Daniel Vervlcmt, Eva lUkmkuw&a, and Jacques Charpin Marseille, France
The mechanisms of anaphylactic reactions to muscle relaxants under general anesthesia are not completely understood. Extending an earlier study, we report 41 cases of anaphylactic shock investigated by intradermal skin tests with muscle relaxants (suxamethonium, pancuronium, gallamine, nortoxiferine), in vitro leukocyte histamine release, and Prausnitz-Kiistner tests. lntradermal tests were signijicantly positive at concentrations ranging ,@om 10 to IO” times less than those in controls. Reproducibility tested,for suxamethonium at a l-year interval in five patients was good. Histamine release induced by muscle relaxants in Tris-albumin-Ca+“-Mgi’ buffer showed positive results in 8125 instances and was inhibited by antigen excess in seven cases. Addition ofSO90 deuterium oxide (LX&t) caused significant increase qf histamine release in positive cases and induced release in all five negative cases studied. Muscle relaxant-induced histamine release was inhibited by in vitro anti-1gE leukocyte desensitiz,ation. The mean maximal histamine releuse dropped,from 58.2% 2 9.7 to 5.890 ? 2 (p < 0.01). Similarly, leukocyte desensitization also inhibited histamine release induced by anti-IgE but not by ,formyl-L-methionyl+leucyl-r-phenylalanine or poly+arginine. Prausnitz-Kiistner tests were positive in ,five out qf’ 21 cases studied and became negative after heat inactivation. These results confirm the usefulness qf intradermal skin tests in diagnosis of patients’ reaction to muscle relaxants and suggest an IgE-mediated rather than an idiosyncratic mechanism. (J ALLERGY CUN IMMUNOL 71:552, 1983. )
Anaphylactic reactions are an important cause of morbidity and mortality in anesthesia. The incidence in Australia ranged from 1: 5000 to 1: 25,000 anesthesias as reported by Fisher and More,’ with a mortality of 3.4%, similar to the British series of Clarke et al .2 Since our first series of 11 cases of anaphylactic reactions to muscle relaxants under general anesthesia reported in 1979,3 other papers have been published on the epidemiology, clinical features, diagnosis, and possible mechanisms of these reactions.4-8 Extending our earlier study, we present here 41 cases of anaphylactic shock after intravenous admin-
From the Department of Chest Diseases, k&p&al Sainte-Marguerite; INSEiW U. 174; and the Department of Anesthesia and Intensive Caw, CHU Timone, Marseille, France. F’resentedin part at the Annual Meeting of the American Academy of Allergy, Montreal, Que., Canada, March 1982. Received for publication July 21, 1982. Accepted for publication Jan. 6, 1983. Reprints requests: Daniel Vervloet, Hkpital Saint+Marguerite, BP 29, I3277 Marseille Cedex 9, France. vol. 71, No. 6, pp, 552-559
i&ration of muscle relaxants, and we re value of skin tests in the Furthermore, the preaen achieve a more reliable distinction nological and idiosyncratic pharmac nisms for such anephylactic reactions. effect of Da0 on the in vitro HR indueed by &s&e relaxants and also the effect of in vitro de by anti-&$ on subsequent specific The effect of Da0 and desensit relaxant-induced HR was compared w&h the erf&cts of these two procedures on HR induced by F-B&etLeu-Phe and Poly-L&g, which are frri)rkievcsld to act through separate, non-IgE-mediated bairns .g arty-one patienti developed an az+&ac& reactia a few minutes after the beginning of general it&t. irnis group consisted of 37 wumen and four men’, [email protected]
‘2241ad 48 years old. Five of them had had no previous ane 12~h& hitd one, 14 had had two, and 10 had had tW or km k&e the accident. These consisted of nrtic&a ($%& i.&&ik-
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Abbreviations used F-Met-Leu-Phe: N-formyl-t-methionyl-t,-leucylphenylalanine Poly-L-Arg: Poly-L-arginine D,O: Deuterium oxide HR: Leukocyte histamine release LD: Leukocyte desensitization EDTA: Ethylenediamine tetraacetate, disodium salt PK: Prausnitz-Kiistner
spasm (13), and cardiovascular collapse (38). Eight patients were atopic (allergic rhinitis, extrinsic asthma, atopic dermatitis); seven had urticaria, contact dermatitis, food allergy, or allergy to drugs; 26 had no history of atopy at all. The main characteristics of these patients are summarized below: No. of patients Female Male No. of previous anesthesias None One Two Three or more Atow Clear Doubtful None Type of accident Collapse Urticaria Bronchospasm
41 37 4 5 12 14 10 8 26 38 20 13
Total IgE was measured in 20 out of 41 patients. It was above 300 W/ml in five and below this limit in 15 cases. Thirty volunteers were used as controls for clinical and various biotogical investigations.
Drugs. The following muscle relaxants (Fig. 1) were used for skin tests: suxamethonium iodide (Kabi Vitmm S .A., Paris, France), pancuronium (Organicon Tecnica, St.-Denis, France), gallamine (Specia, Paris, France) and diallylnortoxiferine (Vi&urn, Vichy-sur-Seine, France). The drugs do not contain any preservative. At the higher concentration of suxamethonium used for HR, the osmolarity was the same as the buffer (298 mOsm). Histamine (Pharmacie Centrale des H&pitaux, Marseille, France) was used as a positive control. To study possible cross-reactivity between quaternary ammonium compounds, a cetrimonium solution at 200 mg/ml was used for scratch testing (I.C.1. Pharma, Enghien-les-Bains , France).
to muscle relaxants
BQers. In HR and LD experiments, the following buffers were used: 1. Tris A. Twenty-five millimolar Tris (Prolabo, Paris, France) containing 120 mM NaCl, 5 mM KCL, 0.03% human serum albumin (Sigma Chemical Co., St. Louis, MO.) and adjusted to pH 7.4. 2. Tris-ACM. Tris A containing 1 mM Ca+’ and 1 mM Mg++. 3. D,O-Tris-ACM. Tris-ACM buffer with 50% D,O (CEA, CEN, Saclay, France). Histamine liberators and antigens. Anti-human IgE serum (sheep antibody to human IgE; Biomerieux, Paris, France); F-Met-Leu-Phe and Poly-t-Arg hydrochloride (Sigma); suxamethonium iodide (Kabi Vitrum). Additional reagents. EDTA in Tris A was used at a final concentration of 4 mM to prevent histamine release during desensitization experiments; dextran T 500 (Pharmacia Fine Chemicals, Uppsala, Sweden); a-D-glUCOSC. (Prolabo); heparin (Fournier F&es, Clichy, France).
Skin tests Tests were performed on the volar surface of the forearm by intradermal injection of 0.02 ml of serial lo-fold dilutions of muscle relaxants and histamine. End point titration was calculated. Results were mad at 15 min, and a wheal and flare greater than 9 and 20 mm, respectively, were recorded as a positive reaction. Positive cutaneous reactions to muscle relaxants were considered as specific if they were positive for concentrations of drugs that gave negative results for all control subjects tested. Controls (20 women and 10 men) were between 18 and 50 years old. Ten were atopic (positive skin tests to house dust, mites, grass pollen). Twelve had previously received muscle relaxants without any accident.
PK tests A 0.1 ml sample of patients’ serum at a 1: 5 dilution was injected intradermally into normal volunteers. These subjects had been demonstrated to respond positively in PK tests, since they exhibited marked skin reaction when they were intradermally injected with grass pollen extract at a site challenged with serum containing a high titer of grass pollen maginic antibodies. The site was challenged 4 and 72 hr later with 0.02 ml of suxamethonium iodide solution. Heat-inactivated patient serum (56” C for 3 hr) was used as control. This technique was used for detection of short-term sensitizing and IgE-type antibodies to suxamethonium.
HR was measured with a slight modification (human serum was not used in the reaction medium) of the technique described by May et al.‘” Briefly, washed leukocytes were isolated from heparinized venous blood by dextran sedimentation. Cells were washed twice in Tris A. The release tests were performed in Tris-ACM or in D,O-TrisACM; 0.1 ml of different concentrations of suxamethonium, anti-IgE, F-Met-Leu-Phe, or Poly-L-Arg was added to tubes containing 0.9 ml of cell suspension. HR proceeded
CM -- cn,
3 a \I K.L.ii N L
I ck - cup
I’ cna z cw - cwz-
F&. 1. Structural
TAB#& I. Skin tests to determine minimal in 40 out of 41 patients with anaphylactic
Suxamethonium (N = 32) Pancuronium (N = 3) Gallamine (N = 3) Gallamine + suxamethonium (N = 1) (N = 1) Diallylnottoxiferine Controls (N = 30)
of muscle relaxants
concentrations shock under
used in the study.
for positive results wneral amsthesia
32 3 I 1
4 3 I 0
15 2 3 0
*Minimal concentrations for positive skin tests in patients. No controls were positive at these conceatratians. [email protected]
N. Reproducibility* of skin tests to suxarnethonium in six patients who had anaphyiactic reaction with suxamethonium
Lus Lat Maz Lut . Pel . Arg . .
100 1 0.01 0.01 0.1 10
10 100 I 0.i 0.1 loo
*Tests were done at 1 yr interval. tMinimd concentration for positive skin tests in controls was * NKIOpg/ml.
for 45 min at 37”, with a mixing every l.9 min, & was stopped by transferring the tubes into an ice ~th,..cleils ware subsequently removed by ckr& @?I~,~~~~~ was assayed for histamine with fluorimetrie ~~~ described by Shore et al.” Tb r&&al c&l&+ &a&&e content of the cells was-w tier exl$c;act&n by b&ling during 6 min. HR was [email protected]
&cl for w sX$t%+e from con&o1 cells, and the re&s were expr&&d as a percentage of total histamine.
Washed leukocytes from pa%&tts tained as deaad above w& SUB buffer flris A plus 4 m.M EmA) iapPese a final concentration of 1 j&8&. C&s [email protected]
ahence of ant&E as coal&&. ahe mr&ti for 30 min at 37” C, Leukocytes were then
Adverse reactions to muscle relaxants
VOLUME 71 NUMBER 6
III. HR induced
HR (% of total cellular Suxamethonium (pglml)
cases out of 25) histamine)*
lo1 10” 102 10 1 10-l
0 0 0 14 4 ND
0 5 55 42 2 ND
0 0 0 16 6 ND
0 0 16 39 38 ND
ND 28 37 27 0 0
0 7 24 42 33 5.4
ND 27 27 13 0 ND
ND 7 12 9 2 0
Pt. = patient; ND = not done. *HR was
ture decanted, and cells washed twice in Tris A and resuspended in an appropriate volume of D,O-Tris-ACM for mchallenge with different concentrations of suxamethonium, anti-IgE, F-Met-Leu-Phe, or Poly-L-Arg as required by the experimental design. HR was then measured as described above.
RESULTS Skin tests Skin tests with four different muscle relaxants usually used during induction of general anesthesia were performed on 40 out of the 41 patients who developed anaphylactic shock under anesthesia. Tests were done between 2 and 6 mo after the accident. The specific muscle relaxant used during anesthesia in the patients and the results of skin tests are presented in Table I. Suxamethonium was used as muscle relaxant in 32 patients, and the skin tests were positive for all of them at suxamethonium concentrations below or equal to 100 pglml; four patients had positive skin test results with 0.01 pglml suxamethonium, seven with 0.1, five with 1, 14 with 10, and two with 100 pg/ml. In all the control group, concentrations equal to or higher than lo3 pg/ml were necessary to yield a positive reaction. Thus patients were 10 to 10,000 times more sensitive to suxamethonium than controls. In this suxamethonium-sensitive group of patients, 15 had also positive skin tests to gallamine, four to pancuronium, and three to diallylnortoxiferine; in patients who developed an anaphylactic reaction to other muscle relaxants, skin tests were also positive for the specific muscle relaxant used during anesthesia at concentrations lower than those required for the control group. Then, we noticed that some of these patients had positive results to very low concentrations of muscle relaxants not used during anesthesia, suggesting a possible cross-reactivity between these drugs. Skin reactions to histamine were identical in patients and controls. The results of skin tests to suxamethonium could be
controlled 12 mo later for six patients. All subjects who were positive the first time were still positive 1 yr later (Table II). The results of scratch tests with a quatemary ammonium compound (cetrimonium) were positive seven times and negative three times in 10 patients who were positive to suxamethonium. Ten controls treated with the same drug concentrations were negative (data not shown). PK tests were done for 22 patients. Seventeen were negative at 4 and 72 hr, four out of five positive results at 72 hr repeated after heating sera 3 hr at 56” were then negative. No serum was positive at 4 hr. The drug controls and heated serum were run in parallel at the same time. No difference was found between the donors whose serum was positive or negative. Leukocyte
Induced by swramethonium in Tris-ACM bufer.
HR was measured with increasing concentrations of suxamethonium (0.1 to lo4 pg/ml) in 25 patients. These patients had positive skin tests to this drug. HR was significantly positive (HR > 10% of total cellular histamine) in eight patients (Table RI). The maximal HR ranged from 14% to 55% of total cellular histamine and was usually obtained with final concentrations of suxamethonium in the range of 10 to 100 pg/ml; these concentrations of suxamethonium still gave specific positive skin tests in patients studied. Tn seven patients, we observed inhibition of HR by supraoptimal doses of this drug. No difference was noticed in skin tests of patients with positive HR as compared with the HR-negative patients. Induced bj suxamethonium in D,O-Tris-ACM buSfer. In eight patients (five were previously negative
in Tris-ACM buffer) HR was also measured in D,O-Tris-ACM buffer. We found that D20 added to buffer not only significantly increased maximal HR in three previously positive patients but also induced
FIG. 2. HR in eight patients with increasing concentrations of suxamethonium in f&ACM and D&I-Tris-ACM buffer. HR was ~10% in controls.
significant release of histamine in the five patients previously negative for HR in Tris-ACM buffer (Fig. 2). Thus HR measured in D$O-Tris-ACM buffer was positive in all eight cases studied. HR was negative (I-IR
FIG. 3. Effect of ~nskizatian of tswkocylteo with anti-l&$ on subsequent HR indqmd by anti-lgE, sux~meth~i~m, F-Met-Leu-Pha, andPoEy+-Arg in paral+& exgxhwwnbin five patients sarisWe to auxanretttbniufn. t# W$sCatrW! out in D20-Tris-ACM buffer. -, Control-c&s; ----, desensitized cetis.
lO+M and 5 x lo-‘M) in [email protected]
optimal carrcentraltirms of s individual @yenta [email protected]
chosen. from I& str&es described above. The results of this ~~~~~ procedure are presented in Fig. 3. Anti-IgE-induced WR was almost c hibited after leukocyte desensit with control cells (mean 62.8% + 11.8 [email protected]
% -e 0.6, p It3.01). Similarly, s~x~~~rn-ind~ HR lulas significantly inhibited after ~~~j~~~,of~~~~~s in all five patients stud&-d (mean [email protected]
HI&decreased from 58.
maximal NR in desensitized cells 43.6% ? control ce&3 43 .O% If 1l.g).
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DISCUSSION The incidence of severe adverse reactions to intravenous drugs used in anesthesia appears to be increasing.i2 Although they have been estimated at around 1 out of 5000 general anesthesias,14 their severity requires attention. Among all drugs used, muscle relaxants seem to play a predominant role. All our 41 patients had a history of severe anaphylactic reaction to muscle relaxants. The predominance of women in our report and in most of publications concerning adverse reactions to muscle relaxantsi l4 has not yet been explained. High frequency of allergic asthma in such patients was reported in two epidemiological studies carried out by Laforest et a1.14 in Australia and by Clarke et a1.i3 in Great Britain. In our group, only eight out of 41 patients had a clear history of allergy. As for total IgE level, our results in 20 patients did not support the view of an atopic diathesis in the majority of these patients. The majority of our patients (36 out of 41) had had previous general anesthesia, which is considered by some authorsI as a risk factor in patients undergoing general anesthesia. However othersI do not support this suggestion. We performed skin testing with cetrimonium, which is chemically close to suxamethonium, and found that seven patients exhibited positive skin tests to cetrimonium out of the 10 patients allergic to suxamethonium who were explored. This should be studied on a larger scale but suggests that some subjects might become sensitive to suxamethonium through previous contacts with other substances with a quatemary, ammonium determinant. In the same line, Fisher and More’ underline the high incidence of sensitivity to cosmetics in this group of patients. Our finding confirms our previous opinion3 that skin testing is a reliable method of determining the drug responsible for an acute anaphylactic-like reaction. As previously shown, the patients were extremely sensitive to these drugs, since positive skin tests were obtained with concentration of suxamethonium as small as 0.01 pg/ml. Doses 10 to 105 times higher were necessary to obtain positive skin tests in normal volunteers. The diagnostic value of skin tests with muscle relaxants was emphasized by Fisher.4 He obtained positive skin tests to these drugs in all 21 patients, whose clinical history suggested that muscle relaxants might be responsible for anaphylactic reaction. Fishels also found two patients clinically sensitive to suxamethonium who presented also cutaneous sensitivity to gallamine; we noticed this phenomenon in 15 of our 32 patients sensitive to suxamethonium who received it during general anesthesia. The clini-
cal significance of such cross-sensitivity between suxamethonium and gallamine and other muscle relaxants found in our study and reported by other authors” is not known. Skin testing with muscle relaxants may also be useful for a better understanding of the mechanisms of these adverse drug reactions. The clinical syndrome of anaphylaxis can be produced by IgE- or IgGmediated reaction, by direct histamine release,16 or by complement activation. l7 Positive intradermal tests suggest, as well, an IgE-mediated anaphylaxis as a direct HR or an involvement of IgG antibody.‘ss is Muscle relaxants are known for their ability to release histamine locally in all subjects when given intradermally at sufficient concentrations.20 In the present study, patients reacted to skin tests with such doses of these drugs that only a specific sensitivity of their skin mast cells could account for direct HR. On the other hand, the fact that that positive PK tests became negative after heat inactivation favors, an IgE-mediated anaphylaxis. Recently, Fishe? found, in 14 patients sensitive to muscle relaxants, 10 positive PK tests (performed on human volunteers or in Mucaca); nine of them had had reactions to muscle relaxants when first exposed. Since a latent period of sensitization is required for IgE-mediated anaphylaxis, the author suggested that these patients may have already been sensitized when they received this drug. This author also reported positive PK tests in patients sensitive to gallamine and alcuronium. However, even passivetransfer test does not mean in and by itself presence of IgE antibodies. Suxamethonium-induced HR in Tris-ACM buffer studied in 24 cases was positive in eight. The mechanism of that release is not known. Histamine bound to granules within basophils and mast cells may be secreted when certain specific membrane proteins are crosslinked (e.g., by antigen or anti-IgE) or in response to C3a, C5a, polyamines, the calcium ionophore A23 187, F-Met peptides, basic peptides, and varied chemical substances.ss*lez3 The mechanism by which suxamethonium may induce HR in vitro and its significance in vivo are not known. It has been suggested that immediate-type allergy33 *l, 24-27 may be responsible for adverse reactions to muscle relaxants. Then, suxamethonium-induced HR would be dependent on an IgE-mediated mechanism. In our experiments, we observed HR inhibition with excess of muscle relaxants (Table III). Although inhibition of HR by antigen excess is considered the hallmark of an IgE-mediated release of mediators, Poly-L-Arg- induced HR may also be inhibited by supraoptimal doses of this substance, as was shown by Foreman and Lichtensteins and confirmed in our control exper-
558 Vervloet et al. iments. Another mechanism, by which suxamethonium may release histamine from basophils, is a direct pharmacological HR (caused by the drug) as a result of a “selective” basophil abnormality (idiosyncrasy). Recently Assem et al .Hreported the case of a young woman who developed anaphylactic-type reaction during a suxamethonium anesthesia induction. In this case, not only suxamethonium but also some other pharmacologically and chemically related muscle relaxants induced in vitro HR from the patient’s leukocytes. The authors suggested that certain individuals react abnormally to neuromuscular blocking drugs by massive release of histamine from basophils, leukocytes, and tissue mast cells; however, the mechanism of this abnormality is not yet understood. In order to obtain a more reliable distinction between immunological and idiosyncratic pharmacological mechanisms of suxamethonium-induced HR, we studied the effect of D,O on HR and of leukocyte desensitization with anti-IgE on suxamethonium-induced HR. D,O (50%), when added to the incubation buffer, not only produced highly significant increase in suxamethonium-induced HR but also induced HR in the previously negative cases. Such enhancement of HR with D,O is typical of IgE-dependent histamine release.21 In our experiments D,O slightly enhanced F-Met-Leu-Phe-induced HR and did not change the release induced by Poly-L-Arg (data not shown); similarly CSa-induced HR was not changed by D20.22* 28 However, D,O may increase HR induced by concavalin A and phytohemagglutinin.2” It is well known that prolonged incubation of basophils with antigen or anti-IgE in Ca ‘+-free buffer results in desensitization of the cells.“u Antigenic desensitization does not cause a similar abrogation of responsiveness to C5a,22 calcium ionophore,31 or F- Met peptides. In all five experiments on leukocytes, anti-IgE desensitization significantly inhibited HR induced by optimal concentrations of suxamethonium. By contrast, previous desensitization did not decrease HR induced by FMet-Leu-Phe or Poly-L-Arg (Fig. 3). The loss of response to antigen but not to Poly-L-Arg after desensitization with antigen E was described by Foreman and Lichtenstein.s Similarly Siraganian and Hook22 showed that cells desensitized to IgE-mediated release after preincubation with antigen E in Ca++-free buffer had lost their ability to release histamine when exposed to either ragweed antigen or anti-IgE but were fully responsive to F-Met peptides, the latter response being even greater after desensitization. Thus inhibition of suxamethonium-induced HR after anti-IgE desensitization may indirectly suggest that IgE mechanism may be involved in this mediator release.
CONCtUStON In conclusion, we confirm our previous 1‘2stilit :&it skin tests are very valuable for the identitic;t!:.rr~ iit agents responsible for severe accidents occurr~~~~: du!-ing general anesthesia. In vitro diagnosis of this hypersensitivity ind~ be improved by adding D20 to incubation buffers tl*,ed in histamine release studies. Furthermore, positive PK tests, enhancement of HR by D,O, and inhibition of HR by antigen excess or by previous desensitization of leukocytes with anti-IgE may suggest, in cases of adverse reactions to muscle relaxants, the involvement of lgE-mediated mechanism. This sensitivity to muscle relaxants seems a longlasting one because positive skin tests are reproducible at least 1 yr later. Positive skin tests to another quatemary ammonium compound (cetrimonium) in patients allergic to suxamethonium could help to explain some cases of anaphylactic accidents occurring after the first use of this muscle relaxant. We thank all the medical staff of Anaesthesiology
FranGois, Marseille, France) who sent us the patients for investigations REFERENGES
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