Incidence and classification of adverse reactions to plasma substitutes

Summary Anaphylactoid reactions have been observed after the infusion of all of the presently available colloid volume substitutes (plasma proteins, dextran, gelatin and hydroxyethyl starch (HES)). The clinical symptoms range from mild reactions with skin manifestation only to severe and life-threatening complications (shock, cardiac and/or respiratory arrest). Fatalities have been reported. The classification of the clinical symptoms into 4 grades of severity (I=skin reaction; IV=cardiac and/or respiratory arrest) proved to be very valuable. A critical review of the literature dealing with the incidence of these complications reveals divergent results: The reported incidences vary between 0.0004% in a retrospective study and 30.0% in a randomized clinical trial. Further analysis of these data shows an inverse relationship between the number of infusions registered and the frequency of adverse reactions reported. This can partly be explained by a more complete examination of the patients in prospective randomized trials with small numbers of patients. Mild reactions (grade I) might partly be missed in larger studies. In contrast, severe — or fatal — reactions are registered rarely in randomized trials. However, information about these complications is of highest interest for the clinicians. In a prospective multicentre study registering adverse reactions only we obtained the following incidences per number of infusion units delivered (total 200, 906): Plasma Protein: 0.014% (85, 630 units), dextran: 0.032% (85, 882 units), gelatin: 0.115% (12, 989 units), HES: 0.085% (16, 405 units).Based on the experience of this study and a critical review of the literature we conclude that future studies should register the number of adverse reactions together with the number of infusions tolerated by single protocols for each application. This type of prospective drug monitoring is advised as a method to obtain informations about the incidence and the natural course of severe adverse reactions.     

Plasma histamine and tryptase during anaphylactoid reactions

We have compared the diagnostic value of plasma histamine and mast cell tryptase to evaluatein vivo histamine-release during anaphylactoid reactions. In 17 patients, plasma histamine was measured within one hour after the reaction, and the result was compared with skin testing performed 8 weeks later. Each subject with a high histamine level had a positive skin test to one of the administered drugs. The plasma histamine level was compared to tryptase in 33 patients. In 13 cases, both were elevated and, in 15 others, both were negative. Two patients had normal histamine but high tryptase: this was due to delayed sampling. Three had high histamine but low tryptase. In one, muscle relaxant allergy was proved by positive skin tests and IgE determination. Mast cell tryptase is an efficient alternative to histamine measurement when blood withdrawing is done late. However, a few anaphylactic reactions may not be associated with high levels of tryptase.     

Plasma histamine and tryptase during anaphylactoid reactions

We have compared the diagnostic value of plasma histamine and mast cell tryptase to evaluatein vivo histamine-release during anaphylactoid reactions. In 17 patients, plasma histamine was measured within one hour after the reaction, and the result was compared with skin testing performed 8 weeks later. Each subject with a high histamine level had a positive skin test to one of the administered drugs. The plasma histamine level was compared to tryptase in 33 patients. In 13 cases, both were elevated and, in 15 others, both were negative. Two patients had normal histamine but high tryptase: this was due to delayed sampling. Three had high histamine but low tryptase. In one, muscle relaxant allergy was proved by positive skin tests and IgE determination. Mast cell tryptase is an efficient alternative to histamine measurement when blood withdrawing is done late. However, a few anaphylactic reactions may not be associated with high levels of tryptase.     

Anaphylactoid reactions and histamine release by plasma substitutes: A randomized controlled trial in human subjects and in dogs

Conclusion All plasma substitutes in clinical use caused analphylactoid reactions in man and dog, but histamine release into the plasma or whole blood was related to them only in the case of Haemaccel. Thus a rational treatment or prophylaxis of this clinical hazard by H₁- and H₂-receptor antagonists can be attempted only in the case of Haemaccel [5].     

Basophil histamine release in children with adverse reactions to cow milk

Basophil histamine release was examined in 26 children suspected of having cow milk allergy (CMA). Following oral challenge with cow milk, the initial adverse reaction reappeared in 20 children, the majority developing urticaria. The urticaria patients showed a high degree of correlation between the results of histamine test, RAST and skin test. Children with gastrointestinal symptoms reacted to milk challenge, but only a few showed a positive histamine test, RAST and skin test. Among the patients with atopic dermatitis, the tests gave mostly negative results, which was in accordance with the lack of response to a milk challenge. The results obtained by removal from and fixation to the cell surface of IgE indicate an IgE-mediated reaction in CMA, which, in connection with the correlation between histamine test and RAST or skin test, suggests basophil histamine release as a suitable method for testing Type I allergy in children suspected of CMA.     

Effects of infused histamine: correlation of plasma histamine levels and symptoms

Plasma and urine histamine levels were measured during sequential infusions of histamine (0.05, 0.1, 0.25, 0.5, and 1.0 microgram/kg/min histamine base for 30 min each) to determine the plasma level required to elicit flushing, headaches, tachycardia, and diastolic hypotension. Each study was performed with subjects on no medications or after pretreatment with hydroxyzine and/or cimetidine in order to confirm the receptor subtype involved in each of the responses. Resting plasma histamine levels were 0.62 +/- 0.12 ng/ml, and levels rose progressively indirect proportion to the concentration of infused histamine. Plasma levels of histamine required to elicit symptoms were as follows: 1.61 +/- 0.30 ng/ml = 30% increase in heart rate, 2.39 +/- 0.52 ng/ml = significant flush and headache, and 2.45 +/- 0.13 ng/ml = 30% increase in pulse pressure. Cimetidine pretreatment failed to influence the histamine level required to elicit symptoms, hydroxyzine pretreatment significantly raised the level required to increase heart rat by 30%, and the combination of antihistamines significantly raised the threshold for histamine to elicit all the response. Urine histamine was increased in direct proportion to the histamine infusions, and because of stability, accessibility, and the capacity for retrospective diagnosis, urine is the suggested fluid to employ to measure histamine release in humans.     

Leukocyte histamine release to suxamethonium in patients with adverse reactions to muscle relaxants

In an earlier study we confirmed the usefulness of intradermal skin tests and histamine release in diagnosis of patients reactive to muscle relaxants, and we suggested an IgE-mediated reaction rather than an idiosyncratic mechanism. In a later study, we studied the relationship between (Formula: see text) that is one of the muscle relaxants producing the most frequent adverse reactions under anesthesia. Histamine release was measured in five patients with increasing concentrations of suxamethonium in the presence or absence of human serum albumin in Tris buffer. Suxamethonium by itself without any carrier in the buffer could, in vitro, act as a true allergen on target leukocytes in the sensitized patients' group. Acetylcholine (20 and 200 micrograms/ml) did not induce significant histamine release in five patients with positive histamine release in the presence of suxamethonium. Preincubation of leukocytes from 11 patients for 30 min with 20 and 200 micrograms of acetylcholine in Tris albumin CA++ Mg++ buffer decreased the histamine release induced by suxamethonium (10 micrograms/ml); mean maximal histamine release of 46% +/- 4.2 was reduced to 31.4 +/- 5.8 and 7% +/- 4 (p less than 0.001), respectively. However, in eight control subjects similar concentrations of acetylcholine did not change the maximal histamine release induced by anti-IgE (0.2 micrograms/ml). In the same way acetylcholine did not modify histamine release induced by Dermatophagoides pteronyssinus extract (1/10,000 w/v) in six patients allergic to this allergen. This study suggests that suxamethonium acts as a true allergen and that acetylcholine or one of its metabolites may act as a hapten inhibitor in the model of histamine release induced by suxamethonium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma histamine concentrations and complement activation during house dust mite-provoked bronchia] obstructive reactions

Lung function and histamine levels in peripheral venous plasma samples were followed after challenge with house dust mite allergen. In eight patients the mean maximal histamine concentration showed a significant rise during the early obstructive reaction when compared with the concentrations at similar time intervals after inhalation of a control solution. In nine other patients treatment with disodium cromoglycate (DSCG) caused a significant fall in plasma histamine concentrations indicating that histamine liberation plays u role during the early obstructive reaction and was released from the lung compartment. Histamine during early obstructive reactions compared with the pre-inhalation values did show a rise in mean maximal histamine concentration (1.5-4.1 ng/ml) but this was statistically not significant. During the late reaction neither significant increase in histamine nor inhibition by DSCG was found. Measurement of complement degradation products did not support the role of complement activation during cither early or lute bronchial obstructive reactions.     

Biorhythmic changes of plasma histamine levels in healthy volunteers

The plasma histamine levels were reported to increase in early hours of the morning in asthmatic patients. It was supposed that this phenomenon would also be observed in normal volunteers. In this study using twelve normal healthy volunteers the plasma histamine levels were examined in a pharmacokinetic manner. It could be shown that plasma histamine levels follow biorhythmic changes with 3 maxima and 3 minima. The acrophases of the maxima are 12.77±0.61, 19.33±0.78 and 5.42±1.83 h. The most important rise in plasma histamine levels was found in the early hours of the morning representing about 55% of the total histamine available in plasma.     

Measurement ofN τ-methylhistamine concentrations in plasma and urine as a parameter for histamine release during anaphylactoid reactions

N -methylhistamine concentrations in plasma and urine were determined using a newly developed simultaneous determination for histamine andN -methylhistamine, based on isotope dilution mass fragmentography. Three groups of patients were investigated: patients receiving intravenously-administered iodamide for excretory urography, patients receiving a wasp-sting challenge, and patients treated with an intravenously-administered muscle relaxant. In all patients showing a distinct systemic anaphylactic or anaphylactoid reaction histamine andN -methylhistamine concentrations were found to be elevated. From the results of this study it can be concluded thatN -methylhistamine in plasma and urine is a good parameter for histamine release, and that the determination of this histamine metabolite are less hampered by possible artefacts (due to basophil disrupture, a very short half-life time or bacterial production) than determinations of histamine itself.     

Increased plasma tele-methylhistamine levels in the rat: Effects on plasma and tissue histamine and its elimination

Inflammation Research -     

Aspirin-sensitive rhinosinusitis/asthma: spectrum of adverse reactions to aspirin

In order to determine the types of respiratory responses observed during aspirin-induced reactions, 50 consecutive asthmatic patients with a history of aspirin sensitivity underwent prospective oral aspirin challenges between 1979 and 1981. Oral aspirin challenges produced 36 asthmatic responses (33 combined with rhinitis and three purely asthmatic) and six acute rhinoconjunctivitis responses (three combined with mild asthma and three purely rhinoconjunctivitis) but failed to stimulate any reaction in eight patients. The results produced by these challenges were then compared with results recorded during additional aspirin challenges in 28 of these patients, performed after the index challenge in 1979-1981 in 26 patients and in the case of two patients before 1979. The type of respiratory response to aspirin varied significantly in 11 (39%) of the 28 patients and included disappearance of aspirin reactivity in four patients.     

An assessment of plasma histamine concentrations during documented endotoxic shock

Recent reviews of the literature involving histamine release during sepsis and endotoxemia have reported that the majority of the studies are inconclusive due to inadequate assays or experimental protocols. In a controlled experimental setting we have employed a specific and sensitive radioenzymatic assay to determine plasma histamine concentrations temporally during documented endotoxin-induced shock in the conscious rat. Cardiovascular and metabolic measurements for the control group (n=7) were normal during the study period. Endotoxin (n=8, LD/90-24 hrs.) induced an early transient hypotensive episode and increase in systemic vascular resistance and a sustained decrease in cardiac index and central venous pressure and increase in heart and respiratory rates. Hypoglycemia and hyperlacticemia were present at the end of the four-hour study period. The small intestine was severely hemorrhaged in all animals given endotoxin. Histamine concentrations for the control group were unchanged throughout the study period. Contrary to previous reports, this model of endotoxemia revealed unchanging histamine concentrations during the first 30 minutes which were temporally coincident with the characteristic early hypotensive episode evoked by endotoxin. The histamine concentrations at 60 and 240 minutes following endotoxin were increased two and three-fold, respectively, compared to the control group. Three of the 8 rats given endotoxin died before four hours; histamine concentrations in plasma taken when death appeared certain were 42, 91, and 174, compared to the control value of approximately 8 ng/ml. There was no clear association of the increases in plasma histamine with any of the parameters measured in this study; however, established histamine effects may have been masked by the pre-existing effects of other mediators known to be active during endotoxemia. In separate groups of animals endotoxin (n=5) elicited early increases in plasma concentrations of norepinephrine (5-fold) and epinephrine (8-fold) that remained elevated for the 4-hour study period while the control group (n=4) remained stable. This study establishes that a) plasma histamine concentrations are increased during endotoxemia, b) plasma histamine is not elevated during the initial hypotension episode following endotoxin, c) plasma histamine increases during the progression of endotoxic shock, and d) plasma histamine concentrations are extremely high prior to death.NIH guidelines for the use of experimental animals were strictly adhered to throughout this study.