Méthode radio-immunologique de détection des IgE spécifiques à l'alcuronium

A radio-immunoassay (RIA) was used to screen for specific IgE to myorelaxants. Alcuronium was coupled to epoxyactivated Sepharose. Sixteen patients with anaphylaxis to alcuronium (n=2), gallamine (n=2) or suxamethonium (n=12) were studied. The diagnosis was established by intradermal tests (ID), passive cutaneous anaphylaxis tests and human basophil degranulation tests. The amount of non specific label retained by Sepharose-ethanolamine (with sera of patients) and Sepharose-alcuronium (with sera of 11 control subjects) was estimated. The RIA was positive 10/16 (8/14 patients having reacted to a muscle relaxant other than alcuronium). The RIA seemed to be useful in the diagnosis of anaphylaxis to muscle relaxants. Drug-reactive antibodies were specific of the quaternary ammonium radical, which was the common allergenic determinant of all molecules of muscle relaxants. This test accounted for in vitro cross-reactivity, but had no predictive value for the clinical risk of crossed-anaphylaxis. This risk was best assessed by ID; it was positive in three cases. Although it was not possible to compare ID and RIA, the interpretation of which was different, both tests should be recommended for the detection of sensitivity to muscle relaxants.     

Prospective preoperative survey of 300 patients using prick tests with muscle relaxants

It is now well established that the retrospective diagnosis of anaphylaxis to muscle relaxants may be based on skin prick testing. These tests, which use undiluted solutions of muscle relaxants, are as sensitive, specific and reproducible as intradermal tests for the diagnosis of IgE related adverse reactions to muscle relaxants. The rate of muscle relaxant anaphylaxis (1/1 500 to 1/5 000) justifies its prevention based on a possible latent sensitization. A prospective investigation was carried out in 300 surgical patients scheduled for general anaesthesia. Prick tests were carried out using the 6 available muscle relaxants: suxamethonium, gallamine, alcuronium, pancuronium, vecuronium and atracurium. The wheal the drug might produce was compared with that obtained with codeine phosphate (a histamine releasing drug). Thirty-seven patients (13%) were considered to be atopic; 262 (87%) had undergone a previous anaesthesia. Three percent (n = 11) of tests were positive for atracurium. The wheal produced by atracurium was in favour of non-specific histamine release. One test was found positive for suxamethonium. Confirmation of this probable latent sensitization was unfortunately not possible. There were no other positive skin tests. Muscle relaxants were subsequently used in 58 patients (80% vecuronium) without any problem. Skin prick testing should be used on a larger scale to detect latent sensitization. However, predictive skin tests with atracurium should be avoided, as wheal reactions with this drug are probably due to non-specific histamine release.     

Anaphylaxis to muscle relaxants. Predictive value of intradermal tests and study of crossed anaphylaxis

37 patients were studied, all of whom presented with anaphylaxis to a muscle relaxant. The diagnosis was made after simultaneous intradermal testing (IDT), human basophil degranulation tests (HBDT) and Prausnitz-Küstner tests (PK) of passive cutaneous anaphylaxis. Three tests were positive in 6 patients, both IDT and PK in 9, and both IDT and HBDT in 8. In 14 patients, the IDT, repeated twice, were positive both times. A search for crossed anaphylaxis to the other muscle relaxants was carried out in all the patients during a second series of tests, a few months to years after the first one. The drugs tested, at dilutions of the pharmaceutical preparation of 10(-3) or more, were: suxamethonium, gallamine, alcuronium, pancuronium, vecuronium, d-tubocurarine. The reliability of IDT in the diagnosis of anaphylaxis is discussed in terms of the small reactive concentration, the producibility of the tests, the one HBDT that did become positive later, and in one case the occurrence of shock by crossed anaphylaxis. Skin reactivity seemed to remain constant with time, so allowing the use of IDT as a diagnostic tool, in cases of old anaphylactoid shocks, occurring during general anaesthetics. The frequency of crossed anaphylaxis was assessed to be about 84%. The sensitivity to one or other drugs varied with each patient. Pancuronium and vecuronium appeared to be the least likely drugs to cause crossed anaphylaxis. The predictive use of these tests is discussed. It is also suggested that muscle relaxants with only one quaternary ammonium group should be used, this chemical characteristic probably reducing the risks of sensitization.     

Reaginic antibodies to drugs used in anesthesia

Twenty-four patients survived life-threatening clinical anaphylaxis due to anesthesia. In each case the diagnosis of anaphylaxis was confirmed and the responsible drug was found by intradermal testing. To determine whether the reactions were anaphylactic or anaphylactoid, serum from each patient was tested for reaginic activity using Prausnitz-Kustner (PK) testing in human subjects and monkeys and passive cutaneous anaphylaxis (PCA) testing at four and 24 hours in monkeys. Positive results of PCA testing at four hours were repeated with serum that had been heated to 56 C for two hours. Drugs used in testing were Althesin, thiopental, succinylcholine, gallamine, d-tubocurarine, and alcuronium. Vehicles and antioxidants were tested separately. Positive tests suggestive of the presence of reaginic antibodies occurred with sera from 15 patients who had had previous exposure to the drug. Nine patients had tests suggestive of IgE antibodies on first exposure, suggesting that cross-sensitivity may be a factor in such reactions to muscle relaxants. Two patients had positive tests for IgG antibodies. This is further evidence of the role of this mechanism in immediate allergy and demonstrates another mechanism by which anaphylaxis can occur without previous sensitization. Four patients had positive tests for IgE antibodies after previous exposure. It was concluded that it is not possible to determine the mechanism of anaphylaxis from a history of previous exposure.     

The value of prick tests in the detection of anaphylaxis caused by muscle relaxants

Intradermal tests (IDR) are a sure diagnostic procedure for confirming the IgE origin of anaphylactoid accidents due to muscle relaxant drugs. Because carrying these out and interpreting them correctly is difficult, epidermal prick-tests (PT) could be used if they proved as sure as IDR. To ascertain this, IDR and PT were carried out in 38 patients who had a shock after being given a muscle relaxant 6 months to 5 years previously; for these tests, increasing concentrations of five muscle relaxants were used (suxamethonium, gallamine, alcuronium, pancuronium and vecuronium). The PT were also carried out with the five same pure and diluted muscle relaxants in a group of 147 volunteer controls. For the 38 patients, PT and IDR were always positive for the same drugs, but at different concentrations, the epiderm seeming less sensitive than the derm (with a ratio of 1 to 100). In the control group, all the tests were negative, even with the pure drug. PT with muscle relaxants were sensitive, specific of anaphylaxis, and permanent. Easy to carry out, easily interpreted, they could be useful as tests for predicting latent sensitisation in risk patients requiring muscle relaxants. But all muscle relaxants must be tested, and not just the one the anaesthetist is likely to use.     

Epidemiology of anesthetic anaphylactoid reactions. Fourth multicenter survey (July 1994-December 1996)]

Since 1984 an epidemiological survey of anaphylactoid reactions occurring during anaesthesia has been obtained in France with regular repeated inquiries by the Perioperative Anaphylactoid Reactions Study Group (Gerap). The members of this group collected during the study period cases of patients having suffered from an anaphylactoid reaction and subsequently tested in their allergoanaesthetic outpatient clinic. The three previous surveys published in the Annales fran?aises d'anesthésie et de réanimation in 1990, 1993 (in English) and 1996 included 1,240, 1,585 and 1,730 patients respectively. The current survey concerned 1,648 patients, tested by the GERAP (38 diagnostic centres) from July 1994 to December 1996. The diagnostic tests for IgE anaphylaxis were cutaneous tests (prick tests and intradermal tests), which minimal dilutions for specific positive skin test were previously determined by comparison with control subjects. The cutaneous tests were performed by all the centres. These tests were associated, in 29 centres, with the detection of specific IgEs against quaternary ammonium compound and inhibition test, and detection of IgEs against propofol, thiopental and latex. Moreover, leukocyte histamine release test was performed in seven centres. The mechanism of the reaction was: anaphylaxis in 692 patients (characteristic clinical symptoms and positive allergological tests), anaphylactoid reactions in 611 patients (characteristic clinical symptoms and negative allergological tests), and other causes in 345 patients (unusual clinical symptoms and negative allergological tests). An immune mechanism was found in 53% of the reactions, with characteristic clinical symptoms occurring during anaesthesia. The 692 cases of anaphylaxis were due to 734 substances (double anaphylaxis in 42 patients): muscle relaxants (61.6%), latex (16.6%), antibiotics (8.3%), hypnotics (5.1%), colloids (3.1%), opioids (2.7%) and others (2.6%) among which aprotinin (four cases) ethylene oxide (five cases) local anaesthetics (two cases). The muscle relaxants implicated in anaphylactic reactions included: vecuronium (n = 130), atracurium (n = 107), suxamethonium (n = 106), pancuronium (n = 41), rocuronium (n = 41), mivacurium (n = 18), and gallamine (n = 9). These results reflected French anaesthetic practice, except for suxamethonium (5% of the French market share of curares). In 70% of the patients who were allergic to one muscle relaxant, cross-sensitivity was found with the other relaxants. The comparison with the three previous surveys confirms that the mechanism of about half of the anaphylatoid reactions occurring during anaesthesia is of immune origin, due to specific IgE antibodies. Muscle relaxants remain the most common cause of anaphylaxis, followed by latex whose incidence seems to decrease, whereas the incidence of anaphylaxis to antibiotics increases. Incidence of reactions to suxamethonium decreased, corresponding however to one quarter of all muscle relaxant anaphylaxis, similar with vecuronium and atracurium. For this survey, more clinical information was obtained in 583 patients, allowing the following conclusions: reactions were always more severe in case of anaphylaxis than nonspecific histamine release; reactions occurred more frequently in females (F/M = 2.5); 17% of patients allergic to a muscle relaxant were never anaesthetized beforehand; a history of reactions during previous anaesthetics was a risk factor for a reaction during subsequent anaesthetics; neither drug allergy nor atopy (except for latex allergy) were a predisposing factor for reactions with anaesthetic agents. Considering that in 1996, 8 million anaesthetics were administered in France, of which 2.5 million included the use of muscle relaxants, the overall incidence for anaphylactic reactions, all agents included, was evaluated as 1 in 13,000 anaesthetics, while the incidence of anaphylaxis to muscle relaxants was 1 in 6,500 anaesthetics.     

Le risque histaminique et anaphylactique de l''atracurium

The histamine releasing potential of atracurium was assessed by testing skin reactivity in ten patients who had previously suffered from a preanaesthetic anaphylactoid accident, but in whom the diagnosis of anaphylaxis had not been confirmed. Atracurium was injected intradermally in increasing concentrations so as to determine the reactivity level, comparing it in the same patient with that due to d-tubocurarine and alcuronium given in the same way. Skin tests with histamine and 48/80 were also carried out at the same time. When a positive reaction was obtained with atracurium, the injection was repeated 4 h after, the patient having taken 50 mg hydroxyzine p.o. The results showed that the skin reactivity level with d-tubocurarine was obtained with 1 in 100 dilution and with atracurium 1 in 10, with nine patients out of ten reacting positively. Alcuronium is the least histamine releasing drug, as it gave rise to a positive reaction in only two patients at a dilution of 1 in 10. Histamine release due to atracurium was greatly reduced by giving hydroxyzine. The allergizing potential was also studied in six other patients who had a tone anaphylaxis to a muscle relaxant and in whom crossed anaphylaxis was being tested for. All the commercial muscle relaxants together with atracurium were tested, even though none of the patients had ever received this last. Anaphylaxis was confirmed when the intradermal reaction was positive with a dilution of 1 in 1,000 and beyond. These tests showed that five patients out of the six had a crossed anaphylaxis, and one of these five was sensitive to all four muscle relaxants (atracurium included).(ABSTRACT TRUNCATED AT 250 WORDS)     

Life-threatening anaphylactoid reactions to propofol (Diprivan)

Fourteen patients who had had a life-threatening reaction within a few minutes after receiving propofol (Diprivan) were investigated for anaphylaxis 4-6 weeks after the incident. Three kinds of immunologic tests were carried out: skin tests (prick tests and intradermal tests with the drugs used and Intralipid, the solvent for propofol), a leukocyte histamine release test, and a radioimmunoassay (RIA) of immunoglobulin E (IgE) against propofol and muscle relaxants, when they had been given with propofol. It had been previously shown that these were always negative in patients anesthetized with propofol without any complications. Thirteen of the 14 patients had at least one positive test supporting hypersensitivity to propofol; 2 patients had three tests positive; 4 had two tests positive; and 7 had one test positive. The skin tests with Intralipid were negative in 4 patients whose tests with propofol were positive. Two patients who had been given muscle relaxants at the same time as the propofol had positive IgE-RIA to both drugs. In one patient, results of all the tests remained negative, and the mechanism involved in the reaction remained unidentified. It is note-worthy that 9 patients of 14 had allergic histories that were known before the anesthetic (atopy; allergy to antibiotics, muscle relaxants, lidocaine, colloids) and that none of the patients had ever received propofol or Intralipid before. It is possible that the IgE that linked abnormally with the propofol had specific binding sites for the phenyl nucleus and the isopropyl groups, which are present in propofol and many other drugs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Substances responsables des chocs anaphylactiques peranesthésiques. Troisième enquête multicentrique française (1992–1994)

Since 1989, the epidemiological survey of anaphylactoid reactions occurring during anaesthesia is obtained in France with repeated inquiries by the Perioperative Anaphylactic Reactions Study Group. The members of this group collect during the study period the cases of patients having suffered from an anaphylactoid reaction and tested in their allergo-anaesthetic outpatient clinic, their characteristics (age, gender), the results of the allergological tests (mechanism, agents responsible for the reactions). The two previous surveys published in the Annales françaises d'anesthésie et de réanimation in 1990 and 1993 included 1,240 and 1,585 patients respectively. The current survey concerned 1,750 patients tested in 27 diagnostic centres, from January 1992 to June 1994.The reactions occurred at all ages, predominantly between 10 and 50 years, the sex-ratio (F/M) was 2.4. Allergological tests carried out to diagnose an immune mechanism for the shock were cutaneous tests in all centres (prick-tests in 21 centres, intradermal tests in 27 centres) using the same dilutions for the tested agents and the same threshold for positivity. Specific IgE antibodies against muscle relaxants, thiopentone and propofol, were measured by radio immunoassays in 20 centres. The leucocyte histamine release test was used in 10 centres. The immune origin of the shock — IgE dependent anaphylaxis — was diagnosed in 1,000 patients (57.8%) and due to 1,030 agents: muscle relaxants (59.2%), latex (19%), hypnotics (5.9%), benzodiazepines (2.1%), opioids (3.5%), plasma substitutes (5.0%), antibiotics (3.1%) and other drugs given during anaesthesia such as aprotinine and protamine (2.2%). Suxamethonium was responsible for 39.3% of muscle relaxant anaphylaxis, vecuronium for 36%, atracurium for 14.5%, pancuronium for 4.8%, gallamine for 3.1% and alcuronium for 2.3%. The latter has been withdrawn from the French market in 1993. These differences in the incidence of reactions are correlated with the clinical use of muscle relaxants in France for vecuronium and atracurium, however not for suxamethonium, responsible for 39% of the reactions but representing only 5% of the muscle relaxants sold in France.The comparison with the two previous surveys confirms that the mechanism of more than half of the anaphylactoid reactions occurring during anaesthesia is of immune origin, due to specific IgE antibodies. It is therefore essential to systematically carry out an allergologic assessment several weeks after the reaction, in order to discard for the subsequent anaestheticts the agent (s) responsible for anaphylaxis. If the muscle relaxants remain the first drugs involved in shock occurring at induction, there is a significant increase in latex shock, as demonstrated by the three epidemiological surveys (0.5%, 12.5 and now 19%). The incidence of other anaesthetic agents, antibiotics and plasma substitutes remains unchanged.     

Substances anesthésiques responsables de chocs anaphylactiques. Enquête multicentrique française

Combined allergological and anaesthetic consultations have been started in the last few years in eight French Teaching Hospitals so as to explore peranaesthetic anaphylactoid shocks. A survey was carried out in these centers in order to collect patients investigated with the same protocol, for the assessment of the incidence of anaphylaxis in France, as well as the involved drugs. Investigations were always carried out at least 6 to 8 weeks after the accident. The tests used to diagnose IgE-dependent anaphylaxis were skin tests (prick and intradermal tests, carried out in all eight centers), the radioimmunological assay of specific anti-quaternary ammonium IgE, together with an inhibition test with thiopentone and propofol (six centers), leukocyte histamine release (five centers) and human basophil degranulation tests (three centers) for those drugs for which no specific antibody assay exists. The collected data involved 1 240 patients, investigated within the last four years. Anaphylaxis was diagnosed in 821 patients (66.2 %). Muscle relaxants were responsible in 668 cases (80 % of cases of anaphylaxis). Suxamethonium was the main cause (54.3 % of shocks due to muscle relaxants), followed by vecuronium (15.3 %). General anaesthetics (hypnotics and benzodiazepines) were responsible for 9.2 % of all cases of anaphylaxis opioids for 2.6 %. There were only three cases of shock due to local anaesthetic agents. Latex and ethylene oxide are becoming increasingly involved. It would therefore seem mandatory to carry out after any anaphylactoid accident an assessment with sensitive and specific tests for anaphylaxis. Diagnosing anaphylaxis means that the involved drug should be used never again in that patient. Because muscle relaxants are by far the most involved drugs, anaesthetists should use them only when really required.     

Anesthetics responsible for anaphylactic shock. A French multicenter study

Combined allergological and anaesthetic consultations have been started in the last few years in eight French Teaching Hospitals so as to explore peranaesthetic anaphylactoid shocks. A survey was carried out in these centers in order to collect patients investigated with the same protocol, for the assessment of the incidence of anaphylaxis in France, as well as the involved drugs. Investigations were always carried out at least 6 to 8 weeks after the accident. The tests used to diagnose IgE-dependent anaphylaxis were skin tests (prick and intradermal tests, carried out in all eight centers), the radioimmunological assay of specific anti-quaternary ammonium IgE, together with an inhibition test with thiopentone and propofol (six centers), leukocyte histamine release (five centers) and human basophil degranulation tests (three centers) for those drugs for which no specific antibody assay exists. The collected data involved 1,240 patients, investigated within the last four years. Anaphylaxis was diagnosed in 821 patients (66.2%). Muscle relaxants were responsible in 668 cases (80% of cases of anaphylaxis). Suxamethonium was the main cause (54.3% of shocks due to muscle relaxants), followed by vecuronium (15.3%). General anaesthetics (hypnotics and benzodiazepines) were responsible for 9.2% of all cases of anaphylaxis opioids for 2.6%. There were only three cases of shock due to local anaesthetic agents. Latex and ethylene oxide are becoming increasingly involved. It would therefore seem mandatory to carry out after any anaphylactoid accident an assessment with sensitive and specific tests for anaphylaxis. Diagnosing anaphylaxis means that the involved drug should be used never again in that patient. Because muscle relaxants are by far the most involved drugs, anaesthetists should use them only when really required.     

Drugs and other agents involved in anaphylactic shock occurring during anaesthesia. A French multicenter epidemiological inquiry

An epidemiological inquiry was carried out in departments of anaesthesia and immunology in French University and General Hospitals, as well as among those who were already known to have an allergo-anaesthesia outpatient clinic. This inquiry aimed to find out how many patients had undergone diagnostic investigations after as well as an anaphylactoid reaction during an anaesthetic in 1990 and 1991, as well as the demographic data, the kind of assessment, the accident mechanism and the drugs involved. Twenty-one French centres replied to the questionnaire and a series of 1,585 patients tested over a two-year period was thus collected. There were three female patients to one male. The reactions occurred mostly in the adult (80 %), but 9 % were observed in children. Allergological tests for IgE-dependent anaphylaxis were the skin tests (21 centres), combined with radioimmunological assays of specific serum antibodies to muscle relaxants (10 centres), propofol (9 centres), latex (5 centres), leukocyte histamine release (9 centres) and human basophil degranulation test (4 centres). The criteria for a positive result were the same for all centres. Among these 1,585 patients, 813 were recognized as having had a reaction of immunological origin (52 %). The substances involved were identified in these 813 patients as being muscle relaxants (70 %), latex (12.6 %), hypnotics (3.6 %), benzodiazepines (2.0 %), opioids (1.7 %), colloids (4.7 %), and antibiotics (2.6 %). Suxamethonium was responsible for 43 % of the IgE-dependent reactions involving a muscle relaxant, vecuronium for 37 %, pancuronium for 13 %, alcuronium for 7.6 %, atracurium for 6.8 % and gallamine for 5.6 %. These results were compared with those obtained with the 1989 inquiry, including 1,240 patients from eight centres [4]. An attempt is made to interpret the results of these two inquiries with the muscle relaxants, by comparing the respective number of reactions due to each drug along with the figures of the French market shares for each drug between 1986 and 1991. By using the current allergological assessment, the substance involved was formally identified in 52 % of these reactions. In the remaining 48 %, the investigations gave negative results, and there remains doubt concerning the drug or drug combination which elicited the non specific release of histamine.     

The use of muscle relaxants for routine induction of anesthesia in Germany

The aim of this study was to evaluate the use of muscle relaxants during induction of anesthesia in patients without risk of aspiration of stomach contents.Of the 2,996 questionnaires sent out, 2,054 (68.6%) could be analysed and the results show that succinylcholine is used regularly in 13.6% of anesthesia departments.The next most commonly used muscle relaxants are atracurium, vecuronium and mivacurium, followed by cis-atracrium, rocuronium and pancuronium. Alcuronium is the least frequently used muscle relaxant. During induction of an elective anesthesia procedure, a priming technique is used by 19% of anesthesiologists, 22% utilize precurarization, and a timing technique is performed in 7.1%.The use of muscle relaxants for on-going relaxation follows the same pattern as for induction of neuromuscular blockade and succinylcholine is used in 1.4% if further relaxation is needed.The desire for specific qualities of muscle relaxants is correlated with higher use of the specific substance: short onset time for rocuronium, good controllability with mivacurium, no side-effects with cisatracurium and economical aspects with alcuronium. Of the participants 76.6% voiced the desire for a non-depolarizing replacement for succinylcholine.Private practices use mivacurium more often than hospitals, level one hospitals use rocuronium and cisatracurium more often.This survey could not show a definite standard of use in terms of muscle relaxants for an elective case.Precurarization, priming and timing are used frequently in patients not at risk of aspiration. This should be reduced by on-going teaching.     

Risk factors in anaphylactoid reactions to muscle relaxants. A retrospective study of 103 cases of shock

A homogeneous series of 103 cases of shock due to muscle relaxants has been used to identify the risk factors in anaphylactoid shocks due to either true anaphylaxis or to non-specific histamine release. Clinical atopy (asthma) and sub-clinical atopy as shown up by skin tests with mites and pollens, as well as a history of IgE-dependent drug allergy, were present with a significantly greater frequency in the history of patients presenting with anaphylaxis. Abnormal histamine release and reactivity to histamine, as assessed by skin tests with 48/80 and histamine, were often found in those patients who presented with non-specific histamine release induced by muscle relaxants. Whatever the mechanism for the shock, the frequency of spasmophilia was increased. A history of non-immunological intolerance to acetyl salicylic acid and other non-steroid anti-inflammatory drugs was more often found than in the reference drugs was more often found than in the reference population. However, 25% of the patients studied did not have any of these risk factors. Several possibilities of preventing anaphylactoid reactions are given, if one or more of these risk factors are found in the history: a better choice of anaesthetic drugs, in the light of previous anaesthetic protocols, the relief of anxiety by appropriate premedication, antihistamine premedication and the prevention of bronchospasm.     

Train-of-four fade of non depolarizing muscle relaxants: an insight into the mechanism of precurarization

This study was carried out to assess the prejunctional effect of non depolarizing muscle relaxants during the onset of neuromuscular blockade using the train-of-four ratio (TR). The prejunctional effect was compared with previous results concerning the ability of the relaxants to prevent suxamethonium-induced fasciculations. Fifty-three adult patients were relaxed with small incremental doses of either alcuronium (0.03 mg.kg-1), atracurium (0.04 mg.kg-1), pancuronium (0.01 mg.kg-1), d-tubocurarine (0.05 mg.kg-1) or vecuronium (0.01 mg.kg-1) during anaesthesia with thiopentone, fentanyl and nitrous oxide in oxygen. The muscle relaxant was given after recovery from an initial suxamethonium blockade needed for tracheal intubation. The evoked integrated EMG response to supramaximal train-of-four (2 Hz) stimulation was recorded every 20 s. TR % was calculated at different first twitch (T1) levels during the onset of neuromuscular blockade. Significant changes occurred at the 100% and 90% T1 levels, alcuronium having the lowest mean TR values. Atracurium, pancuronium and vecuronium gave similar TR values. Results with d-tubocurarine placed it between alcuronium and the others. These train-of-four ratio results were compared with the ability of non depolarizing muscle relaxants to prevent fasciculations. In conclusion, the stronger the train-of-four fade, the greater was the ability of the relaxant to prevent suxamethonium-induced fasciculations. This supports the theory that the blockade of prejunctional cholinergic receptors is the mechanism of action of precurarization.     

The interaction of neuromuscular relaxants with rabbit lung muscarinic receptors

The interaction of muscle relaxants with airway muscarinic receptors of rabbit lung was investigated in vitro by the [3H]QNB binding technique. Pancuronium, vecuronium, alcuronium and succinyl choline chloride (SCC) inhibited the binding of [3H]QNB to rabbit lung muscarinic receptors in a dose-dependent manner. The values of IC50 (the concentration giving 50% inhibition) of pancuronium, vecuronium, alcuronium and SCC were 1.54 x 10(-5), 2.52 x 10(-5), 8.40 x 10(-5), and 4.00 x 10(-3) mol/l respectively. As the values of Kd increased with minimal change in the value of Bmax, while not influencing the number of receptors, these muscle relaxants had an inhibitory action on the affinity of muscarinic receptors to [3H]QNB in the order: pancuronium greater than or equal to vecuronium greater than alcuronium greater than SCC. Applying IC50 values to human conditions, clinical doses of these muscarinic relaxants are unlikely to exhibit any significant vagolytic action in lung tissue.     

Anaphylactic and Anaphylactoid Reactions Occurring during Anesthesia in France in 1999-2000

Background: Anaphylactic and anaphylactoid reactions occurring during anesthesia remain a major cause of concern for anesthesiologists. The authors report the results of a 2-yr survey of such reactions observed during anesthesia in France.

Methods: Between January 1, 1999, and December 31, 2000, 789 patients who experienced immune-mediated (anaphylaxis) or nonimmune-mediated (anaphylactoid) reactions were referred to one of the 40 participating centers. Anaphylaxis was diagnosed on the basis of clinical history, skin tests, and/or specific immunoglobulin E assay.

Results: Anaphylactic and anaphylactoid reactions were diagnosed in 518 cases (66%) and 271 cases (34%), respectively. The most common causes of anaphylaxis were neuromuscular blocking agents (NMBAs) (n = 306, 58.2%), latex (n = 88, 16.7%), and antibiotics (n = 79, 15.1%). Rocuronium (n = 132, 43.1%) and succinylcholine (n = 69, 22.6%) were the most frequently incriminated NMBAs. Cross-reactivity between NMBAs was observed in 75.1% of cases of anaphylaxis to an NMBA. No difference was observed between anaphylactoid and anaphylactic reactions when the incidences of atopy, asthma, or drug intolerance were compared. However, atopy, asthma, and food allergy were significantly more frequent in the case of latex allergy when compared with NMBA allergy. Clinical manifestations were more severe in anaphylaxis. The positive predictive value of tryptase for the diagnosis of anaphylaxis was 92.6%; the negative predictive value was 54.3%. The diagnostic value of specific NMBA immunoglobulin E assays was confirmed.     

Neuromuskuläre Blockade nach Atracurium und Alcuronium unter dem Einfluß von Propofol und Thiopental

Does propofol or thiopentone enhance the effect of nondepolarizing muscle relaxants? We evaluated the effects of propofol and thiopentone on the pharmacodynamics of atracurium and alcuronium in 43 surgical patients (ASA I and II) under general anaesthesia. Methods. The patients were randomized into five groups, A–E. Anaesthesia was induced in all patients with fentanyl 4?μg/kg i.v. Patients in groups A and C patients received thiopentone 7?mg/kg i.v., and relaxation was achieved with alcuronium 0.25?mg/kg (group A) and atracurium 0.5?mg/kg (group C). Electromyography (train of four, TOF) was used to determine the time of onset of relaxation (AZ) and the maximum degree of blockade (T%). The recovery times to 25%, 50% and 75% of baseline muscle strength were recorded. Additionally, the TOF ratio T4:T1 was calculated, indicating the probable end of relaxation at a ratio of 0.7. At the beginning of the recovery phase (T1=15%) propofol 1% 3?mg/kg was given, and the effect on the TOF was measured. Patients in groups B and D patients received total intravenous anaesthesia (TIVA) with propofol 1% 6–12?mg/kg per hour continuously after induction with 3?mg/kg. The action profile of alcuronium 0.25?mg/kg (group B) and atracurium 0.5?mg/kg (group D) were recorded. Group E patients received thiopentone (10?mg/kg per hour) under the use of atracurium 0.5?mg/kg. Ventilation was performed with 30%/70% oxygen and N₂O. The results were analyzed for significance using the Mann-Whitney U-test (P=0.019). Results. A slight difference in AZ was noted for alcuronium under the use of TIVA between propofol and thiopentone: 13?min and 5?min, respectively. Otherwise, the pharmacodynamics (T% and recovery of neuromuscular function) of the two relaxants exhibited no major differences related to thiopentone, propofol or their combination. The TOF was not influenced under additional propofol application. Noteworthy were the wide distribution of the time course of action (up to 3?h) and the magnitude of T% depression under alcuronium. Conclusion. Propofol and thiopentone have no potentiating influence on the time course of action and the magnitude of relaxation with alcuronium and atracurium. Pharmacodynamics of nondepolarizing muscle relaxants do not seem to be influenced by these two hypnotics.     

Studies on Muscle Relaxants During Haemodialysis

Signs of neuromuscular block were evident more than 20 hours after the administration of alcuronium to an anuric patient. Complete recovery occurred during haemodialysis. We therefore decided to study the dialysance of three radioactive non-depolarising relaxants during haemodialysis of four patients with chronic renal failure. Although dimethyl tubocurarine and alcuronium were equal as regards dialysance, the concentration of the former, in plasma, falls faster than does alcuronium. It is believed that a larger volume of distribution occurs with dimethyl tubocurarine. In spite of the fact that the dialysance of muscle relaxants is small, haemodialysis might lower the concentration of these substances in the plasma to a level below the critical point which produces paralysis.     

Rocuronium and cisatracurium-positive skin tests in non-allergic volunteers: determination of drug concentration thresholds using a dilution titration technique

BACKGROUND: Muscle relaxants are believed to be responsible for 2/3 of the cases of anaphylactic reactions during anesthesia. This assumption is based mainly on positive skin tests obtained in individuals that have experienced anesthesia-related anaphylaxis. A positive skin test is supposed to be associated with mast cell degranulation of vasoactive amines. In the present study we tested the frequency of positive skin tests with two commonly used muscle relaxants, rocuronium and cisatracurium, in a selected group of volunteers with low potential for allergic reactions. METHODS: Thirty healthy volunteers without known allergy or previous exposure to muscle relaxants were studied. Low potential for allergic reactions was determined prior to inclusion in the study, using various allergy tests. Each individual was tested with intradermal and skin prick tests, and molar drug concentration thresholds for positive skin reactions were determined using a dilution titration technique. The presence or absence of mast cell degranulation was tested by electron microscopic investigation of skin biopsies obtained from positive and negative skin reactions. RESULTS: None of the volunteers had a positive skin prick test. More than 90% of the volunteers had a positive intradermal test with both rocuronium and cisatracurium. The highest molar drug concentration that was not associated with a positive intradermal test was 10(-6) M (rocuronium) and 10(-7) M (cisatracurium), equivalent to vial dilution 1 : 1000 for both drugs. In none of the volunteers was mast cell degranulation detected. CONCLUSION: Non-mast-cell-mediated positive intradermal skin reactions are frequently occurring with rocuronium and cisatracurium, even at vial dilution 1 : 1000. A clinically applicable test technique is needed that is able to separate positive skin tests associated with mast cell degranulation from non-mast-cell-mediated reactions.