Anaphylaxis during induction of general anesthesia: Subsequent evaluation and management

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1 Anaphylaxis during induction of general anesthesia: Subsequent evaluation and management Richard A. Moscicki, MD, Steven M. Sockin, MD, Bruce F. Corsello, MD, Martin G. Ostro, MD, and Kurt J. Bloch, MD Boston, Mass. Twenty-seven patients were referred for evaluation of anaphylaxis after induction of general anesthesia (GA) in which thiobarbiturates, muscle relaxants, or antibiotics were administered intravenously. Skin testing by the prick and intracutaneous methods was performed with dilutions of the thiobarbiturates and muscle relaxants; fl-lactam reagents were used in patients who had also received these drugs. No skin test reactivity was noted in 16 normal subjects. Skin tests were positive in 13 patients (thiobarbiturates in five, muscle relaxants in six, and antibiotics in two patients). Two patients were dermatographic and yielded indeterminate skin test results. Eleven of the 27 patients subsequently had GA; all patients received a premedication regimen of prednisone and diphenhydramine. Of three patients with negative skin tests, one experienced an arrhythmia, but no other signs attributable to anaphylaxis were noted. One patient with dermatographism had GA without a reaction. Positive skin tests implicated an agent that was avoided in seven patients; one of these patients experienced delayed urticaria/ angioedema after the completion of GA. Thus, no patients developed anaphylaxis during subsequent GA for which agents producing positive skin tests were avoided, and a premedication regimen was used. ( J ALLERGY CLIN IMMUNOL 1990;86: ) Anaphylaxis to intravenous agents used during GA occurs in approximately one in 5000 to one in 15,000 operations. 1-5 The mortality of anaphylactic reactions to drugs used in GA was reported to be 4% to 6% Identification of the responsible agent is difficult because of the multiplicity of drugs used during GA. The primary agents used during induction of anesthesia in the United States are the neuromuscular blocking agents and thiobarbiturates, primarily thiopental, This article provides the first North American description of anaphylaxis to the neuromuscular blocking agents. Controversy exists regarding the mechanism of anaphylaxis induced by agents used during the induction of anesthesia, s-h but there is considerable evidence for a role of IgE antibodies directed against these agents. ~2-~s Skin testing, to detect IgE From the Department of Medicine, Harvard Medical School, and the Clinical Immunology and Allergy Units, General Medical Services, Massachusetts General Hospital, Boston, Mass. Received for publication July 11, Revised April 6, Accepted for publication April 24, Reprint requests: Richard A. Moscicki, MD, Massachusetts General Hospital, Clinical Immunology and Allergy Units, 32 Fruit St., Bulfinch 422, Boston, MA / 1 / Abbreviations used GA: General anesthesia PO: By mouth antibodies to agents used during intravenous GA has been used to evaluate patients who react adversely to these agents in Australia and Europe. ~2' 16, Few studies are available that review the North American experience with skin testing to these agents, and limited information is available regarding the outcome of subsequent anesthesia with agents chosen on the basis of such skin tests. Our experience with hypersensitivity to agents used during GA and our approach to its management are reviewed in this article. PATIENTS AND METHODS From 1980 to 1988, 27 patients were referred to the Clinical Immunology and Allergy Units of the Massachusetts General Hospital for evaluation of anaphylaxis during GA. With one exception, all the operations were scheduled procedures. The patients ranged in age from 51/2 to 70 years, with a mean of 54 years. Twenty patients were female, and seven were male. Twelve patients (44.4%) had a previous 325

2 326 Moscicki et ah J. ALLERGY CLiN. IMMUNOL. SEPTEMBER 1990 TABLE I Signs of Drugs Patient Age/Sex Prior Onset anaphylaxis inducing no. (yr) GA hx Atopy (rain) (c, b, or h) Drugs received (+) ST 1 11/M N N 5 c,b,h TP, SC,TC,F SC 2 51/2/F Y N Unknown c,b TP, PC,MH,F,B SC 3 52/F Y Y 5 c,b TP NR 4 30/F N Y -<30 c,b,h TP, PC,F,B NR 5 29/F Y N 10 c,b,h TP, SC,F,MA TP 6 42/F Y N >30 Resp. failure TP, SC,M NR 7 28/M Y Y 10 c,b,h TP, SC NR 8 62/M Y N 30 sec c,h TP, MC,PC,P MC 9 10/M N D 5 c,b TP, PC D 10 56/F Y N >30 c,b,h TP, PC,SC,F TP; TA 11 33/F Y N 5 c,h TP, PC,SC,F TP; TA 12 14/F Y N 5 c,h TP, SC,M,B NR 13 50/F Y N -<30 c TP, SC,F,B B 14 35/F Y Y -<30 c,b,h TP, PC,SC,TC SC 15 63/F Y N -<30 c,h TA,SC,F,B B 16 11/M N Y <30 b TP, MC,M NR 17 31/F Y Y Unknown b,h TP, SC NR 18 58/F Y D 5 c TP, B D 19 21/F Y N Unknown c,h TP, SC,F TP 20 34/F Y N <5 Resp. failure TP NR / F Y Y <5 b TP, SC,TC NR 22 13/F N Y <5 c,b,h TP, SC,TC SC / F N Y <5 c,b,h TP, PC, SC,F,MA SC 24 33/F Y Y -<-30 c TP, SC,TC,B NR 25 42/M Y Y >30 c TP, SC,F NR 26 42/M Y N 5 c,b,h TP, PC,SC,M,B NR 27 70/F Y Y <5 c,b,h TP, SC,F,B TP hx, History; c, cutaneous reaction; b, bronchospa.~m; h, hypotension; ST, skin test; N, no; TP, thiopental; SC, succinylcholine; F, fentanyl; Y, yes; PC, pancuronium; MH, methohexital; B, 13-1actam antibiotics; MA, midazolarn; M, morphine; MC, metocurine; TC, tubocurarine; TA, thioamylal; resp, respiratory; D, dermatographism; NR, nonreactive. history of atopy, three (11.1%) had a history of urticaria, and five patients (18.5%) had a previous history of drug reactions. Atopy was defined as a history of allergic rhinitis, asthma, atopic dermatitis, or positive skin tests to airborne or food allergens. Twenty-one patients reported one or more uneventful experiences with GA before the anesthesia that was accompanied by anaphylaxis. The interval between induction of anesthesia and onset of anaphylaxis and the signs of anaphylaxis are presented in Table I. The drugs administered during GA, as well as the results of the skin testing, are also listed in Table I. Most patients (23/27) were evaluated at least 1 month after their anaphylactic event. Four patients were evaluated at less than 1 month, between days 12 to 27. Administration of any drug known to interfere with skin testing was stopped at least 48 hours before evaluation. The patients' informed consent was obtained. All patients were tested with a battery of anesthetic agents, as listed in "fable II. If any patient had received an agent not included in our panel, then an attempt was made to include that agent in the skin testing procedure. All skin test materials were prepared on the day of testing; the agents were diluted in normal saline without preservatives. Prick tests were performed on the volar surface of the forearm; the concentrations of the agents tested are listed in Table II. The results of the prick tests were assessed at 15 minutes. Intradermal testing was subsequently performed with 0.02 ml of the agents that yielded a negative skin test by the prick method. The concentrations of these agents are also listed in Table II; concentrations selected were based on previous studies. ~' 20 Normal saline, without preservatives, was used as a negative control, and histamine diphosphate was used as the positive control for both prick and intradermal testing. Skin test reactivity for the intradermal tests was assessed at 15 minutes. For those patients who had received 13-1actam antibiotics before the anaphylactic event, either preoperatively or during GA, skin testing was performed with penicillin G and benzylpenicilloyl poly- L-lysine. A minor determinant mixture was also used in,patients requiring penicillin testing after Skin tests were considered positive if the wheal diameter was 50% larger than wheal of the control and was associated with

3 VOLUME 86 Anaphylaxis during general anesthesia 327 NUMBER 3, PART 1 TABLE II. Concentrations of agents used in skin testing Agent Stock reagent Dilution for Dilution for concentration prick test intradermal test (mg/ml) (mg/ml) (mg/ml) Thiopental 20 Thioamylal 10 Methohexital 10 Succinylcholine 20 Pancuronium 2 Tubocurarine 3 Metocurine 2 Negative control Histamine control 1:10 (2.0) 1:100 (0.2) 1:10 (1.0) 1:100 (0.1) 1:10 (1.0) 1:100 (0.1) 1:100 (0.2) 1:1,000 (0.02) 1:100 (0.02) I:1,000 (0.002) 1:1000 (0.003) 1:10,000 (0.0003) 1:100 (0.02) 1:1,000 (0.002) Normal saline Normal saline (2.75 rng/ml) (0.275 mg/ml) surrounding erythema. The above skin testing for general anesthetic agent hypersensitivity was performed in 16 normal control subjects in addition to the 27 patients. In those patients who were skin test positive, avoidance of the implicated agent was recommended. Regardless of the skin test results, all patients were advised to receive premedication with 50 mg of prednisone, p.o., at 13 hours, 7 hours, and 1 hour before GA, and diphenhydramine, 50 mg p.o. or intramuscularly 1 hour before anesthesia. Information regarding GA, subsequent to our evaluation and skin testing, was available for 24 of the 27 patients. Statistical analysis was performed with Fisher's exact test. RESULTS The signs attributed to anaphylaxis during GA included cutaneous reactions in 22 patients (81.5%), bronchospasm in 16 patients (59.3%), hypotension in 16 patients (59.3%), and arrhythmias in five patients (18.5%). Of the patients with cutaneous reactions, 11 experienced flushing (40.7%), 13 developed urticaria/angioedema (48.2%), and two patients had cyanosis (7.4%). These signs are listed in Table I. Of the 27 patients evaluated, 15 (55.6%) developed anaphylaxis within 10 minutes after the intravenous induction of anesthesia. Six patients (22.2%) had the onset of signs more than 10 minutes but less than 30 minutes after induction of anesthesia, whereas three patients (11%) had the onset of signs attributed to anaphylaxis more than 30 minutes after the initiation of GA. The time of onset of anaphylaxis was unknown in three patients (Table I). Twenty-five of the 27 patients referred for evaluation had received multiple drugs for intravenous anesthesia (Table I). All patients received a thiobarbiturate, most patients (26/27)received thiopental, one received thioamylal, and one patient received methohexital and thiopental. Twenty-four of the 27 patients were administered a muscle relaxant; 10 patients received more than one agent during their procedure. Nineteen patients were administered succinylcholine; nine patients, pancuronium; five patients, tubocurafine; and two patients received metocurine. In addition to these agents, 13 patients received fentanyl, five were administered morphine, and two patients were administered midazolam. Seven patients received a 13- lactam antibiotic either preoperatively or intraoperatively. No skin test reactivity to the panel of reagents listed in Table II was found in the 16 normal control subjects. No adverse local or systemic reactions occurred during or after skin testing in either patients or control subjects. Skin tests were positive in 13 of the 27 patients. Of these 13 patients, five reacted to the thiobarbiturates (five, thiopental; two, thioamylal; 0, methohexital), six reacted to the muscle relaxants (five, succinylcholine; one patient, metocurine), and two patients reacted to penicillin determinants. Of the five patients who reacted positively to a thiobarbiturate, two were positive to both thiopental and thioamylal, and yet both patients had received only thiopental. One of the five patients with a positive skin test to succinylcholine had received pancuronium, but not succinylcholine, as the neuromuscular blocking agent during GA. Of the seven patients who were administered a 13-1actam antibiotic either preoperatively or intraoperatively, two demonstrated positive skin tests. Of the entire group of patients, the prick test was positive in only the one patient who reacted to succinylcholine. Skin tests were negative in 12 of the 27 patients and yielded indeterminate results in two patients with dermatographism. Several correlations were found between the physical signs noted during anaphylaxis (Table I) and the results of skin testing. Patients who had experienced multiple physical signs during their anaphylactic event (19/27) were more likely to have positive skin tests

4 328 Moscicki et al. J. ALLERGY CLIN. IMMUNOL. SEPTEMBER 1990 (12/19) than were patients with an isolated physical sign (8/27). Of these patients, only one of eight patients had a positive skin test. The correlation between multiple signs and positive skin tests yielded ap value of Patients who experienced a cutaneous reaction, bronchospasm, and hypotension (10/27) were likely to have a positive skin test(s) identifying a possible causative agent (7/10) for their anaphylactic event (p = 0.01). Patients who developed a cutaneous reaction and hypotension (5/27) had a high incidence (4/5) of positive skin tests, although this association did not achieve statistical significance compared to the frequency of positive skin tests in the other patients (p = 0.13). Of the three patients with a cutaneous reaction plus bronchospasm, one patient (33%) had positive skin tests; the one patient with hypotension plus bronchospasm had negative skin tests. Of the patients with isolated physical signs constituting their anaphylactic event, four patients had only a cutaneous manifestation and one of these patients yielded a positive skin test. Two patients experienced only bronchospasm and two developed respiratory failure; none of these patients had positive skin tests. There were no patients who manifested hypotension alone as their physical sign of anaphylaxis. All 13 patients with positive skin tests had experienced a cutaneous reaction associated with their anaphylactic event. Seven patients had developed urticaria/angioedema, five developed significant flushing, and one patient developed both of these reactions. In contrast, six of the 12 patients with negative tests developed cutaneous signs, four experiencing urticaria/angioedema and two patients developing flushing. The association of a cutaneous sign of anaphylaxis with a positive skin test(s) was significant (p = 0.005). Twelve of the 13 patients with positive skin tests had experienced multiple physical signs during their anaphylactic event compared to six of the 12 patients with negative skin tests (p = 0.03). Of the 13 patients, 11 had experienced hypotension; in contrast, five of the 12 patients with negative skin tests had hypotension. No significant difference was noted in the physical manifestations of anaphylaxis in patients with positive skin tests to thiobarbiturates in comparison to those who reacted to muscle relaxants. Regarding the 12 patients with negative skin tests, six manifested only a single sign of anaphylaxis during general anesthesia. Five of the 12 patients had received other agents that may have produced sign(s) attributed to anaphylaxis, but for which skin testing is not reliable. Two patients had received morphine and a cephalosporin, one received morphine, one was administered fentanyl, and one patient received fen- tanyl and a cephalosporin. As mentioned previously, one patient who was skin test negative to the panel of agents listed in Table II reacted on intradermal testing to a dilution of 1 : 100 of succinylcholine, but not the usual 1:1000 dilution. An additional patient who had received d-tubocurarine reacted positively on intradermal testing at a concentration of 1 : 1000, but not at 1 : 10,000 dilution of this drug. Eleven of 24 patients for whom follow-up information was available had GA after the episode of anaphylaxis. All patients were premedicated with prednisone, 50 mg p.o., at 13 hours, 7 hours, and 1 hour before surgery, along with diphenhydramine, 50 mg p.o. or intramuscularly 1 hour preoperatively. Of the 11 patients, seven had had positive skin tests that implicated an agent that was subsequently avoided. One of these seven patients experienced a reaction after the completion of GA; the reaction consisted of urticaria and angioedema. Three of these 11 patients had had negative skin tests; there was no adverse reaction to repeat GA in two of these patients. The third patient developed an arrhythmia but no other signs of anaphylaxis. One of the patients who had repeat GA had dermatographism and did not develop a reaction. No patient in this group experienced anaphylaxis on repeat administration of GA. DISCUSSION This North American patient population referred for evaluation of anaphylaxis after induction of GA shared several features with other groups studied in France, Britain, and Australia, although several differences did exist.* The mean age of our population (54 years; range, 51/2 to 70 years) was older than the other groups reviewed. Although in most studies, a predominence of female patients has been noted, the percentage of female patients in our group was unusually high at 74%. The incidence of atopic disease was 44.4% in our group; the reported incidence of atopy in the general US population is 5% to 22%? 8, 29 Atopy was present in four of 13 (31%) patients with positive skin tests, eight of 12 (66%) patients with negative skin tests, and in neither of the two patients with dermatographism. Three of the six patients with positive skin tests to muscle relaxants were atopic in contrast to only one of five patients reacting to thiobarbiturates. There are conflicting accounts on the incidence of atopic disease associated with intravenous general anesthetic agent hypersensitivity.t Fisher and More 4 and LaForest et al. 25 demonstrated an increase in atopy among patients with anaphylaxis during GA in comparison to other patients who had anesthesia without a reaction (31.8% versus 8.5%). 4 Fisher and Munro 21 *References 2, 4-7, 10, 12, 16, 21, treferences 2, 4-6, 10, 21,

5 VOLUME 86 Anaphylaxis during general anesthesia 329 NUMBER 3, PART 1 noted a higher incidence of atopy (39%) in patients reactive to muscle relaxants in comparison to patients reactive to induction agents (29%). British and French studies have supported an increase in atopy among patients reacting during GA in comparison to unmatched populations. 7' lo, 30 However, Charpin et al.6 were unable to find evidence of increased atopy in patients with anaphylaxis to succinylcholine in a casecontrol study in which criteria for the designation of atopy were more narrowly defined. Similarly, other studies have failed to demonstrate a greater incidence of drug allergy in atopic patients. 31 In keeping with the experience of other investigators,2, 4, only 77% of our patients had received prior GA. This finding suggests that sensitization to anesthetic agents may occur outside of the operating room or that nonspecific mechanisms are involved in some reactions. Although the incidence of atopy may be increased in patients who have experienced anaphylaxis during induction of GA, LaForest et al. 25 and Fisher et al. 26 have recognized that a history of atopy does not aid the selection of anesthetic drugs for initial or repeat anesthesia. Allergy to drugs other than drugs used in anesthesia may be more frequent in patients who subsequently reacted during GA in comparison to the general population; neither this factor nor a history of uneventful prior anesthesia allows prediction of which patients are at risk for anaphylaxis during anesthesia. In the patients examined in this study, signs of anaphylaxis appeared shortly after the induction of anesthesia. In one third of the patients, however, these signs did not appear until more than 10 minutes after intravenous administration of the general anesthetic agents. In three patients (11%), signs of anaphylaxis were noted more than 30 minutes after the start of anesthesia. Two of these patients had only isolated signs and negative skin tests. It remains possible that other explanations may account for the signs in these patients. Cutaneous signs were the most frequent clinical manifestations of anaphylaxis in our patients (81.5 %). Flushing was noted in 40.7% of the patients, which is similar to the 40% to 50% incidence reported by other groups. 4" 5 Approximately one half the patients had urticaria or angioedema similar to the incidence reported in reaction to muscle relaxants in France, 5" 16 and 60% had bronchospasm. In contrast, Fisher and More a reported a 14% incidence of bronchospasm accompanying anaphylaxis caused by induction agents and a 26% incidence caused by muscle relaxants. Hypotension and circulatory collapse were more frequent in our group (59%), compared to that reported by some investigators. 4' 7 Vervloet et a1.,12' 16 however, reported a much higher incidence of circulatory collapse in his study, as did Laxenaire et al.3o Skin testing with agents used during GA in those patients who have experienced anaphylaxis has been used by Fisher 15' and Fisher and Munro 21 since Other investigators have further established the value and safety of skin testing to intravenous anesthetic drugs , Most investigators used intradermal testing for diagnosis, whereas Leynadier et al.:3 suggested that puncture testing may also have use in diagnosis. They noted a high degree of correlation between puncture and intradermal test results but did not list the concentrations of the drugs used. Our experience revealed that prick testing, positive in only one of the 13 patients with positive intradermal test results, provided little useful information. Possibly, the dilute solutions we used were not equivalent to dilute solutions of Leynadier et al. 23 The diagnostic use of skin testing with agents used during GA has been strongly emphasized by Fisher and Baldo, 3 Fisher, 15, 20 and Sage 24 and for muscle relaxants by Vervloet et al.12' 16 Skin testing has been considered to be of primary diagnostic value in IgEmediated phenomena, especially phenomena involving intact protein antigens. Small haptenic determinants, however, have proved useful as well in the assessment of 13-1actam antibiotic hypersensitivity, especially if the major and minor determinants of metabolic products are included. The pathogenesis of anaphylaxis to agents used at the induction of GA remains uncertain. Histamine release appears to be important, but the mechanism of release is debated, s-lz' 16, Both neuromuscular blocking agents, as well as induction agents, are capable of directly inducing histamine release. Usually, this phenomenon does not lead to clinical signs of anaphylaxis in most subjects receiving these drugs. Furthermore, on intradermal injection of appropriate dilutions, these agents do not elicit a wheal-and-flare response in normal individuals. In contrast, many of the patients who experienced signs of anaphylaxis after receiving these agents did exhibit a wheal-andflare response on testing with dilute solutions of these agents, thereby demonstrating cutaneous hypersensitivity. Possibly, the dermal mast cells of these patients are idiosyncratically more sensitive to nonspecific release of mediators provoked by agents administered during anesthesia. Available evidence suggests that clinically important anaphylactic reactions induced by muscle relaxants are, in most cases, IgE-antibody mediated. This evidence includes the demonstration of positive Prausnitz-Kiistner transfer, 12' detection of muscle relaxant-specific IgE antibodies by RAST test, and of

6 330 Moscicki et al. J. ALLERGY CLIN. IMMUNOL. SEPTEMBER 1990 leukocyte histamine release induced by these agents after their addition in vitro to passively (presumably by IgE antibodies) sensitized basophils, lz' 16, 34 Baldo and Fisher 17 initially demonstrated that sera of patients with a history of anaphylaxis after injection of muscle relaxants contained IgE antibody reactive with the quaternary ammonium determinant of many of these reagents. 18 Subsequently, Vervloet et al.34 demonstrated that succinylcholine, which consists of two quaternary ammonium groups separated by an aliphatic chain, produced cross-linking of cell surfacebound IgE antibodies to produce mediator release. Molecules that rigidly held quaternary ammonium determinants apart at a critical distance did not trigger mediator release. There is also evidence for an antibody-mediated mechanism involving the thiobarbiturates. 13' 3541 Indirect basophil degranulation has been demonstrated 13 Of note, thiopental induced in vitro histamine release from leukocytes of a patient who had anaphylaxis, but passive sensitization of normal leukocytes could not be demonstrated. 9 It remains possible that such passive sensitization techniques are insufficiently sensitive. Dolovich et al. 35 demonstrated binding of serum immunoglobulin to 14C-thiopental in a case report illustrating cross-reactivity among the thiobarbiturates. The identification of passive transfer in some patients suggested an IgE-mediated mechanism, is, 20 More recently, RAST was used to demonstrate IgE antibodies reactive with thiopental in other case reports. 38 Harle et al. 39 demonstrated IgE specific for the thiopentone molecule with a radiommunoassay. With this assay, cross-reactivity was demonstrated between several barbiturate analogues. 4~ Alterations in serum complement have been reported after anaphylaxis in the setting of induction of anesthesia. 1~ 42 There is evidence, however, that such alterations may be secondary to IgE antibody-mediated events and may be produced by alterations in compartmental volume and protein distribution 43 or may be mediated by the proteases released during anaphylaxis. 44' 45 In this study, skin testing with the intravenous agents used at induction of GA was performed without adverse reactions and aided in the identification of the agent that was a likely cause of anaphylaxis in about one half the patients. Skin testing was most useful in identifying a likely causative agent in those patients who manifested multiple signs of anaphylaxis. All patients with positive skin tests had experienced at least a cutaneous sign during their anaphylactic event. Patients who experienced the three classic features of anaphylaxis, including a cutaneous reaction, bronchospasm, and hypotension, were especially likely to have positive skin tests identifying a possible cans- ative agent. Those patients in our group who had exhibited an isolated physical sign of anaphylaxis were less likely to yield a positive skin test. The diagnosis of anaphylaxis may be suspect in these cases, albeit the referral for evaluation was made by anesthesiologists based on their clinical suspicion that anaphylaxis had occurred in their patients. Of the 12 patients with negative skin tests, five patients had more than one physical sign (including a cutaneous sign) of anaphylaxis. In these cases, anaphylaxis may have been induced by other agents administered during GA, for example, narcotics, midazolam, dextrans or a cephalosporin. Five of the skin test-negative patients had received these agents. Skin testing with these agents has not yet been demonstrated to be reliable. Other agents recognized to produce anaphylaxis during anesthesia include protamine, blood products, and colloidal plasma expanders. 46 The patients reported here did not receive these agents. Of interest are recent accounts of anaphylaxis related to intraoperative exposure to rubber surgical gloves or masks. 47 Four of the patients with negative skin tests have been subsequently evaluated for sensitivity to latex and were found to be negative. One patient with a history of angioedema on exposure to rubber was positive to skin testing with latex. Skin testing with the panel of thiobarbiturates and muscle relaxants in this patient had been indeterminant because she had a positive reaction to a muscle relaxant other than the muscle relaxant used during her GA. The latex extract used was able to cause cutaneous wheal and flare in three other patients with histories suggestive of latex hypersensitivity. No patients developed anaphylaxis during subsequent anesthesia in which agents producing positive skin tests were avoided. However, all patients were premedicated with prednisone and diphenhydramine according to a dosage schedule that was demonstrated to be useful in reducing anaphylaxis after administration of radiocontrast media. 4s' ~9 Fisher and More A and FisheP ~ had previously suggested a similar regimen of pretreatment for patients who had experienced anaphylactic reactions to anesthetic drugs. Only one study of pharmacologic pretreatment for reactions to induction agents exists? 1 This precautionary measure was taken because the predictive value of positive and negative skin tests was not yet ascertained for the intravenous general anesthetic agents. Avoidance of anaphylaxis during subsequent GA may have been related to these precautionary measures. The predictive value of a positive skin test cannot be definitively assessed in the present study because a combined approach of premedication and avoidance of the implicated agent was used. Although no skin test reactivity

7 VOLUME 86 Anaphylaxis during general anesthesia 331 NUMBER 3, PART 1 was noted among the normal control subjects in our study, it would be of interest to determine the frequency of positive skin tests among patients who have recently had GA without anaphyaxis. To allow better assessment of the value of skin tests, it may be necessary to subsequently challenge patients under well-controlled circumstances with all agents producing negative and positive skin tests. Challenge with agents producing positive tests raises serious ethical considerations and was not undertaken in this study. The number of our patients with negative skin tests who subsequently had GA is small; the predictive value of negative skin tests is therefore even less certain. Of three such patients, none experienced anaphylaxis on subsequent anesthesia. A combined approach to the management of general intravenous anesthetic agent hypersensitivity, with avoidance of the drug implicated by positive skin testing and premedication before subsequent GA, was associated with uneventful general anesthesia in all 11 patients. Our recommended approach to these patients includes the following: use of an alternative method of anesthesia if this is possible (i.e., inhalational, local or spinal), obtaining a complete list of all drugs used in the preoperative period and during GA, skin testing with appropriate agents, including other suspected agents such as 13-1actam antibiotics, followed by strict avoidance of the agent(s) producing a positive skin test, and premedication with prednisone and diphenhydramine preoperatively. A Medic-Alert bracelet (Medic-Alert Foundation International, Turlock, Calif.) should be issued to the skin test-positive patients. Although our approach did not definitively assess the predictive value of skin testing with agents used during GA, it did demonstrate the safety of the diagnostic testing and the efficacy of the combined approach in avoiding subsequent general anesthetic agent-related anaphylaxis. We are grateful to Mary R. Niederberger for preparation of the manuscript. REFERENCES 1. Stoelting RK. Allergic reactions during anesthesia. Anesth Analg 1983;62: Clarke RSJ. Adverse effects of intravenously administered drugs used in anaesthetic practice. Drugs 1981;22: Fisher MM. Baldo BA. Anaphylactoid reactions during anesthesia. Clin Anesthesiology 1984;2: Fisher MM, More DG. The epidemiology and clinical features of anaphylactic reactions in anaesthesia. Anaesth Intensive Care 1981;9(3): Laxenalre MC, Moneret-Vautrin DA, Boileau S, Moeller R. Adverse reactions to intravenous agents in anaesthesia in France. Klin Wochenschr 1982;60: Charpin D, Benzarti M, Hrmon Y, et al. 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