0.008 to 0.6%. These differences are prob(cid:173)
`ably due to the design of the studies performed (retruspective, prospective,
`double-blind etc.) or to the criteria chosen for classification of symptoms,
`whether the incidence is given per bottle of dextran infused or per patient,
`and difficulties encountered in the statistical evaluation of adverse drug
`reactions occurring with a low incidence. The pathomechanisms for these
`reactions have only been elucidated during the last decade (Hedin et al,
`1976, 1979; Hedin and Richter, 1982). A number of factors may contribute
`to the development of DIAR. Early workers attributed the responses to the
`antigenicity of dextran or to contamination of the dextran by bacterial
`
`Table 1. Severity scale for quantification of intensity of anaphylactoid reactions (Ring and
`Messmer, 1977).
`
`Grade
`
`Symptoms
`
`I
`II
`
`III
`IV
`
`Skin symptoms and/or mild fever reactions
`Measurable, but not life-threatening, cardiovascular reaction (tachycardia,
`hypotension)
`Gastrointestinal disturbance (nausea)
`Shock, life-threatening spasm of smooth muscles (bronchi, uterus etc.)
`Cardiac and/or respiratory arrest
`
`

`

`670
`
`S. N. KOX AND W. J. KOX
`
`endotoxin; however, later studies found no evidence for a pathogenic role of
`contaminating macromolecules (Richter, 1970; Hedin et al, 1976; Ring et al,
`1977; Richter, 1980). The anaphylactoid reaction-inducing potential of
`dextran appears to be a function of both molecular size and branching
`frequency, the anaphylactoid potential increasing as molecular size and
`branch number increase (Wilkinson and Stoney, 1953; Thorsen, 1954;
`Kabat et al, 1957; Ring and Messmer, 1977). Change from the previously(cid:173)
`used branched dextran to the nearly linear B512 dextran now widely
`employed minimized the mild allergic reactions seen earlier (Kabat et al,
`1957).
`Native high-molecular-weight dextran induces the formation of small
`amounts of circulating antibodies (Allen and Kabat, 1958); single or
`repeated doses of dextrans of clinical size do not induce antibody formation
`(Kabat and Berg, 1953; Gronwall, 1959). Naturally occurring dextran(cid:173)
`reactive antibodies (DRA) have been demonstrated in human sera (Kabat
`and Berg, 1953; Grabar, 1955). Animal studies indicated that dextran
`incompatibility was caused by direct histamine release (Voorhees et al,
`1951; Hahn, 1954). In humans, however, dextran in its clinically used form
`was not a potent histamine releaser (Lorenz, 1975), although Lorenz et al
`(1976), on the basis of plasma histamine level measurements in patients and
`volunteers after infusion of dextran, suggested that histamine could contri(cid:173)
`bute to the development of DIAR.
`Hedin et al (1976) examined 123 patients who reacted to dextran over a
`5-year period and showed that there was direct correlation between pre(cid:173)
`exposure levels of dextran-reactive antibodies (DRA) and the severity of
`subsequent DIAR. Patients who reacted to dextran tended to have higher
`levels of DRA than those who did not (Hedin and Richter, 1982). Hedin et
`al (1976) found no dextran-reactive antibodies of IgE class in blood of
`dextran reactors and concluded that D IAR did not correspond to IgE(cid:173)
`mediated cytotropic anaphylaxis. They found a positive correlation between
`titres of haemagglutinating DRA and the degree of severity of DIAR. All
`patients with grade III or IV reactions had high titres (mainly IgG), indicat(cid:173)
`ing a pathogenic role for such antibodies. Examination of IgG subclasses
`revealed high titres of IgG1 and IgG2 . Thus the authors concluded that
`infusion of clinical dextran (Dextran-70 or -40) into patients with high
`lgG-DRA levels generates noxious immune complexes which activate com(cid:173)
`plement, as shown by decreased levels of Clq, and induce release of vaso(cid:173)
`active mediators, leading to symptoms of anaphylaxis. Thus severe DIAR
`should be classified as IgG-mediated immune-complex-mediated (Type III)
`anaphylaxis (Gell and Coombs, 1968). The clinically less important DIAR
`(grades I and II) can be either antibody-dependent or not.
`On the basis of immunopathological findings of immune complex ana(cid:173)
`phylaxis, hapten inhibition has been proposed as a measure to prevent
`DIAR (Richter, 1973a, 1973b; Hedin et al, 1976). A hapten is a substance
`which is capable of binding to specific antibodies without inducing antibody
`production. A hapten can be monovalent or polyvalent with regard to the
`number of antigenic determinants (Figure 2). A polyvalent hapten can
`bridge antibodies like an antigen, but a monovalent hapten can bind only to
`
`

`

`ALLERGIC AND ANAPHYLACTIC REACTIONS
`
`671
`
`~ ifa r .. 7
`Com·~r· ;p
`
`(a)
`
`Monovalent hapten
`
`(b)
`
`Polyvalent antigen
`
`Figure 2. Interaction of hapten and antigen with antibodies. (a) Binding of a monovalent hapten
`dextran to individual antibody combining sites. (b) Binding of polyvalent clinical dextran to
`antibodies and formation of immune complexes.
`
`single combining sites of antibodies and can thus inhibit immune complex
`formation and elicitation of anaphylaxis by competitive binding. It was
`found that the most effective inhibition was achieved with dextran fragments
`consisting of four to six glucose units (Richter, 1973a; Hedin et al, 1980).
`Animal experiments (Richter, 1973b, 1973c; Messmer et al, 1980; Schwarz
`et al, 1980), as well as clinical investigations (Ljungstrom et al, 1983; Renck
`et al, 1983), have shown the incidence of severe DIAR to be significantly
`reduced by hapten inhibition employing dextran with a MW of 1000
`(Dextran-1). Pretreatment with hapten dextran or treatment with an
`admixture of Dextran-1 and clinical dextran are both effective. One fatal
`reaction has occurred in a patient treated with the admixture, but this
`patient had a very high titre of DRA (Ljungstrom, 1983). On the basis of
`experimental and clinical experience, injection of 20 ml of hapten dcxtran
`(Promit) prior to infusion of Macrodex or Rheomacrodex is recommended
`to improve the safety of dextran administration.
`
`GELATIN
`
`Gelatin is prepared in two stages (Nitschmann and Stoll, 1969) by hydrolysis
`
`

`

`672
`
`S. N. KOX AND W. J. KOX
`
`of collagen, which consists of three chains of peptides, each of which has a
`molecular weight of 100 000-120 000 arranged in a three-stranded helical
`structure. The first stage involves action of alkali which causes swelling of
`the collagen and hydrolysis of ester and peptide bonds. In the second stage
`the addition of boiling water leads to the formation of an aqueous solution.
`Some of the peptide chains are split during hydrolysis, since the average
`molecular weight of the gelatin molecules is below 100 000. For gelatin to be
`of clinical value it should retain a high molecular weight in order to exert a
`viable osmotic effect but at the same time have a low gel melting point to
`remain fluid at low temperatures. Since the 1940s attempts have been made
`to modify gelatin to meet these requirements. At present there are three
`types of commercially prepared gelatin solutions for intravenous infusion.
`These are succinylated gelatin or modified fluid gelatin (Tourtelotte and
`Williams, 1958) (Gelofusine, Plasmagel or Physiogel), urea-linked gelatin
`solution or polygeline (Schmidt-Thome et al 1962) (Haemaccel) and oxy(cid:173)
`polygelatin (Campbell et al, 1951), (Gelifundol); the latter is available only
`on the Continent. The urea solution is prepared by cross-linking poly(cid:173)
`peptides derived from gelatin, each with a molecular weight of 12 000-
`15 000, using hexamethyl di-isocyanate (Schone, 1969). The resulting pro(cid:173)
`duct has an average molecular weight (MW) of 35 000 and a number average
`molecular weight (Mn) of 24500. The process of preparing succinylated
`gelatin differs from that of the urea-linked product in that the polypeptides
`have a mean molecular weight of around 20 000 and are modified by the
`addition of succinic acid anhydride. No cross-linking occurs and the
`molecular weight is unaltered; thus the resulting product has a MW of 35 000
`and an Mn of 22 000.
`It was originally claimed that modified gelatins were non-antigenic and
`free from anaphylactoid reactions (Lundsgaard-Hansen, 1969), but all types
`of gelatin have now been associated with allergic reactions of varying
`severity (Schoning and Koch, 1975), including a fatal case (Freeman, 1979);
`however, this study failed to provide any real proof as to the role of
`Haemaccel. Lund (1973) reported an anaphylactoid reaction induced by
`infusion of Haemaccel, and a positive skin test to Haemaccel diluted
`1:100000, but no controls were investigated in this study. Wisborg (1973)
`reported eight cases of intolerance, with skin reactions attributed to infusion
`of Haemaccel. Five out of six intradermal skin tests with Haemaccel diluted
`1: 10 showed a positive reaction. Only one control test was performed, and
`the patients received muscle relaxants during anaesthesia which may cause
`anaphylactic reactions (Vervloet et al, 1979). According to Ring and
`Messmer's multicentre report (1977) the incidence of all grades of allergic
`reactions (see under dextran) to succinylated gelatin was low (0.066%) and
`marginally less than that of Dextran-70 (0.069%) and hydroxyethyl starch
`(0.085% ). The urea-linked preparation was associated with more than twice
`the anaphylactoid reactions (0.146%) of the succinylated form.
`Lunsgaard-Hansen and Tschirren (1981) reported an incidence of ana(cid:173)
`phylactoid reactions of 0.075% with succinylated gelatin, a figure similar to
`that of Ring and Messmer (1977). They suggested that trace contaminants in
`the gelatin source may be responsible for the reactions.
`
`

`

`ALLERGIC AND ANAPHYLACTIC REACTIONS
`
`673
`
`Anaphylactoid reactions are usually observed soon after the commence(cid:173)
`ment of the infusion and seem more likely to occur in non-anaesthetized and
`normovolaemic subjects (Lunsgaard-Hansen and Tschirren, 1978). The
`pathophysiology of the reactions is not well understood. Many workers have
`reported histamine release in man by gelatin (Lorenz et al, 1970, 1971, 1976;
`Seidel et al, 1973), but whether this was a result of histamine release from
`mast cells (Paton, 1956) or a result of anaphylaxis (Bauer and Ostling, 1970;
`Lorenz et al, 1974b) is not clear. Lorenz et al (1976) observed allergic and
`anaphylactoid reactions following infusion with Haemaccel in seven out of
`53 subjects. Histamine release was demonstrated in all of these by both
`direct and indirect methods. The incidence of histamine release varied with
`different batches, which suggests that the histamine response to this plasma
`substitute is not a result of an immunological process but a pharmacological
`action of Haemaccel on the histamine system. Vervloet et al (1983) reported
`three cases of anaphylactic shock and suggested that skin test and leukocyte
`histamine release might be valuable in the screening of patients who might
`be reactive to gelatin. Furthermore, whilst their findings suggested the
`release of mediators from mast cells or basophils, no discrimination between
`immunological and
`idiosyncratic pharmacological mechanisms was
`obtained. As histamine has been shown to be the principal mediator of
`gelatin-induced reactions, pretreatment with histamine antagonists has
`been recommended. The frequency of anaphylactoid reactions after urea(cid:173)
`linked gelatin infusion was reduced by pretreatment with a combination of
`Hi- and Hz-receptor antagonists (Lorenz et al, 1977; Schoning et al, 1982).
`Since 1981, in an attempt to reduce the amount of histamine released
`(Schoning and Lorenz, 1981), the manufacturers of the urea-linked product
`have reduced the number of cross-linkages within the molecules; the clinical
`significance of this change has yet to be assessed.
`
`HYDROXYETHYL STARCH
`
`Hydroxyethyl starch (HES) is a modified natural polymer that is non-toxic.
`Native starches are hydrolysed rapidly by ubiquitous amylases, and have an
`intravascular elimination half-time of about 10 minutes (Terashima, 1937;
`Thompson et al, 1960). Amylase hydrolysis may be retarded selectively by
`modifying the natural starch molecule (Thompson et al, 1960). Of the
`derivatives tested, hydroxyethyl starches were the most stable and least toxic
`in vivo. HES is composed primarily of amylopectin; hydroxyethyl groups are
`introduced onto the glucose units of the starch, which is then subjected to acid
`hydrolysis to yield a material with an average molecular weight of 450 000
`(ranging from 40 000--1000 000) or a number average molecular weight of
`70 000 (Hespan, Plasmasteril). The pharmacokinetics distribution, elimi(cid:173)
`nation and colloidal effect are determined by molecular size and rate of
`metabolism factors can be independently controlled when synthesizing HES.
`For example, hydroxyethylation to different extents may provide controlled
`rates of elimination from plasma that vary from 10 to 1000 minutes. Increased
`hydroxyethylation retards degradation and clearance and prolongs half-life
`
`

`

`674
`
`S. N. KOX AND W. J. KOX
`
`(Thompson et al, 1962; Thompson, 1978). The degree of acid hydrolysis
`determines the molecular weight and the subsequent distribution.
`Anaphylactoid reactions to HES have been infrequent and rather mild
`(Thompson et al, 1960; Ring et al, 1976; Ring and Messmer, 1977). HES was
`found to be non-antigenic in human volunteers, even when fractions of very
`high molecular weight were injected with adjuvants (Brickman et al, 1966;
`Maurer and Berardinelli, 1968). Ring et al (1976) reported an incidence of
`overall HES incompatibility reactions in grades I-IV of 0.085% (14 out of
`16405 infusions), which was lower than that of other plasma substitutes
`(Schmidt and Pfluger, 1971b; Ring et al, 1976). Regarding the clinical
`symptoms, the HES incompatibility reactions were similar to other ana(cid:173)
`phylactoid incompatibility, with skin and cardiovascular manifestations
`(Ring et al, 1975).
`The pathophysiology of the anaphylactoid reactions after infusion of HES
`is not clear. Antibodies to HES are not present, and no histamine release was
`observed in humans after rapid infusion of HES (Lorenz et al, 1975).
`However, one report described specific antibodies to HES in rabbits (Richter
`and deBelder, 1976). A study in dogs and humans conducted to evaluate
`histamine involvement in anaphylactoid reactions with plasma substitutes,
`including Hetastarch, failed to relate skin reactions to histamine release
`(Lorenz et al, 1978). Thus the anaphylactoid reactions seen in their study were
`either independent of histamine release, or the histamine levels were too low
`to detect in plasma though sufficient to cause skin reactions (Doenicke et al,
`1977). Porter and Goldberg (1986) reported two cases of intraoperative
`reactions to HES. One patient had concurrent depression of serum total
`complement levels and no increase in plasma histamine levels, suggesting a
`complement-mediated reaction to HES. Since HES is metabolized to
`molecules of varying size, high-molecular-weight particles could lead to
`complement activation via the alternative pathway, and this may constitute
`part of the mechanism for anaphylactoid reactions. This type of activation has
`been described for high-molecular-weight substances (Konig et al, 1973;
`Strauss et al, 1980). HES, with a mean molecular weight of 450000, could
`elicit direct C3 activation. Ring et al (1976) attempted to correlate comple(cid:173)
`ment levels with the reactions reported but did not perform a full evaluation of
`complement series.
`
`CONCLUSIONS
`
`Anaphylactoid reactions associated with all of the currently available
`plasma substitutes have been reported. The clinical symptoms can be
`classified into four grades of severity, ranging from skin reactions to severe
`life-threatening complications.
`The pathomechanisms of these anaphylactoid reactions vary for different
`colloids. The reported incidence of dextran-induced reactions varies con(cid:173)
`siderably in different studies. No evidence for the role of contaminants has
`been found, but the dextran molecule itself appeared to be the causative
`agent. Severe DIAR can be classified as IgG-mediated immune complex
`
`

`

`ALLERGIC AND ANAPHYLACTIC REACTIONS
`
`675
`
`anaphylaxis. The technique of hapten inhibition-i.e., administration of a
`low-molecular-weight dextran prior to dextran infusion-is recommended
`to reduce the frequency of DIAR. Histamine seems to be the principal
`mediator of anaphylactic reactions due to gelatin infusion, particularly for
`urea-linked products. The di-isocyanate present in some batches may be the
`histamine-releasing substance. Further purification and pretreatment with
`Hi- and H 2-receptor antagonists reduce the frequency of clinical reactions
`considerably. Changes in complement levels have been observed in patients
`with anaphylactoid reactions to HES; no histamine release has been found
`following infusion of HES.
`
`REFERENCES
`
`Allen PZ & Kabat EA (1958) Persistence of circulating antibodies in human subjects
`immunized with dextran, levan and blood group substances. Journal of Immunology 80:
`495-500.
`Bauer A & Ostling G (1970) Dextran-induced anaphylactoid reactions in connection with
`surgery. Acta Anaesthesiologica Scandinavica supplement 37: 182-185.
`Bottinger LE, Furhoff AK & Holmberg L (1979) Fatal reactions to drugs. Acta Medica
`Scandinavica 205: 451-456.
`Brickman RD, Murray GF, Thompson WL & Ballinger WF (1966) The antigenicity of
`hydroxyethyl starch in humans. Studies in seven volunteers. JAMA 196: 575.
`Erisman R, Parks LC & Haller JA (1968) Anaphylactoid reactions associated with the clinical
`use of dextran 70. JAMA 204: 824----825.
`Campbell DH, Koepfli JB, Pauling Let al (1951) The preparation and properties of a modified
`gelatin (oxypolygelatin) as an oncotic substitute for serum albumin. Texas Reports on
`Biology and Medicine 9: 235-280.
`Carlsson C, Gustafson I, Nilsson E, Nordstrom L, Persson PO & Soderberg M (1972)
`Anafylaktoid reaktion pa dextran. Lakartidningen 69: 3690-3692.
`Doenicke A, Grote B & Lorenz W (1977) Blood and blood substitutes. British Journal of
`Anaesthesia 49: 681-688.
`Eberlein HJ & Dobberstein H (1962) Kreislaufmessungen an Blutspendern bei rascher
`Infusion eines neuen Plasma expanders. Arzneimittelforschung 12: 494----497.
`Editorial (1981) Adverse drug reactions. British Medical Journal 282: 1819-1820.
`Fischer MMcD (1975) Severe histamine mediated reactions to intravenous drugs used iri
`anaesthesia. Anaesthesia and Intensive Care 3: 180-197.
`Freeman MK (1979) Fatal reaction to haemaccel. Anaesthesia 34: 341-343.
`Furhoff AK (1977) Anaphylactoid reaction to dextran-a report of 133 cases. ActaAnaesthesio(cid:173)
`logica Scandinavica 21: 161-167.
`Gell PGH & Coombs RRA (1968) Classification of allergic reactions responsible for clinical
`hypersensitivity and disease. In Gell PGG & Coombs RRA (eds) Clinical Aspects of
`Immunology, 2nd edn. Oxford: Blackwell.
`Grabar P (1955) Reactions de divers serums normaux avec des substances macromoleculaires
`naturelles ou synthetiques. Anna/es de l'Institut Pasteur 88: 11-23.
`Gronwall A (1959) Antigenicity of Swedish clinical dextran (Macrodex). Acta Societatis
`Medicorum Upsaliensis 64: 244----246.
`Hahn F (1954) Toxicity of dextran in rats and the formation of anaphylactic toxins. Journal of
`Pharmacology and Experimental Therapeutics 110: 24.
`Hedin H & Richter W (1982) Pathomechanism of dextran-induced anaphylactoid/anaphylactic
`reactions in man. International Archives of Allergy and Applied Immunology 68: 122-126.
`Hedin H, Richter W & Ring J (1976) Dextran-induced anaphylactoid reactions in man: role of
`dextran rective antibodies. International Archives of Allergy and Applied Immunology 52:
`145-159.
`
`

`

`676
`
`S. N. KOX AND W. J. KOX
`
`Hedin H, Kraft D, Richter W, Scheiner O & Devey M (1979) Dextran reactive antibodies in
`patients with anaphylactoid reactions to dextran. Immunobiology 156: 289.
`Hedin H, Richter W, Messmer K, Renck H, Ljungstrom KG & Laubenthal H (1981) Inci(cid:173)
`dence, pathomechanism and prevention of dextran induced anaphylactoid/anaphylactic
`reactions in man. Developments in Biological Standardization 48: 179-189.
`Isbister JP & Fischer MMcD (1980) Adverse effects of plasma volume expanders. Anaesthesia
`and Intensive Care 8: 145-151.
`Kabat EA & Berg D (1953) Dextran-an antigen in man. Journal of Immunology 70: 514.
`Kabat EA, Turino GM, Tarrow AB & Maurer PH (1957) Studies on the immunochemical basis
`of allergic reactions to dextran in man. Journal of Clinical Investigation 36: 1160.
`Konig W, Bitter-Suermann D, Dierich M & Hadding U (1973) Bypass activation of the
`complement system starting with C3. II. C3-activation by gamma-1-immune aggregates in
`guinea pig serum. Immunochemistry 10: 431-437.
`Ljungstrom KG (1983) Prophylaxis of Postoperative Thromboembolism with Dextran 70:
`Improvements of Efficacy and Safety. Stockholm: Akademisk Avhandling Karolinska
`Institute , pp. 1-96.
`Ljungstrom K-G, Renck H, Hedin H, Richter W & Rosberg B (1983) Prevention of dextran(cid:173)
`induced reactions by hapten inhibition. Acta Chirurgica Scandinavica 149: 341-348.
`Lorenz W (1975) Histamine release in man. Agents Actions 5: 402-416.
`Lorenz W, Doenicke A, Feifel Get al (1970) Histamine release in man by propanidid (Epontol),
`gelatin (Haemaccel), histalog, pantagastrin and insulin. Naunyn Schmiedeberg!s Archiv fur
`Pharmakologie 266: 396-397.
`Lorenz W, Doenicke A, Messmer K & Reimann H-J (1971) Histamine release in man and dog
`by plasma substitutes. Acta Pharmacologica et Toxicologica 29 (supplement 4): 31.
`Lorenz W, Doenicke A & Freund M (1974a) Plasma histamine levels in man following infusion
`of hydroxyethyl starch: a contribution to the question of allergic or anaphylactoid reactions
`following administration of a new plasma substitute. Anaesthesist 24: 228-230.
`Lorenz W, Seidel W, Doenicke A et al (1974b) Elevated plasma histamine concentrations in
`surgery: causes and clinical significance. Klinische Wochenschrift 52: 419-425.
`Lorenz W, Doenicke A, Freund M et al (1975) Plasma histaminspiegel beim Menschen nach
`rascher Infusion von Hydroxyathylstarke: ein Beitrag zur Frage allergischer oder
`anaphylaktoider Reaktionen mach Gabe eines neuen Plasmaexpanders. Anaesthesist 24:
`228-230.
`Lorenz W, Doenicke A, Messmer K et al (1976) Histamine release in human subjects by
`modified gelatin (haemaccel) and dextran: an explanation for anaphylactoid reactions
`observed under clinical conditions? British Journal of Anaesthesia 48: 151-165.
`Lorenz W, Doenicke A, Dittmann I et al (1977) Anaphylaktoide Reaktionen nach Applikation
`von Blutersatz-mitteln beim Menschen: erhinderung dieser Nebenwirkung von Haem(cid:173)
`accel <lurch Praemedikation mit Hl- und H2-Rezeptorantagnisten. Anaesthesist 268: 644.
`Lorenz W, Doenicke A, Reimann HJ, Schmal A , Schwartz B & Dorman P (1978) Anaphyl(cid:173)
`actoid reactions and histamine release by plasma substitutes: a randomized controlled trial
`in human subjects and in dogs. Agents Actions 8: 379-399.
`Lund N (1973) Anaphylactic reaction induced by infusion of Haemaccel. British Journal of
`Anaesthesia 45: 929.
`Lundsgaard-Hansen P (1969) Treatment of shock with dextran and gelatins. Vax Sanguinis 17:
`161-193.
`Lundsgaard-Hansen P & Tschirren B (1978) Modified fluid gelatin as a plasma substitute.
`Progress in Clinical and Biological Research 19: 227-257.
`Lundsgaard-Hansen P & Tschirren B (1981) Clinical experience with 120 000 units of modified
`fluid gelatin. Developments in Biological Standardization 48: 251-256.
`Maddi VI, Wyso EM & Zinner EN (1969) Dextran anaphylaxis. Angiology 20: 243-248.
`Maurer PH & Berardinelli B (1968) Immunologic studies with hydroxyethyl starch (HES), a
`proposed plasmu expander. Transfusion 8: 265-268.
`Meisel G & Zockler H (1971) Anaphylaktische Reaktion nach der Gabe von Plasmaexpandern
`auf Gelatinebasis. Bibliotheca Haematologica 37: 348-358.
`Messmer K, Ljungstrom KG, Gruber UF et al (1980) Prevention of dextran-induced
`anaphylactoid reactions by hapten inhibition. Lancet i: 975.
`Nitschmann H & Stoll HR (1969) Gelatin as starting material for the manufacture of plasma
`substitute preparations. Bibliotheca Haematologica 33: 55-74.
`
`

`

`ALLERGIC AND ANAPHYLACTIC REACTIONS
`
`677
`
`Paton WDM (1956) The mechanism of histamine release. In CIBA Foundation Symposium on
`Histamine, p 49. London: Churchill.
`Paull J (1987) A prospective study of dextran-induced anaphylactoid reactions in 5745 patients.
`Anaesthesia and Intensive Care 15: 163-167.
`Porter SS & Goldberg RJ (1986) Intraoperative allergic reactions to hydroxyethyl starch: a
`report of two cases. Canadian Anaesthetists Society Journal 33: 394--398.
`Renck H, Ljungstrom K-G, Rosberg B, Dhuner K-G & Dahl S (1983) Prevention of dextran(cid:173)
`induced anaphylactic reactions. Hapten inhibition. Acta Chirurgica Scandinavica 149:
`349-353.
`Revenas B, Smedegard G, Hedin H, Richter W & Saldeen T (1980) Immune complex mediated
`anaphylactic shock in humans? 7th World Congress of Anaesthesiologists, Hamburg
`(abstract).
`Richter W U970) Absence of immunogenic impurities in clinical dextran tested by passive
`cutaneous anaphylaxis. International Archives of Allergy and Applied Immunology 39:
`469-478.
`Richter W (1973a) Hapten inhibition of passive dextran anaphylaxis in guinea pigs: role of
`molecular size in anaphylactogenicity and predictability of dextran fractions. International
`Archives of Allergy and Applied Immunology 41: 826.
`Richter W (1973b) Immunological in vivo and in vitro studies of the dextran-antidextran system.
`Dissertation, Uppsala, Faculty of Medicine, 1.
`Richter W (1973c) Built-in hapti:'n inhibition of anaphylaxis by the low molecular weight
`fractions of a B512 dextran fraction of MW 3400. International Archives of Allergy and
`Applied Immunology 45: 930.
`Richter W (1980) A new immunochemical purity test for clinical dextran. Methodology and
`studies on clinical dextran preparations. International Archives of Allergy and Applied
`Immunology 61: 457-466.
`Richter W & deBelder AN (1976) Antibodies against hydroxyethyl-starch produced in rabbits
`by immunization with a protein-hydroxyet