Dru Experience
Drug Safety 5 (2): 86-93, 1990 0114-5916/90/0003-0086/$04,00/0 © ADiS Press Limited All rights reserved. MEDT03 DRUG SAFETY 149
Adverse Reactions to Plasma Volume Expanders Malcolm McD. Fisher and Peter W. Brady Intensive Therapy Unit and Department of Cardiothoracic Surgery, Royal North Shore Hospital of Sydney, St Leonards, New South Wales, Australia
Contents
Summary ................ ,., ....... " ....... ,., ...... ,........ ' ................................................ ,., ..... ",., ...... ,.", .... ,.,. 86 I. Types of Plasma Volume Expanders ........... ,.. ,.............................. ,........ ,.... ,........... .. ,.... ,...... 87 1.1 Plasma Protein Fractions ,...... ,................................................ ,.. ,.......... ,...... ,................... 87 1.2 Plasma Derivatives ........................................................................................................... 87 1.3 Albumin 25% ........................................ ............................................................................. 87 1.4 Modified Gelatins ............................................................................................................. 87 1.5 Dextrans ............................................................................................................................. 87 1.6 Hydroxyethyl Starch ......................................................................................................... 88 1.7 Fluorinated Hydrocarbons .............................................................. .......... ....................... 88 2. Adverse Effects of Plasma Volume Expanders ..................................................................... 89 2.1 Fluid Overload .................................................................................................................. 89 2.2 Contamination and Infection ...................... ..................................................................... 89 2.3 Haemostasis and Cross-Matching .............................................................. .. .................... 89 2.4 Renal Function .................................................................................................................. 89 2.5 Cardiovascular Function .................................................................................................. 90 2.6 Incomplete Metabolism and Storage ............................................................................... 90 2.7 Anaphylactoid Reactions .................................................................................................. 90 3. Mechanism of Reactions ..................................................................................... ................... 90 3.1 Gelatins .............................................................................................................................. 91 3.2 Hydroxyethyl Starch .......................... ............................................................................... 91 3.3 Plasma Protein Solutions ................................................................................................. 91 3.4 Dextrans ............................................................................................................................. 91 3.5 Fluorinated Hydrocarbons ............................................................................................... 92 4. Treatment of Anaphylactoid Reactions ................................................................................. 92
Summary
Plasma volume expanders are effective in the restoration of blood volume. All the available plasma volume expanders may rarely induce anaphylactoid reactions, although such reactions are extremely uncommon in shocked patients. The reactions are caused by different mechanisms depending on the solution, and there is little evidence that IgE antibodies are involved. In addition to these reactions, effects on haemostasis and renal function may occur, and the persistence of hydroxyethyl starch in the body has led to concern about its potential role as a carcinogen, although there is no evidence to suggest that this has occurred.
87
Adverse Reactions to Plasma Volume Expanders
The use of intravenous fluids in the replacement of blood volume is one of the most effective and accepted forms of medical therapy. The fluids used are broadly divided into 2 groups: crystalloids or electrolyte solutions, and colloids which contain compounds of large molecular weight, which are osmotically active and remain in the intravascular compartment longer than crystalloids. The circumstances under which crystalloid fluids are more effective than colloids are the subject of ongoing medical controversy. In favour of crystalloid solutions are their low cost and absence of adverse effects, while the main argument in favour of colloids is their greater efficacy, i.e. less is required to replace a given volume of blood. However, this is achieved at considerable financial cost and with the risk of a number of adverse effects. The data relating reduced mortality to the use of either group are not convincing. The use of fluids other than blood to replace blood volume carries benefits in providing haemodilution and allowing both time for crossmatching of blood and its conservation. The risk of blood-borne infectious diseases is reduced, and the use of specific replacement of plasma losses in burns, anaphylaxis and plasmapheresis is possible (Raper & Fisher 1984). Thus, the use of colloid solutions is widespread in acute blood volume replacement, perioperative haemodilution and prophylaxis of thromboembolism. The various properties of the available solutions of plasma volume expanders are given in table I.
1. Types
0/ Plasma
Volume Expanders
1.1 Plasma Protein Fractions Stable plasma protein solution 5% (SPPS) is pasteurised from donated human plasma, and is therefore relatively expensive.
vantages of containing clotting factors, but carry the risk of transmission of hepatitis and human immunodeficiency virus. They also have a high sodium content. It has been suggested that cryoprecipitate may improve renal function due to its opsoninic content (Annest et al. 1980).
1.3 Albumin 25%
This is the most expensive solution to prepare, and the most limited resource. It is hyperosmotic and will assist the movement of fluid from the extravascular space to the vascular compartment. Its use is usually reserved for patients such as those with burns or low colloid osmotic pressure, in whom plasma volume is contracted and the extracellular space expanded.
1.4 Modified Gelatins
The 2 most commonly used modified gelatin solutions are 'Haemaccel', in which the gelatin is cross-linked by urea, and 'Gelofusin', in which it is cross-linked by succinylation. The latter appears to have a longer half-life. 'Haemaccel' has a lO-fold higher content of calcium (6.25 mmol/L) and potassium (5.1 mmol/L) than 'Gelofusin', in which the concentration of both elements is less than 0.4 mmol/L. This higher calcium content can lead to clotting in warming coils when 'Haemaccel' is infused with blood.
1.5 Dextrans
1.2 Plasma Derivatives Plasma derivatives are available in a freeze-dried form , as fresh frozen plasma, as cryosupernate and as cryoprecipitate. These formulations have the ad-
The dextrans are produced by the action of the bacteria Leuconostoc mesenteroides on sucrose, and the 2 most commonly produced solutions, dextran
88
Drug Safety 5 (2) 1990
Table I. Properties of plasma volume expanders
Solution
Albumin Dextran 40 (,Rheomacrodex') Dextran 70 ('Macrodex') 'Fluosol - DA 20%'b Fresh frozen plasma Hydroxyethyl starch Modified gelatins urea-linked gelatin (,Haemaccel') succinylated gelatin ('Gelofusin') Stable plasma protein solution
tv.
Distribution (%)
Osmotic activity
Sodium content (mosmol/L)
EV
IV
5-1Od 6-9h 12h Short (h) As for plasma components 24h
20
80a 100 100 100 100
Depends on dilution Hyperosmotic Hyperosmotic Isosmotic Isosmotic
Depends on diluent 154 154
100
Isosmotic
154
4h 5h 5-10d
50 50 20
Isosmotic Isosmotic Isosmotic
145 154 130-150
50 50 80 a
170-190
a Depends on permeability of the capillary endothelium. b Fluorinated hydrocarbon whole blood substitute. Abbreviation: ty, = half-life.
40 and dextran 70, have an average molecular weight of dextran of 40,000 and 70,000 daltons,
respectively. In addition to their plasma volume expanding capability, they have an advantage over other plasma volume expanders in a rheological effect which improves microcirculatory flow, and because of this they have been used in the prophylaxis of thromboembolic disorders (Claggett & Reisch 1988). 1.6 Hydroxyethyl Starch Hydroxyethyl starch is a synthetic macromolecular polymer which has been shown to be an effective plasma volume expander. 1. 7 Fluorinated Hydrocarbons ('Fluosol DA 20%') 'Fluosol - DA 20%' (table II) is a whole blood substitute consisting of an emulsion of 2 fluorinated hydrocarbons in saline. Particle size averages O.12llm, with a maximum size of 0.6Ilm. As a comparison, the average size of red blood cells is 0.7Ilm. These substances are clinically and pharmacologically inert, dissolving oxygen in large quantities in a linear relationship to p02 (unlike haemoglo-
bin, which binds oxygen in a sigmoid relationship). In addition, they have a high affinity for carbon dioxide. Clinically, 'Fluosol - DA 20%' has been shown to be an effective plasma volume expander, and useful in the management of acute carbon monoxide poisoning. It has been reported to be both safe and effective in long term primate studies and in clinical practice (Mitsuno et al. 1982; Tremper et al. 1980). Table II. Composition of 'Fluosol - DA 20%' (data from Mitsuno et al. 1982)
Agent
W/V%
CaCI2 Glucose Glycerol Hydroxyethyl starch KCI
0.028 0.180 0.8 3.0 0.034 0.020 0.60 0.210 14.0 6.0 2.7 0.4
MgCI2 NaCI NaHC03 Perfluorodecalin Perfluorotripropylamine Pluronic F-68a Yolk phospholipids b a b
Emulsifier. Surfactant.
Adverse Reactions to Plasma Volume Expanders
89
2. Adverse Effects of Plasma Volume Expanders
nificantly affect modem cross-matching techniques, with the exception of occasional difficulties in patients who may accumulate high molecular weight components during prolonged infusion (Isbister & Fisher 1980). Hydroxyethyl starch (HES) causes a fall in serum proteins, including clotting factors, similar to albumin infusion. Lucas and colleagues (1988) suggest that this is due to an oncotically induced extravascular protein relocation. However, in no studies where moderate volumes of HES were used for blood volume replacement in shock was there any evidence of clinical bleeding, although mild elevations of prothrombin time and activated partial thromboplastin occurred. Lockwood, Bullen and Machin (1988) have described a severe coagulopathy related to HES volume replacement in 1 patient. A 5% albumin solution, compared with Ringer lactate in the dog haemorrhage model, showed an increase in prothrombin and partial thromboplastin time in the albumin group and similar change in platelet count, platelet function and fibrinogen levels. There was no increase in clinical bleeding (Coghill et al. 1981). In trauma patients, blood transfusion requirements were increased in a group who received supplemental albumin; platelet count was decreased, and prothrombin time and partial thromboplastin time were prolonged (Johnson et al. 1979). 'Fluosol - DA 20%' is associated with coagulation abnormalities in dogs. Biro (1985) showed .that all coagulation parameters (with the exception of prothrombin ratio) were adversely affected, and hyperfibrinolysis occurred. Elliott et al. (1989) showed a reduction in serum proteins, prolonged prothrombin time and activated partial thromboplastin time, and reduced platelet levels. There have been no reports of excessive blood loss due to altered coagulation states in humans.
2.1 Fluid Overload Fluid overload is a common cause of drugrelated death. In overload states the greater intravascular half-life of colloids over crystalloids becomes a significant disadvantage, as the ability to rapidly remove excess fluid with diuretics is limited. 2.2 Contamination and Infection All available solutions support bacterial growth, but nevertheless carry a lower risk of infection than does the use of donated blood. 2.3 Haemostasis and Cross-Matching There is no evidence of significant effects on haemostasis for gelatin solutions, SPPS or albumin. The various plasma fractions are used therapeutically in massive transfusions, because of their content of factors V and VIII. Dextrans are used therapeutically to reduce thromboembolic disease by limiting platelet aggregation, although when they are infused in volumes over 1500ml they may produce pathological bleeding (Alexander 1978). In large volumes, dextrans induce an acquired von Willebrand's state, and it appears that some hours of circulation must occur prior to this. In studies of the use of dextrans for the prevention of postoperative thromboembolism (Isbister & Fisher 1980) these agents have not been found to be associated with increased haemorrhage or wound haematoma, but they provide less effective prevention of thromboembolic disease than low-dose heparin (Claggett & Reisch 1988). Paull (1987), in a study of Australian women, has shown that the risk of anaphylaxis to dextrans outweighs the postoperative thromboembolic prevention benefits. High molecular weight dextrans caused marked rouleau formation in red cells and made interpretation of saline cross-match difficult. There is, however, no evidence that current dextrans sig-
2.4 Renal Function It is difficult to separate the alleged beneficial effects of plasma volume expanders on renal function from their volume expanding function. Both
Drug Safety 5 (2) 1990
90
cryoprecipitate, in trauma and surgical patients, and hetastarch in a dog renal ischaemia model, improved renal function (Annest et al. 1980; Rajagopalan et al. 1983). Dextran 40 produces reversible histological changes in renal tubules (Engberg 1976) and has been implicated in renal failure (Schwarz et al. 1984); however, there is no good evidence to suggest a similar role for dextran 70. 2.5 Cardiovascular Function Dahn et al. (1979) showed a negative inotropic effect of 5% albumin resuscitation, although the patients all received what appeared to be excessive quantities of fluid. In the same group of patients, Kovalik et al. (1981) showed that ionised calcium levels were reduced in the albumin-resuscitated group, and postulated that the negative inotropism may be in part due to this effect. 2.6 Incomplete Metabolism and Storage HES is incompletely metabolised and persists in the body (Boon et al. 1976), which suggests that a carcinogenic effect may be possible. However, there have been no data to suggest this is so. 2.7 Anaphylactoid Reactions Of all the adverse effects of colloid plasma volume expanders, anaphylactoid reactions have received the most study and are their major disadvantage over crystalloid solutions. There are a number of important aspects to these reactions which are often not appreciated. First, anaphylactoid reactions to plasma volume expanders are extremely rare in shocked patients (Ring, personal communication), and are more common in unanaesthetised awake normovolaemic patients (Boon et al. 1976). A number of factors probably contribute to this phenomenon. It is theoretically possible that the vasodilatation that is the most common severe feature in such reactions may be missed in a hypovolaemic patient. It is further possible that the endogenous catechol-
Table III. Incidence of anaphylactoid reactions to plasma volume expanders in prospective studies (adapted from Ring 1984; Ring & Messmer 1977) Colloid
Units infused
Reactions (%)
Dextran 40 Dextran 70 Gelatins 'Haemaccel' modified 'Haemaccel' 'Gelofusin' HES Human serum albumin SPPS Abbreviations: HES
51261 36614
0.008 0.11
7448 6178
0.84 0.42
6000 16405 60048 25582
0.02 0.085 0.012 0.02
= hydroxyethyl starch; SPPS = stable plasma
protein solution.
amine, endorphin, and corticosteroid response to shock both produces blocking of mediator effects and opposes the effects of mediators on target organs (Fisher 1987). Secondly, although multicentre and large population studies have determined incidences of reactions to specific plasma volume expanders they are relatively rare events, and as such confidence limits for reaction rates (which are rarely if ever calculated) will be large. No statistically significant difference between the rates of reaction to plasma volume expanders has been determined; the most frequently quoted incidences are from the work of Ring and colleagues, and are shown in table III. Thirdly, although the incidence of severe reactions to a particular plasma volume expander influences the decision of users, there may be no validity in such logic due to the relative rarity of such reactions (particularly in shock).
3. Mechanism of Reactions Anaphylactoid reactions are those which mimic the effects of anaphylaxis (Type I hypersensitivity) but do not appear to involve reaginic antibodies. IgE antibodies have not been found to any of the available plasma volume expanders, although some reactors to 'Haemaccel' have positive intradermal tests to dilutions of this agent, which is suggestive, but not diagnostic of an antibody-mediated reaction (Vervloet et al. 1983).
Adverse Reactions to Plasma Volume Expanders
3.1 Gelatins The release of histamine from mast cells and basophils by a direct effect of drugs is a common event in anaesthesia and surgery, and is usually associated with detectable clinical manifestations. Whether life-threatening reactions can be caused by this mechanism is questionable, however (Fisher 1988). 'Haemaccel' definitely produces reactions of minor severity by this mechanism; the reactions are blocked by H I and H2 antihistamines. There is little evidence to support such a mechanism with dextrans, and it appears less common with other polypeptides (Lorenz et al. 1981). There is some evidence that the histamine release from 'Haemaccel' was in part related to the manufacturing process causing an excess of diisocyanate linkages, which released histamine, and modification of this process has reduced the incidence and severity of the problem (Lorenz et al. 1981). Despite the improved formulation, 'Haemaccel' is one of the most common causes of Iifethreatening anaphylactoid reactions presenting to the Royal North Shore Hospital Anaesthetic Allergy Clinic in Sydney, and the reactions appear to occur in groups. It is the belief (prejudice?) of these authors that such severe reactions are immunemediated. Although immunological sensitisation to gelatin is possible (Ring 1984), there is no correlation between the presence of anticollagen antibodies in human serum and anaphylactoid reactions to gelatin (Adlmann & Schoning 1980). 3.2 Hydroxyethyl Starch Serum antibodies against HES have been produced in animals and detected in human sera, but do not correlate with reactions. Plasma histamine levels do not increase during infusion, and although in some reactors factors Band C3 decrease (suggesting complement activation), there is no proof of direct activation by HES. The mechanism of such reactions is unknown (Ring 1984). HES has also been shown to rarely produce erythema multiforme (Klein & Kogollon 1984) and macroamylasaemia (Kohler et al. 1977).
91
3.3 Plasma Protein Solutions Serum sickness-like reactions have been described by Ring (1981). Anaphylactic reactions may be induced by IgE anti-IgA antibodies in IgAdeficient individuals, and the caprylate stabiliser in some preparations may produce reactions due to caprylate-specific antibodies (Hossaini et al. 1975; Ring et al. 1979). In addition, protein aggregates in the solutions may produce aggregate anaphylaxis and right ventricular failure. The vasodilator effects of plasma protein fractions were first reported during bypass by Torda et al. (1973) and Bland et al. (1973) and subsequently during plasma exchange by Isbister & Biggs (1976). These reactions are due to Hageman factor fragments (prekallikrein activator) that activate the kinin system (Colman 1978). Modifications to the pasteurisation technique in Australia appear to have reduced the risk. A rare syndrome occurring after cardiopulmonary bypass, in which there is massive leak of plasma through pulmonary capillaries, has been attributed to both plasma protein fractions and protamine; but a direct cause and effect relationship between the disorder and the putative causes has not been established (Fisher 1987). 3.4 Dextrans Severe reactions to dextrans are related to IgG antibodies and involve activation of the classical complement pathway (Hedin et al. 1976; Kraft et al. 1982). Autopsy studies reveal leucocyte, platelet and fibrin deposits occluding pulmonary vessels (Ziegler 1978). This work has led to the exciting development of a monovalent hapten dextran of molecular weight 1000 daltons, which has been clearly shown to greatly reduce the incidence of severe dextran reactions if administered 2 minutes prior to dextran infusions (Messmer et al. 1980; Renck et al. 1983). Severe reactions in spite of such therapy have been documented (Bernstein et al. 1987).
92
Drug Safety 5 (2) 1990
3.5 Fluorinated Hydrocarbons Isolated cases of systemic hypotension associated with acute pulmonary hypertension have been described with the use of 'F1uosol - DA 20%', although large studies have failed to show any adverse reaction (Mitsuno et al. 1982). The activation of plasma complement by perfluocarbons is considered to be the mechanism of adverse pulmonary reactions. Test doses of 'F1uosol - DA 20%' Iml have shown transient and modest falls in neutrophil and platelet count (Vercellotti et al. 1982).
4. Treatment of Anaphylactoid Reactions The treatment of anaphylactoid reactions is the same as that of true anaphylaxis, and consists of oxygen, sympathomimetic drugs, asthmatic drugs and volume replacement, preferably with an alternative plasma volume expander. Steroids are usually given as drugs of second choice, and antihistamines may be useful in control of persistent cutaneous or cardiovascular signs (Fisher 1987). An important and often overlooked aspect of treatment is the provision of a warning bracelet for patients who react to plasma volume expanders.
References Adlmann B, Schoning B. Binding of native and denatured collagen to immunoglobulins and cold insoluble globulin (CIG) in serum of patients undergoing orthopaedic surgery. Klinische Wochenschrift 58: 625-629, 1980 Alexander B. Effects of plasma expanders on coagulation and haemostasis: dextran, hydroxyethyl starch, and other macromolecules revisited; blood colloids and plasma expanders. Progress in Clinical and Biological Research 19: 292-298, 1978 Annest SJ, Scoulli WA, Blumenstock FA, Stratton HH, Newell JC, et al. Increased creatinine clearance following cryoprecipitate infusion in trauma and surgical patients with decreased renal function. Journal of Trauma 20: 726-730, 1980 Bernstein RL, Rosenberg AD, Pada EY, Jaffe FF. A severe reaction to dextran despite hapten inhibition. Anaesthesiology 67: 567-569, 1987 Biro GP. Fluorocarbons in resuscitation of haemorrhage. International Anaesthesiology Clinics 23: 143-168, 1985 Bland JHL, Laver MB, Lowenstein E. Vasodilator effect of commercial 5% plasma protein solutions. Journal of the American Medical Association 224: 1721-1723, 1973 Boon JC, Jesch F, Ring J, Messmer K. Long term intravascular persistence of hydroxyethyl starch (HES) in man. European Surgical Research 8: 497-503, 1976 Claggett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients: results of meta-analysis. Annals of Surgery 208: 227-240, 1988
Coghill TH, Moore EE, Dunn EL, Cohen RG. Coagulation changes after albumin resuscitation. Critical Care Medicine 9: 22-26, 1981 Colman WR. Paradoxical hypotension after volume expansion with protein fractions. New England Journal of Medicine 229: 66-69, 1978 Dahn MS, Lucas CE, Ledgerwood AM, Higgins RF. Negative inotropic effect of albumin resuscitation for shock. Surgery 86: 235-239, 1979 Elliott LA, Legerwood AM, Lucas CM, et al. Role of F1uosol DA 20% in prehospital resuscitation. Critical Care Medicine 17: 166-172,1989 Engberg A. Effects of dextran 40 on the proximal renal tubule. Acta Chirurgica Scandinavica 142: 172-175, 1976 Fisher MM. Anaphylaxis. Disease a Month 33: 435-479, 1987 Fisher MM. Direct histamine release in anaesthesia and surgery: unanswered questions. Theoretical Surgery 3: 145-147, 1988 Hedin H, Richter W, Ring J. Dextran-induced anaphylactoid reactions in man: role of dextran reactive antibodies. Internal Archives of AJlergy and Applied Immunology 52: 145-159, 1976 Hossaini AA, Wasserman JJ, Venart GP. Experimental induction of caprylate dependent albumin antibodies. American Journal of Clinical Pathology 65: 513-516, 1975 Isbister JP, Biggs Jc. Reaction to rapid infusion of soluble plasma protein solution during large volume plasma exchange. Anaesthesia and Intensive Care 4: 105-109, 1976 Isbister JP, Fisher MM. Adverse effects of plasma volume expanders. Anaesthesia and Intensive Care 8: 145-151, 1980 Johnson SO, Lucas CE, Gerrick SJ, Ledgerwood AM, Higgins RF. Altered coagulation after albumin supplements for treatment of oligemic shock. Archives of Surgery 114: 379-383, 1979 Klein RE, Kogollon G. Erythema multi forme following the infusion of hydroxyethyl starch. Transfusion 68: 166-167, 1984 Kohler H, Kirch W, Horstman HJ. Hydroxyethyl starch-induced macroamylasemia. International Journal of Clinical Pharmacology and Biopharmacy 15: 428-429, 1977 Kovalik SG, Ledgerwood AM, Lucas CE, Higgins RF. The cardiac effect of altered calcium haemostasis after albumin resuscitation. Journal of Trauma 21(4): 275-279, 1981 Kraft 0, Hedin H, Richter W, Scheiner 0, Rumpold H, et al. Immunoglobulin class and subclass distribution of dextranreactive antibodies in human reactors and non reactors to clinical dextran. Allergy 37: 481-489, 1982 Lockwood DNJ, Bullen C, Machin SJ. A severe coagulopathy following volume replacement with hydroxyethyl starch in a Jehovah's Witness. Anaesthesia 43: 391-393, 1988 Lorenz W, Doenicke A, Schoning B, Karges H, Schmal A. Incidence and mechanisms of adverse reactions to polypeptides in man and dog. In Joint WHO/lABS Symposium of the Standardization of Albumin, Plasma Substitutes, and Plasmaphoresis, Geneva 1980, Development Biological Standard 48, S. Karger Basel, pp. 207-234, 1981 Lucas CE, Denis R, Legerwood AM, Grabow D. The effects of hespan on serum and lymphatic albumin, globulin and coagulant protein. Annals of Surgery 207: 416-420, 1988 Messmer K, Ljunstrom K-G, Gruber U-F, Richter W, Hedin H. Prevention of dextran-induced anaphylactoid reactions by hapten inhibition. Lancet I: 975-977, 1980 Mitsuno T, Ohyanagi H, Naito R. Clinical studies of a perfluorochemical whole blood substitute (F1uosol DA). Annals of Surgery 195: 60-69, 1982 Paull J. A prospective study of dextran-induced anaphylactoid reactions in 5745 patients. Anaesthesia and Intensive Care 15: 163-167, 1987 Rajagopalan PR, Reines HD, Pulliam C, Fitts CT, LeVeen HH. Reversal of acute renal failure using haemodilution with hydroxyethyl starch. Journal of Trauma 23: 795-800, 1983 Raper RF, Fisher MM. Resuscitation in acute haemorrhage. Anaesthesia and Intensive Care 12: 212-216, 1984
Adverse Reactions to Plasma Volume Expanders
93
Renck H. Ljungstrom K-G. Hedin H. Richter W. Prevention of dextran-induced anaphylactic reactions by hapten inhibition. Acta Chirurgica Scandanavica 149: 355-360. 1983 Ring J. Colloids. Clinics in Anaesthesiology 2: 619-641,1984 Ring J. Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet I: 466-469. 1977 Ring J. Stephan W. Brendel W. Anaphylactoid reactions to infusion of plasma protein and human serum albumin. Clinical Allergy 9: 89-99. 1979 Schwarz J. Ihle B. Dowling J. Acute renal failure induced by low molecular weight dextran. Australian and New Zealand Journal of Medicine 14: 688-690. 1984 Torda TA. Harrisson GA. McCulloch CH. Wright JS. Stacey R. et al. Circulatory effects of stable plasma protein solution (SPPS). Medical Journal of Australia I: 798-800. 1973 Tremper KK. Lapin R. Levine E. et al. Haemodynamic and oxy-
gen transport effects of a perfluorochemical blood substitute. Critical Care Medicine 8: 738-741, 1980 Vercellotti G, Hammerschmidt BE, Craddock P. Activation of plasma complement by perfluorocarbon: possible mechanism of adverse pulmonary reactions in treated patients. Blood 59: 1299-1304, 1982 Vervloet D, Senft M, Dugue P. Arnaud A, Charpin J. Anaphylactic reactions to modified gelatins. Journal of Allergy and Clinical Immunology 71: 535-540. 1983 Ziegler HK. Sektionstefund bei Dextranzwischenfall. Medizinische Klinik 73: 1089-1090. 1978
Authors' address: Dr M. Fisher, Head, Intensive Therapy Unit. Royal North Shore Hospital of Sydney. St Leonards, NSW 2065, Australia.
First fCR International Clinical Symposium
The Role of Clinical Measurement the Evaluation of New Drugs Date: 8-10 May 1990 Venue: Edinburgh, Scotland For further information, please contact: Symposium Secretariat CEP Consultants Ltd 26-28 Albany Street Edinburgh EHI 3QH
COTLAND
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In
Drug Safety 5 (2): 86-93, 1990 0114-5916/90/0003-0086/$04,00/0 © ADiS Press Limited All rights reserved. MEDT03 DRUG SAFETY 149
Adverse Reactions to Plasma Volume Expanders Malcolm McD. Fisher and Peter W. Brady Intensive Therapy Unit and Department of Cardiothoracic Surgery, Royal North Shore Hospital of Sydney, St Leonards, New South Wales, Australia
Contents
Summary ................ ,., ....... " ....... ,., ...... ,........ ' ................................................ ,., ..... ",., ...... ,.", .... ,.,. 86 I. Types of Plasma Volume Expanders ........... ,.. ,.............................. ,........ ,.... ,........... .. ,.... ,...... 87 1.1 Plasma Protein Fractions ,...... ,................................................ ,.. ,.......... ,...... ,................... 87 1.2 Plasma Derivatives ........................................................................................................... 87 1.3 Albumin 25% ........................................ ............................................................................. 87 1.4 Modified Gelatins ............................................................................................................. 87 1.5 Dextrans ............................................................................................................................. 87 1.6 Hydroxyethyl Starch ......................................................................................................... 88 1.7 Fluorinated Hydrocarbons .............................................................. .......... ....................... 88 2. Adverse Effects of Plasma Volume Expanders ..................................................................... 89 2.1 Fluid Overload .................................................................................................................. 89 2.2 Contamination and Infection ...................... ..................................................................... 89 2.3 Haemostasis and Cross-Matching .............................................................. .. .................... 89 2.4 Renal Function .................................................................................................................. 89 2.5 Cardiovascular Function .................................................................................................. 90 2.6 Incomplete Metabolism and Storage ............................................................................... 90 2.7 Anaphylactoid Reactions .................................................................................................. 90 3. Mechanism of Reactions ..................................................................................... ................... 90 3.1 Gelatins .............................................................................................................................. 91 3.2 Hydroxyethyl Starch .......................... ............................................................................... 91 3.3 Plasma Protein Solutions ................................................................................................. 91 3.4 Dextrans ............................................................................................................................. 91 3.5 Fluorinated Hydrocarbons ............................................................................................... 92 4. Treatment of Anaphylactoid Reactions ................................................................................. 92
Summary
Plasma volume expanders are effective in the restoration of blood volume. All the available plasma volume expanders may rarely induce anaphylactoid reactions, although such reactions are extremely uncommon in shocked patients. The reactions are caused by different mechanisms depending on the solution, and there is little evidence that IgE antibodies are involved. In addition to these reactions, effects on haemostasis and renal function may occur, and the persistence of hydroxyethyl starch in the body has led to concern about its potential role as a carcinogen, although there is no evidence to suggest that this has occurred.
87
Adverse Reactions to Plasma Volume Expanders
The use of intravenous fluids in the replacement of blood volume is one of the most effective and accepted forms of medical therapy. The fluids used are broadly divided into 2 groups: crystalloids or electrolyte solutions, and colloids which contain compounds of large molecular weight, which are osmotically active and remain in the intravascular compartment longer than crystalloids. The circumstances under which crystalloid fluids are more effective than colloids are the subject of ongoing medical controversy. In favour of crystalloid solutions are their low cost and absence of adverse effects, while the main argument in favour of colloids is their greater efficacy, i.e. less is required to replace a given volume of blood. However, this is achieved at considerable financial cost and with the risk of a number of adverse effects. The data relating reduced mortality to the use of either group are not convincing. The use of fluids other than blood to replace blood volume carries benefits in providing haemodilution and allowing both time for crossmatching of blood and its conservation. The risk of blood-borne infectious diseases is reduced, and the use of specific replacement of plasma losses in burns, anaphylaxis and plasmapheresis is possible (Raper & Fisher 1984). Thus, the use of colloid solutions is widespread in acute blood volume replacement, perioperative haemodilution and prophylaxis of thromboembolism. The various properties of the available solutions of plasma volume expanders are given in table I.
1. Types
0/ Plasma
Volume Expanders
1.1 Plasma Protein Fractions Stable plasma protein solution 5% (SPPS) is pasteurised from donated human plasma, and is therefore relatively expensive.
vantages of containing clotting factors, but carry the risk of transmission of hepatitis and human immunodeficiency virus. They also have a high sodium content. It has been suggested that cryoprecipitate may improve renal function due to its opsoninic content (Annest et al. 1980).
1.3 Albumin 25%
This is the most expensive solution to prepare, and the most limited resource. It is hyperosmotic and will assist the movement of fluid from the extravascular space to the vascular compartment. Its use is usually reserved for patients such as those with burns or low colloid osmotic pressure, in whom plasma volume is contracted and the extracellular space expanded.
1.4 Modified Gelatins
The 2 most commonly used modified gelatin solutions are 'Haemaccel', in which the gelatin is cross-linked by urea, and 'Gelofusin', in which it is cross-linked by succinylation. The latter appears to have a longer half-life. 'Haemaccel' has a lO-fold higher content of calcium (6.25 mmol/L) and potassium (5.1 mmol/L) than 'Gelofusin', in which the concentration of both elements is less than 0.4 mmol/L. This higher calcium content can lead to clotting in warming coils when 'Haemaccel' is infused with blood.
1.5 Dextrans
1.2 Plasma Derivatives Plasma derivatives are available in a freeze-dried form , as fresh frozen plasma, as cryosupernate and as cryoprecipitate. These formulations have the ad-
The dextrans are produced by the action of the bacteria Leuconostoc mesenteroides on sucrose, and the 2 most commonly produced solutions, dextran
88
Drug Safety 5 (2) 1990
Table I. Properties of plasma volume expanders
Solution
Albumin Dextran 40 (,Rheomacrodex') Dextran 70 ('Macrodex') 'Fluosol - DA 20%'b Fresh frozen plasma Hydroxyethyl starch Modified gelatins urea-linked gelatin (,Haemaccel') succinylated gelatin ('Gelofusin') Stable plasma protein solution
tv.
Distribution (%)
Osmotic activity
Sodium content (mosmol/L)
EV
IV
5-1Od 6-9h 12h Short (h) As for plasma components 24h
20
80a 100 100 100 100
Depends on dilution Hyperosmotic Hyperosmotic Isosmotic Isosmotic
Depends on diluent 154 154
100
Isosmotic
154
4h 5h 5-10d
50 50 20
Isosmotic Isosmotic Isosmotic
145 154 130-150
50 50 80 a
170-190
a Depends on permeability of the capillary endothelium. b Fluorinated hydrocarbon whole blood substitute. Abbreviation: ty, = half-life.
40 and dextran 70, have an average molecular weight of dextran of 40,000 and 70,000 daltons,
respectively. In addition to their plasma volume expanding capability, they have an advantage over other plasma volume expanders in a rheological effect which improves microcirculatory flow, and because of this they have been used in the prophylaxis of thromboembolic disorders (Claggett & Reisch 1988). 1.6 Hydroxyethyl Starch Hydroxyethyl starch is a synthetic macromolecular polymer which has been shown to be an effective plasma volume expander. 1. 7 Fluorinated Hydrocarbons ('Fluosol DA 20%') 'Fluosol - DA 20%' (table II) is a whole blood substitute consisting of an emulsion of 2 fluorinated hydrocarbons in saline. Particle size averages O.12llm, with a maximum size of 0.6Ilm. As a comparison, the average size of red blood cells is 0.7Ilm. These substances are clinically and pharmacologically inert, dissolving oxygen in large quantities in a linear relationship to p02 (unlike haemoglo-
bin, which binds oxygen in a sigmoid relationship). In addition, they have a high affinity for carbon dioxide. Clinically, 'Fluosol - DA 20%' has been shown to be an effective plasma volume expander, and useful in the management of acute carbon monoxide poisoning. It has been reported to be both safe and effective in long term primate studies and in clinical practice (Mitsuno et al. 1982; Tremper et al. 1980). Table II. Composition of 'Fluosol - DA 20%' (data from Mitsuno et al. 1982)
Agent
W/V%
CaCI2 Glucose Glycerol Hydroxyethyl starch KCI
0.028 0.180 0.8 3.0 0.034 0.020 0.60 0.210 14.0 6.0 2.7 0.4
MgCI2 NaCI NaHC03 Perfluorodecalin Perfluorotripropylamine Pluronic F-68a Yolk phospholipids b a b
Emulsifier. Surfactant.
Adverse Reactions to Plasma Volume Expanders
89
2. Adverse Effects of Plasma Volume Expanders
nificantly affect modem cross-matching techniques, with the exception of occasional difficulties in patients who may accumulate high molecular weight components during prolonged infusion (Isbister & Fisher 1980). Hydroxyethyl starch (HES) causes a fall in serum proteins, including clotting factors, similar to albumin infusion. Lucas and colleagues (1988) suggest that this is due to an oncotically induced extravascular protein relocation. However, in no studies where moderate volumes of HES were used for blood volume replacement in shock was there any evidence of clinical bleeding, although mild elevations of prothrombin time and activated partial thromboplastin occurred. Lockwood, Bullen and Machin (1988) have described a severe coagulopathy related to HES volume replacement in 1 patient. A 5% albumin solution, compared with Ringer lactate in the dog haemorrhage model, showed an increase in prothrombin and partial thromboplastin time in the albumin group and similar change in platelet count, platelet function and fibrinogen levels. There was no increase in clinical bleeding (Coghill et al. 1981). In trauma patients, blood transfusion requirements were increased in a group who received supplemental albumin; platelet count was decreased, and prothrombin time and partial thromboplastin time were prolonged (Johnson et al. 1979). 'Fluosol - DA 20%' is associated with coagulation abnormalities in dogs. Biro (1985) showed .that all coagulation parameters (with the exception of prothrombin ratio) were adversely affected, and hyperfibrinolysis occurred. Elliott et al. (1989) showed a reduction in serum proteins, prolonged prothrombin time and activated partial thromboplastin time, and reduced platelet levels. There have been no reports of excessive blood loss due to altered coagulation states in humans.
2.1 Fluid Overload Fluid overload is a common cause of drugrelated death. In overload states the greater intravascular half-life of colloids over crystalloids becomes a significant disadvantage, as the ability to rapidly remove excess fluid with diuretics is limited. 2.2 Contamination and Infection All available solutions support bacterial growth, but nevertheless carry a lower risk of infection than does the use of donated blood. 2.3 Haemostasis and Cross-Matching There is no evidence of significant effects on haemostasis for gelatin solutions, SPPS or albumin. The various plasma fractions are used therapeutically in massive transfusions, because of their content of factors V and VIII. Dextrans are used therapeutically to reduce thromboembolic disease by limiting platelet aggregation, although when they are infused in volumes over 1500ml they may produce pathological bleeding (Alexander 1978). In large volumes, dextrans induce an acquired von Willebrand's state, and it appears that some hours of circulation must occur prior to this. In studies of the use of dextrans for the prevention of postoperative thromboembolism (Isbister & Fisher 1980) these agents have not been found to be associated with increased haemorrhage or wound haematoma, but they provide less effective prevention of thromboembolic disease than low-dose heparin (Claggett & Reisch 1988). Paull (1987), in a study of Australian women, has shown that the risk of anaphylaxis to dextrans outweighs the postoperative thromboembolic prevention benefits. High molecular weight dextrans caused marked rouleau formation in red cells and made interpretation of saline cross-match difficult. There is, however, no evidence that current dextrans sig-
2.4 Renal Function It is difficult to separate the alleged beneficial effects of plasma volume expanders on renal function from their volume expanding function. Both
Drug Safety 5 (2) 1990
90
cryoprecipitate, in trauma and surgical patients, and hetastarch in a dog renal ischaemia model, improved renal function (Annest et al. 1980; Rajagopalan et al. 1983). Dextran 40 produces reversible histological changes in renal tubules (Engberg 1976) and has been implicated in renal failure (Schwarz et al. 1984); however, there is no good evidence to suggest a similar role for dextran 70. 2.5 Cardiovascular Function Dahn et al. (1979) showed a negative inotropic effect of 5% albumin resuscitation, although the patients all received what appeared to be excessive quantities of fluid. In the same group of patients, Kovalik et al. (1981) showed that ionised calcium levels were reduced in the albumin-resuscitated group, and postulated that the negative inotropism may be in part due to this effect. 2.6 Incomplete Metabolism and Storage HES is incompletely metabolised and persists in the body (Boon et al. 1976), which suggests that a carcinogenic effect may be possible. However, there have been no data to suggest this is so. 2.7 Anaphylactoid Reactions Of all the adverse effects of colloid plasma volume expanders, anaphylactoid reactions have received the most study and are their major disadvantage over crystalloid solutions. There are a number of important aspects to these reactions which are often not appreciated. First, anaphylactoid reactions to plasma volume expanders are extremely rare in shocked patients (Ring, personal communication), and are more common in unanaesthetised awake normovolaemic patients (Boon et al. 1976). A number of factors probably contribute to this phenomenon. It is theoretically possible that the vasodilatation that is the most common severe feature in such reactions may be missed in a hypovolaemic patient. It is further possible that the endogenous catechol-
Table III. Incidence of anaphylactoid reactions to plasma volume expanders in prospective studies (adapted from Ring 1984; Ring & Messmer 1977) Colloid
Units infused
Reactions (%)
Dextran 40 Dextran 70 Gelatins 'Haemaccel' modified 'Haemaccel' 'Gelofusin' HES Human serum albumin SPPS Abbreviations: HES
51261 36614
0.008 0.11
7448 6178
0.84 0.42
6000 16405 60048 25582
0.02 0.085 0.012 0.02
= hydroxyethyl starch; SPPS = stable plasma
protein solution.
amine, endorphin, and corticosteroid response to shock both produces blocking of mediator effects and opposes the effects of mediators on target organs (Fisher 1987). Secondly, although multicentre and large population studies have determined incidences of reactions to specific plasma volume expanders they are relatively rare events, and as such confidence limits for reaction rates (which are rarely if ever calculated) will be large. No statistically significant difference between the rates of reaction to plasma volume expanders has been determined; the most frequently quoted incidences are from the work of Ring and colleagues, and are shown in table III. Thirdly, although the incidence of severe reactions to a particular plasma volume expander influences the decision of users, there may be no validity in such logic due to the relative rarity of such reactions (particularly in shock).
3. Mechanism of Reactions Anaphylactoid reactions are those which mimic the effects of anaphylaxis (Type I hypersensitivity) but do not appear to involve reaginic antibodies. IgE antibodies have not been found to any of the available plasma volume expanders, although some reactors to 'Haemaccel' have positive intradermal tests to dilutions of this agent, which is suggestive, but not diagnostic of an antibody-mediated reaction (Vervloet et al. 1983).
Adverse Reactions to Plasma Volume Expanders
3.1 Gelatins The release of histamine from mast cells and basophils by a direct effect of drugs is a common event in anaesthesia and surgery, and is usually associated with detectable clinical manifestations. Whether life-threatening reactions can be caused by this mechanism is questionable, however (Fisher 1988). 'Haemaccel' definitely produces reactions of minor severity by this mechanism; the reactions are blocked by H I and H2 antihistamines. There is little evidence to support such a mechanism with dextrans, and it appears less common with other polypeptides (Lorenz et al. 1981). There is some evidence that the histamine release from 'Haemaccel' was in part related to the manufacturing process causing an excess of diisocyanate linkages, which released histamine, and modification of this process has reduced the incidence and severity of the problem (Lorenz et al. 1981). Despite the improved formulation, 'Haemaccel' is one of the most common causes of Iifethreatening anaphylactoid reactions presenting to the Royal North Shore Hospital Anaesthetic Allergy Clinic in Sydney, and the reactions appear to occur in groups. It is the belief (prejudice?) of these authors that such severe reactions are immunemediated. Although immunological sensitisation to gelatin is possible (Ring 1984), there is no correlation between the presence of anticollagen antibodies in human serum and anaphylactoid reactions to gelatin (Adlmann & Schoning 1980). 3.2 Hydroxyethyl Starch Serum antibodies against HES have been produced in animals and detected in human sera, but do not correlate with reactions. Plasma histamine levels do not increase during infusion, and although in some reactors factors Band C3 decrease (suggesting complement activation), there is no proof of direct activation by HES. The mechanism of such reactions is unknown (Ring 1984). HES has also been shown to rarely produce erythema multiforme (Klein & Kogollon 1984) and macroamylasaemia (Kohler et al. 1977).
91
3.3 Plasma Protein Solutions Serum sickness-like reactions have been described by Ring (1981). Anaphylactic reactions may be induced by IgE anti-IgA antibodies in IgAdeficient individuals, and the caprylate stabiliser in some preparations may produce reactions due to caprylate-specific antibodies (Hossaini et al. 1975; Ring et al. 1979). In addition, protein aggregates in the solutions may produce aggregate anaphylaxis and right ventricular failure. The vasodilator effects of plasma protein fractions were first reported during bypass by Torda et al. (1973) and Bland et al. (1973) and subsequently during plasma exchange by Isbister & Biggs (1976). These reactions are due to Hageman factor fragments (prekallikrein activator) that activate the kinin system (Colman 1978). Modifications to the pasteurisation technique in Australia appear to have reduced the risk. A rare syndrome occurring after cardiopulmonary bypass, in which there is massive leak of plasma through pulmonary capillaries, has been attributed to both plasma protein fractions and protamine; but a direct cause and effect relationship between the disorder and the putative causes has not been established (Fisher 1987). 3.4 Dextrans Severe reactions to dextrans are related to IgG antibodies and involve activation of the classical complement pathway (Hedin et al. 1976; Kraft et al. 1982). Autopsy studies reveal leucocyte, platelet and fibrin deposits occluding pulmonary vessels (Ziegler 1978). This work has led to the exciting development of a monovalent hapten dextran of molecular weight 1000 daltons, which has been clearly shown to greatly reduce the incidence of severe dextran reactions if administered 2 minutes prior to dextran infusions (Messmer et al. 1980; Renck et al. 1983). Severe reactions in spite of such therapy have been documented (Bernstein et al. 1987).
92
Drug Safety 5 (2) 1990
3.5 Fluorinated Hydrocarbons Isolated cases of systemic hypotension associated with acute pulmonary hypertension have been described with the use of 'F1uosol - DA 20%', although large studies have failed to show any adverse reaction (Mitsuno et al. 1982). The activation of plasma complement by perfluocarbons is considered to be the mechanism of adverse pulmonary reactions. Test doses of 'F1uosol - DA 20%' Iml have shown transient and modest falls in neutrophil and platelet count (Vercellotti et al. 1982).
4. Treatment of Anaphylactoid Reactions The treatment of anaphylactoid reactions is the same as that of true anaphylaxis, and consists of oxygen, sympathomimetic drugs, asthmatic drugs and volume replacement, preferably with an alternative plasma volume expander. Steroids are usually given as drugs of second choice, and antihistamines may be useful in control of persistent cutaneous or cardiovascular signs (Fisher 1987). An important and often overlooked aspect of treatment is the provision of a warning bracelet for patients who react to plasma volume expanders.
References Adlmann B, Schoning B. Binding of native and denatured collagen to immunoglobulins and cold insoluble globulin (CIG) in serum of patients undergoing orthopaedic surgery. Klinische Wochenschrift 58: 625-629, 1980 Alexander B. Effects of plasma expanders on coagulation and haemostasis: dextran, hydroxyethyl starch, and other macromolecules revisited; blood colloids and plasma expanders. Progress in Clinical and Biological Research 19: 292-298, 1978 Annest SJ, Scoulli WA, Blumenstock FA, Stratton HH, Newell JC, et al. Increased creatinine clearance following cryoprecipitate infusion in trauma and surgical patients with decreased renal function. Journal of Trauma 20: 726-730, 1980 Bernstein RL, Rosenberg AD, Pada EY, Jaffe FF. A severe reaction to dextran despite hapten inhibition. Anaesthesiology 67: 567-569, 1987 Biro GP. Fluorocarbons in resuscitation of haemorrhage. International Anaesthesiology Clinics 23: 143-168, 1985 Bland JHL, Laver MB, Lowenstein E. Vasodilator effect of commercial 5% plasma protein solutions. Journal of the American Medical Association 224: 1721-1723, 1973 Boon JC, Jesch F, Ring J, Messmer K. Long term intravascular persistence of hydroxyethyl starch (HES) in man. European Surgical Research 8: 497-503, 1976 Claggett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients: results of meta-analysis. Annals of Surgery 208: 227-240, 1988
Coghill TH, Moore EE, Dunn EL, Cohen RG. Coagulation changes after albumin resuscitation. Critical Care Medicine 9: 22-26, 1981 Colman WR. Paradoxical hypotension after volume expansion with protein fractions. New England Journal of Medicine 229: 66-69, 1978 Dahn MS, Lucas CE, Ledgerwood AM, Higgins RF. Negative inotropic effect of albumin resuscitation for shock. Surgery 86: 235-239, 1979 Elliott LA, Legerwood AM, Lucas CM, et al. Role of F1uosol DA 20% in prehospital resuscitation. Critical Care Medicine 17: 166-172,1989 Engberg A. Effects of dextran 40 on the proximal renal tubule. Acta Chirurgica Scandinavica 142: 172-175, 1976 Fisher MM. Anaphylaxis. Disease a Month 33: 435-479, 1987 Fisher MM. Direct histamine release in anaesthesia and surgery: unanswered questions. Theoretical Surgery 3: 145-147, 1988 Hedin H, Richter W, Ring J. Dextran-induced anaphylactoid reactions in man: role of dextran reactive antibodies. Internal Archives of AJlergy and Applied Immunology 52: 145-159, 1976 Hossaini AA, Wasserman JJ, Venart GP. Experimental induction of caprylate dependent albumin antibodies. American Journal of Clinical Pathology 65: 513-516, 1975 Isbister JP, Biggs Jc. Reaction to rapid infusion of soluble plasma protein solution during large volume plasma exchange. Anaesthesia and Intensive Care 4: 105-109, 1976 Isbister JP, Fisher MM. Adverse effects of plasma volume expanders. Anaesthesia and Intensive Care 8: 145-151, 1980 Johnson SO, Lucas CE, Gerrick SJ, Ledgerwood AM, Higgins RF. Altered coagulation after albumin supplements for treatment of oligemic shock. Archives of Surgery 114: 379-383, 1979 Klein RE, Kogollon G. Erythema multi forme following the infusion of hydroxyethyl starch. Transfusion 68: 166-167, 1984 Kohler H, Kirch W, Horstman HJ. Hydroxyethyl starch-induced macroamylasemia. International Journal of Clinical Pharmacology and Biopharmacy 15: 428-429, 1977 Kovalik SG, Ledgerwood AM, Lucas CE, Higgins RF. The cardiac effect of altered calcium haemostasis after albumin resuscitation. Journal of Trauma 21(4): 275-279, 1981 Kraft 0, Hedin H, Richter W, Scheiner 0, Rumpold H, et al. Immunoglobulin class and subclass distribution of dextranreactive antibodies in human reactors and non reactors to clinical dextran. Allergy 37: 481-489, 1982 Lockwood DNJ, Bullen C, Machin SJ. A severe coagulopathy following volume replacement with hydroxyethyl starch in a Jehovah's Witness. Anaesthesia 43: 391-393, 1988 Lorenz W, Doenicke A, Schoning B, Karges H, Schmal A. Incidence and mechanisms of adverse reactions to polypeptides in man and dog. In Joint WHO/lABS Symposium of the Standardization of Albumin, Plasma Substitutes, and Plasmaphoresis, Geneva 1980, Development Biological Standard 48, S. Karger Basel, pp. 207-234, 1981 Lucas CE, Denis R, Legerwood AM, Grabow D. The effects of hespan on serum and lymphatic albumin, globulin and coagulant protein. Annals of Surgery 207: 416-420, 1988 Messmer K, Ljunstrom K-G, Gruber U-F, Richter W, Hedin H. Prevention of dextran-induced anaphylactoid reactions by hapten inhibition. Lancet I: 975-977, 1980 Mitsuno T, Ohyanagi H, Naito R. Clinical studies of a perfluorochemical whole blood substitute (F1uosol DA). Annals of Surgery 195: 60-69, 1982 Paull J. A prospective study of dextran-induced anaphylactoid reactions in 5745 patients. Anaesthesia and Intensive Care 15: 163-167, 1987 Rajagopalan PR, Reines HD, Pulliam C, Fitts CT, LeVeen HH. Reversal of acute renal failure using haemodilution with hydroxyethyl starch. Journal of Trauma 23: 795-800, 1983 Raper RF, Fisher MM. Resuscitation in acute haemorrhage. Anaesthesia and Intensive Care 12: 212-216, 1984
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Renck H. Ljungstrom K-G. Hedin H. Richter W. Prevention of dextran-induced anaphylactic reactions by hapten inhibition. Acta Chirurgica Scandanavica 149: 355-360. 1983 Ring J. Colloids. Clinics in Anaesthesiology 2: 619-641,1984 Ring J. Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet I: 466-469. 1977 Ring J. Stephan W. Brendel W. Anaphylactoid reactions to infusion of plasma protein and human serum albumin. Clinical Allergy 9: 89-99. 1979 Schwarz J. Ihle B. Dowling J. Acute renal failure induced by low molecular weight dextran. Australian and New Zealand Journal of Medicine 14: 688-690. 1984 Torda TA. Harrisson GA. McCulloch CH. Wright JS. Stacey R. et al. Circulatory effects of stable plasma protein solution (SPPS). Medical Journal of Australia I: 798-800. 1973 Tremper KK. Lapin R. Levine E. et al. Haemodynamic and oxy-
gen transport effects of a perfluorochemical blood substitute. Critical Care Medicine 8: 738-741, 1980 Vercellotti G, Hammerschmidt BE, Craddock P. Activation of plasma complement by perfluorocarbon: possible mechanism of adverse pulmonary reactions in treated patients. Blood 59: 1299-1304, 1982 Vervloet D, Senft M, Dugue P. Arnaud A, Charpin J. Anaphylactic reactions to modified gelatins. Journal of Allergy and Clinical Immunology 71: 535-540. 1983 Ziegler HK. Sektionstefund bei Dextranzwischenfall. Medizinische Klinik 73: 1089-1090. 1978
Authors' address: Dr M. Fisher, Head, Intensive Therapy Unit. Royal North Shore Hospital of Sydney. St Leonards, NSW 2065, Australia.
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