Allergic and anaphylactic reactions following plasma substitute infusion

11

Allergic and anaphylactic reactions following plasma substitute infusion S. N I L D E N K O X W O L F G A N G J. K O X

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; Bottinger et al, 1979). M E C H A N I S M S OF A N A P H Y L A C T I C 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 lymphocytes 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, slowreacting 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 BailliOre's ClinicaIAnaesthesiology--Vol. 2, No. 3, September1988

667

S. N. KOX AND W. J. KOX

668

@ M a s cell t

~Fcl,

~

2

~

}a

rgen

Release of mediators (e.g. histamine) from granules Anaphylaxis

Figure 1. Type I: anaphylactichypersensitivity.Mast-celldegranulation followsinteraction of antigen with bound homocytotropicantibodies. (a) IgE binds to mastcellsthrough its Fc piece (fragmentcrystallizable),the portion of the molecule differentto the antigen combiningsites. (b) When antigen (allergen O O) cross-links two adjacent IgE molecules, an allosteric modificationof the antibodiesoccurswhichinducesthe releaseof mediatorsfromthe mastcell. 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 C1. The activated products of the complement pathway, such as C3a and C5a, are anaphylatoxins and are capable of producing mast cell degranulation or lysis with release of chemical mediators. In the latter pathway activation of the complement system involves direct activation of complement 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 ANAPHYLACTICREACTIONS

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 activation 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 D e x t r a n - l l 0 (MW 110000, Mn 55 000), available as Dextraven-110. Dextran-60, Dextran-75 and Dextran150 are also available. Dextran-induced anaphylactoid/anaphylactic reactions ( D I A R ) 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 D I A R varies from 0.03 to 4.7%, and that of severe D I A R from 0.008 to 0.6%. These differences are probably due to the design of the studies performed (retrospective, 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 D I A R . Early workers attributed the responses to the antigenicity of dextran or to contamination of the dextran by bacterial 1. Severity scale for quantification of intensity of anaphylactoid reactions (Ring and Messmer, 1977).

Table

Grade

Symptoms

I

Skin symptoms and/or mild fever reactions Measurable, but not life-threatening, cardiovascular reaction (tachycardia, hypotension) Gastrointestinal disturbance (nausea) Shock, life-threateningspasm of smooth muscles (bronchi, uterus etc.) Cardiac and/or respiratory arrest

If III IV

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 previouslyused 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 dextranreactive 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 contribute 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 preexposure levels of dextran-reactive antibodies (DRA) and the severity of subsequent DIAR. Patients who reacted to dextran tended to have higher levels of D R A 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 I A R did not correspond to IgEmediated cytotropic anaphylaxis. They found a positive correlation between titres of haemagglutinating D R A and the degree of severity of DIAR. All patients with grade III or IV reactions had high titres (mainly IgG), indicating 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 IgG-DRA levels generates noxious immune complexes which activate complement, as shown by decreased levels of Clq, and induce release of vasoactive mediators, leading to symptoms of anaphylaxis. Thus severe D I A R should be classified as IgG-mediated immune-complex-mediated (Type III) anaphylaxis (Gell and Coombs, 1968). The clinically less important D I A R (grades I and II) can be either antibody-dependent or not. On the basis of immunopathological findings of immune complex anaphylaxis, hapten inhibition has been proposed as a measure to prevent D I A R (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

671

ALLERGIC AND ANAPHYLACTIC REACTIONS

J ! (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 (Richte L 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 D I A R 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 D R A (Ljungstrom, 1983). On the basis of experimental and clinical experience, injection of 20 ml of hapten dextran (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 100000-120 000 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 oxypolygelatin (Campbell et al, 1951), (Gelifundol); the latter is available only on the Continent. The urea solution is prepared by cross-linking polypeptides derived from gelatin, each with a molecular weight of 1200015 000, using hexamethyl di-isocyanate (Schone, 1969). The resulting product has an average molecular weight (MW) of 35 000 and a number average molecular weight (Mn) of 24 500. 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 1:100 000, 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 anaphylactoid 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 commencement 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 urealinked gelatin infusion was reduced by pretreatment with a combination of H1- and H2-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. H Y D R O X Y E T H Y L 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, hydroxyethylstarches 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 70000 (Hespan, Plasmasteril). The pharmacokinetics distribution, elimination and colloidal effect are determined by molecular size and rate of metabolism factors can be independently controlled when synthesizing HES. For example, hydroxyethylationto 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 . K O X A N D W . J. K O X

(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 anaphylactoid 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 450 000, could elicit direct C3 activation. Ring et al (1976) attempted to correlate complement 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 considerably 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 D I A R can be classified as IgG-mediated immune complex

ALLERGIC AND ANAPHYLACTICREACTIONS

675

a n a p h y l a x i s . T h e t e c h n i q u e of h a p t e n i n h i b i t i o n - - i . e . , a d m i n i s t r a t i o n of a l o w - m o l e c u l a r - w e i g h t d e x t r a n prior to d e x t r a n i n f u s i o n - - i s r e c o m m e n d e d to r e d u c e t h e f r e q u e n c y of D I A R . H i s t a m i n e seems to b e the p r i n c i p a l m e d i a t o r of a n a p h y l a c t i c reactions d u e to gelatin i n f u s i o n , p a r t i c u l a r l y for u r e a - l i n k e d products. T h e di-isocyanate p r e s e n t in some batches m a y be the h i s t a m i n e - r e l e a s i n g s u b s t a n c e . F u r t h e r purification a n d p r e t r e a t m e n t with H1- a n d H 2 - r e c e p t o r a n t a g o n i s t s r e d u c e the f r e q u e n c y of clinical r e a c t i o n s c o n s i d e r a b l y . C h a n g e s in c o m p l e m e n t levels have b e e n o b s e r v e d in p a t i e n t s with a n a p h y l a c t o i d reactions to H E S ; n o h i s t a m i n e release has b e e n f o u n d following i n f u s i o n of H E S .

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. Brisman 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: 36903692. 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 Plasmaexpanders. 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 in anaesthesia. Anaesthesia and Intensive Care 3: 180-197. Freeman MK (1979) Fatal reaction to haemaccel. Anaesthesia 34: 341-343. FurhoffAK (1977) Anaphylactoid reaction to dextran--a report of 133 cases. Acta Anaesthesiologica 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. Annales 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. InternationalArchives 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. InternationalArchives 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) Incidence, 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 E A & Berg D (1953) Dextran--an antigen in man. Journal oflmmunology 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-l-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 dextraninduced 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 G e t al (1970) Histamine release in man by propanidid (Epontol), gelatin (Haemaccel), histalog, pantagastrin and insulin. Naunyn Schmiedeber~s ArchivfRr 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 e t 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 yon 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: 15!-165. Lorenz W, Doenicke A, Dittmann I e t al (1977) Anaphylaktoide Reaktionen nach Applikation von Blutersatz-mitteln beim Menschen: erhinderung dieser Nebenwirkung von Haemaccel durch Praemedikation mit H1- und H2-Rezeptorantagnisten. Anaesthesist 268: 644. Lorenz W, Doenicke A, Reimann HJ, Schmal A, Schwartz B & Dorman P (1978) Anaphyl 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 dextrin and gelatins. Vox 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 plasma 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. BibIiotheca 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 dextraninduced 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 (1970) 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 hapten 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-hydroxyethyl-starch conjugate. InternationalArchives & Allergy and Applied Immunology 52: 307. Ring J & Messmer K (1977) Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet i: 466-469. Ring J, Seifert J, Messmer K & Brendel W (1975) Untersuchung zur Frage der Nebenwirkungen bei Anwendung von Plasmasatzmitteln. Klinische Anasthesiologie und Intensivtherapie 9" 58-72. Ring J, Seifert J, Messmer K & Brendel W (1976) Anaphylactoid reactions due to hydroxyethyl starch infusion. European Surgical Research S: 389-399. Ring J, Hedin H, Richter W, Jesch F & Messmer K (1977) Immunological properties of a high molecular weight component from yeast cell autolysate in dogs and evaluation of its potential role in human dextran reactions. European Surgical Research 9: 338-346. Schmidt H & Pfluger H (1971a) Nebenwirkungen bei Volumensubstitution mit Gelatinpraparaten. Medche Welt 22: 1073-1077. Schmidt H & Pfluger H (1971b) Reactions d'intolerance apres substitutes du plasma. Anaesthesia and Analgesia 28: 871. Schmidt-Thome J, Mager A & Schone HH (1962) Zur Chemie eines neuen Plasmaexpanders. Arzneimittelforschung 12: 378-380. Schone HH (1969) Chemistry and physicochemical characterization of gelatin plasma substitutes. Bibliotheca Haematologica 33: 78-70. Sch6ning B & Koch H (1975) Pathergiequote verschiedener Plasmasubstitute and Haut und Respirationstrakt ortopadischer Patienten. Anaesthesist 24: 507-513. Sch6ning B & Lorenz W (1981) Prevention of allergoid (cutaneous anaphylactoid) reactions to polygeline (Haemaccel) in orthopaedic patients by premedication with H1- and H2receptor antagonists. Developments in Biological Standardization 48: 241-249. Sch6ning B, Lorenz W & Doenicke A (1982) Prophylaxis of anaphylactoid reactions to a polypeptidal plasma substitute by H1- plus H2-receptor antagonists: synopsis of three randomized controlled trials. Klinische Wochenschrift 60:1048 Schwartz JA, Radchak M & Koch W (1980) Verhinderung Antikorperbedingter DextranNebenwirkungen durch monovalentes Hapten (Dextran 1). Allergologie 3: 24. Seidel W, Lorenz W, Doenicke A, Mann G & Uhlig R (1973) Histamine release in man and acute gastroduodenal ulcers. British Journal of Surgery 60: 320.

678

s . N . KOX AND W. J. KOX

Stoelting RK (1983) Allergic reactions during anaesthesia. Anesthesia and Analgesia 62: 341-356. Strauss RG, Spitzer RE, Stitzel AE et al (1980) Complement changes during leukapheresis. Transfusion 20: 32-38. Strebel L & Siegler PE (1968) Experience with clinical testing of dextran solutions. Archives of Surgery 96: 471. Terashima T (1937) Nutritional significance of parenteral administration of polysaccharides. Japanese Journal of Gastroenterology 9: 273-285. Thompson L (1978) Hydroxyethyl starch. In Blood Substitutes and Plasma Expanders, pp 383-392. New York: A. Liss. Thompson WL (1980) Hydroxyethyl starch. Developments in Biological Standardization 48: 259-266. Thompson WL, Britton JJ & Walton RP (1960) Blood levels of glucose and carbohydrate following intravenous infusions of dextran and hydroxyethylated starches. Federation Proceedings 19: 103. Thompson WL, Britton JJ & Walton RP (1962) Persistence of starch derivative and dextran when infused after hemorrhage. Journal of Pharmacology and Experimental Therapeutics' 136: 125-132. Thorsen G (1954) Dextran-position in therapy in Sweden 1953 and problems. Annals Chirurhiae Fenniae 43 (supplement 5): 445-450. Tourtelotte D & Williams HE (1958) Acylated gelatins and their preparations. US Patent 2: 827. van Arsdel PP (1982) Diagnosing of drug allergy. JAMA 247: 2576-2581. Vervloet D, Arnaud A, Vellieux P, Kaplanski S & Charpin J (1979) Anaphylactic reactions to muscle relaxants under general anaesthesia. Journal of Allergy and Clinical Immunology 63: 348-353. Vervloet D, Senft M, Dugue P, Arnaud A & Charpin J (1983) Anaphylactic reactions to modified fluid gelatins. Journal of Allergy and Clinical Immunology 71: 535-540. Voohees AB, Baker HJ & Pulaski EJ (1951) Reactions of albino rats to injections of dextran. Proceedings of the Society for Experimental Biology and Medicine 76: 254. Wilkinson AW & Stoney ID (1953) Reactions to dextran. Lancet ii: 956-958. Wisborg K (1973) Anaphylactic reaction induced by infusion of polygeline (Haemaccel). British Journal of Anaesthesia 47: 116.