ORIGINAL ARTICLE

Study of Hypersensitivity Reactions and

Anaphylaxis During Anesthesia in Spain
T Lobera,1 MT Audicana,2 MD Pozo,1 A Blasco,1 E Fernández,2 P Cañada,3
G Gastaminza,2 I Martinez-Albelda,4 I González-Mahave,1 D Muñoz2
1
Department of Allergology, Hospital San Pedro/San Millán, Logroño, Spain
2
Department of Allergology, Hospital Santiago Apóstol, Vitoria, Spain
3
Department of Anesthesia, Hospital San Pedro/San Millán, Logroño, Spain
4
Department of Anesthesia, Hospital Santiago Apóstol, Vitoria, Spain
Financial support by SERIS (Hospital San Pedro/San Millán, Logroño, Spain) and OSAKIDETZA
(Hospital Santiago Apóstol, Vitoria, Spain)

■ Abstract

Background: Several studies have identified neuromuscular blocking agents as the most common cause of anaphylaxis during general
anesthesia. The reported frequencies vary considerably between countries. There are few reports from Spain, probably due to the low
prevalence of reactions.
Methods: For 5 years (1998-2002), all the patients who presented perioperative anaphylactic-type reactions, were studied in 2 Spanish
allergy departments (Santiago Apostol, Vitoria-Gasteiz and San Pedro, Logroño). The diagnostic protocol consisted of a case history (age,
gender, number of previous interventions, characteristics of the reaction, reaction phase, previously administered drugs), serum tryptase
measurements, skin tests, and specific immunoassays (immunoglobulin [Ig] E determination against latex, penicillin, and Echinococcus).
Results: Forty-eight patients were studied, with ages ranging from 7 to 86 years. The ratio of women to men was 3:2. An IgE-mediated
mechanism was confirmed in 27/48 patients (56%). The etiological agents were antibiotics in 12 cases (44%) (10 betalactams, 1 vancomycin,
and 1 ciprofloxacin), muscle relaxants in 10 cases (37%), pyrazolones in 2 cases, latex in 2 cases, and Echinococcus in 1 case.
Conclusions: Fifty-six percent of the perianesthetic reactions studied were IgE-mediated. Antibiotics and neuromuscular blocking agents
were the most frequent causal agents, as verified by skin tests, and specific IgE and/or challenge tests. It is important to keep appropriate
documentation on any of the drugs used during surgery, since our results show that those drugs involved in the reaction as the etiological
agent, such as antibiotics and nonsteroidal anti-inflammatory agents, can be used again outside the context of surgery.
Key words: Anesthesia. Hypersensitivity. Anaphylaxis. Muscle relaxants. Antibiotics. Perianesthetic reactions.

■ Resumen
Antecedentes: Los agentes miorelajantes son reconocidos por varios estudios como la causa más común de anafilaxia durante la anestesia
general. Su frecuencia varía entre diferentes países. Hay pocas referencias españolas, probablemente debido a la baja prevalencia de
reacciones.
Métodos: Durante 5 años (1998-2002), todos los pacientes que presentaron reacciones peroperatorias de tipo anafiláctico, se estudiaron
en dos Servicios de Alergología de España (Hospital Santiago Apóstol de Vitoria y San Pedro de Logroño). El protocolo diagnóstico
conjunto constaba de historia clínica (edad, sexo, número de intervenciones quirúrgicas previas, características de la reacción, fase de
la reacción, fármacos administrados previamente), determinación de triptasa sérica, pruebas cutáneas y determinación de IgE específica
(latex, penicilina y Echinococcus).
Resultados: Se estudiaron 48 pacientes con edades comprendidas entre los 7 y 86 años. La proporción por sexo (F:M) fue 3:2. Se confirmó
un mecanismo IgE mediado en 27/48 (56%). Los agentes etiológicos fueron antibióticos en 12 casos (44%)(10 betalactámicos, 1
vancomicina, 1 ciprofloxacino), relajantes musculares en 10 casos (37%), pirazolonas en 2 casos, y latex y Echinococcus en 2 casos y 1
caso, respectivamente.
Conclusiones: El 56% de las reacciones peranestésicas fueron mediadas por IgE. Los antibióticos y los relajantes musculares fueron las
causas más frecuentes, confirmadas mediante pruebas cutáneas, determinación de IgE específica y/o pruebas de provocación. Creemos
importante guardar documentación apropiada sobre todos los fármacos administrados en la intervención puesto que, de acuerdo a nuestros
resultados, algunos de estos fármacos involucrados en la reacción como agentes etiológicos, como los antibióticos o antiinflamatorios,
pueden ser usados de nuevo fuera del contexto quirúrgico.
Palabras clave: Anestesia. Hipersensibilidad. Anafilaxia. Relajantes musculares. Antibióticos. Reacciones peranestésicas.

© 2008 Esmon Publicidad J Investig Allergol Clin Immunol 2008; Vol. 18(5): 350-356
351 T Lobera, et al

Introduction Table 1. Patient Characteristics

Anesthesiologists administer several Drug Prick Test Intradermal Test

drugs during surgery and many of these
drugs have side effects that are similar to Benzodiazepines
those induced by immunologic mechanisms. Midazolam 5 mg/mL 10-2
Anaphylactoid reactions, or nonallergic Diazepam 5 mg/mL 0.1 mg/mL 10-2
drug hypersensitivity, occur through direct Opioid analgesics
nonimmunologic immunoglobulin (Ig) E- Morphine Undiluted 10-5
induced release of mediators from mast cells Fentanyl, alfentanil, remifentanil Undiluted 10-2 10-1
or from complement activation induced by the Pentazocine Undiluted 10-2
drugs, mainly neuromuscular blocking agents
(NMBA) and opioids. Drug hypersensitivity Barbiturates
reactions are considered allergic reactions to Thiopental Undiluted 10-2
drugs when immunologic mechanisms have Pentothal 200 mg/mL 1 mg/mL
been demonstrated and IgE-mediated drug Muscle relaxants
allergy when we wish to highlight the role of Succinyl-choline (Suxamethonium) 10-3 10-2 10-1a
IgE antibody [1]. Anaphylaxis, considered an Pancuronium Undiluted 10-3 10-2 10-1
acute type I hypersensitivity reaction resulting Cisatracurium Undiluted 10-3 10-2 10-1a
primarily from rapid antigen induction–usually Atracurium Undiluted 10-3 10-2a
IgE-dependent release of potent mediators Vecuronium Undiluted 10-3 10-2 10-1
from mast cells and basophils–has been Rocuronium Undiluted 10-3 10-2 10-1a
reported [2], although the term anaphylaxis Mivacurium 10-1 10-3 10-2a
should only be used for the most severe IgE- Gallamine Undiluted 10-3 10-2 10-1a
mediated, life-threatening, generalized, or
systemic hypersensitivity reaction [1]. Other induction drugs
The perioperative adverse reactions Propofol Undiluted 10-2 10-1
described above are uncommon, and their Local anesthetics
frequency varies with the type of procedure. Procaine Undiluted 0.05 mg/mL
The estimated overall frequency has been Lidocaine Undiluted 2 mg/mL
reported to range from 2.8 per 10 000 Mepivacaine Undiluted 0.2 mg/mL
procedures in French series to 0.5 per 10 000
in an Australian study [3-6]. An IgE-mediated Analgesics
mechanism has been confirmed in 40%-70% Dipyrone (metamizole) 40 mg/mL 1 mg/mL-4 mg/mL
of cases [7]. Betalactams
Severe adverse reactions are infrequent Penicillin-G 10 000 U 10 000U
during surgery, and IgE-mediated allergic Ampicillin 10 10
reactions are the main contributors to morbidity Amoxicillin 10 10
and mortality in this kind of reaction during PPL
surgery [6]. Therefore, an allergologic study MDM
of patients who experience a suspected Cefazolin 1 1
perianesthetic allergic reaction could prove Ceftriaxone 1 1
useful for future interventions. Cefuroxime 1 1
In Spain, there have been few reports
Other antibiotics
of allergic reactions during anesthesia [8].
Vancomycin 0.005 mg/mL 0.005 mg/mL
We present the experience of 2 hospitals
Ciprofloxacin 0.02 mg/mL 0.02 mg/mL
that carried out a study following the same
Levofloxacin 5 mg/mL 0.05 mg/mL
protocol coordinated by their allergy and
anesthesiology teams from 1998 to 2002. Other drugs
• Sterilizers: ethylene oxide modified prick by prick with a sterile glove
• Latex commercial extracts
Materials and Methods Heparin Undiluted 10-2 10-1
Gelatin Undiluted 10-2 10-1
We carried out a 5-year prospective study
Monovalent haptens
(January 1998-December 2002) of all patients
Etamsylate Undiluted 10-1
who presented a suspicious perianesthetic
Cytidine-5-diphosphocholine Undiluted Undiluted
hypersensitivity reaction and were referred
from the anesthesiology department to the a
allergy departments of Hospital Santiago The test can be irritative at the last concentration.

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 Perianesthetic Hypersensitivity Reactions 352

Apostol in Vitoria, Spain and Hospital San Millán-San Pedro drugs (NSAIDs) or benzodiazepines, and subcutaneous
in Logroño, Spain. challenge and parenteral challenge were performed with
cephalosporins. We administered progressively higher doses
Patients until the therapeutic dose was reached for each drug. Doses
were administered 30 minutes apart.
An anaphylactic or anaphylactoid reaction [9] was the
A descriptive statistical analysis (mean, median, percentage,
criterion for inclusion. All patients presented reactions in the
and confidence interval) was performed using G-Stat 2.0.
operating room and/or recovery room.
Each patient was referred from the anesthesiology
department to the allergy department for examination
approximately 2 months after the reaction. The diagnostic Results
workup included the clinical history, skin tests, controlled
challenge tests, and serum-specific immunoassays. During the study period, 71 063 surgical interventions were
The medical history included data on age, sex, number of carried out under general anesthesia. Forty-eight patients suffered
previous interventions, characteristics of the reaction, reaction a perianesthetic hypersensitivity reaction (6.7/10 000 interventions
phase (induction/premedication, maintenance, recovery) and or 1/1480 interventions). Eighteen were male (37%) and 30 female
previously administered drugs. Data on the characteristics (63%), with ages ranging from 7 to 86 years (mean 45.3).
of the reaction, reaction phase, and drugs administered were With regard to the reaction phase, 31 reactions occurred
submitted by the anesthetist. during the induction/preparation phase (Table 2), 6 during
the maintenance phase (Table 3), and 11 during the recovery
Tryptase Determination phase (Table 4). All the patients were treated effectively with
epinephrine, antihistamines, ß-mimetics, and/or fluid therapy.
Two blood samples were taken by the anesthetist, the first No patients died.
within 15 minutes and the second 2 hours after the reaction. Most patients (32/48), had already undergone 1 or 2
Levels of serum tryptase were measured by fluoroimmunoassay surgical interventions under general anesthesia (mean 1.2 per
(CAP System, Pharmacia Diagnostics AB, Uppsala, Sweden). patient). Eleven patients had not had previous surgery and it
Values higher than 13.5 µg/L were considered positive. is surprising that an allergic mechanism was involved in 4
out of these 11 patients: NMBAs were responsible in 2 cases
Skin Tests and antibiotics were responsible in 2 cases. In contrast, only
All patients underwent skin prick tests and intradermal tests 5 cases had had 3 previous surgical operations and 4 of these
with a battery of muscle relaxants (mivacurium, atracurium, were included in the study. Two of these patients were positive
suxamethonium, gallamine, vecuronium, pancuronium, and to NMBAs and 1 to ciprofloxacin.
rocuronium) and a skin prick test with latex (Leti SL, Barcelona, As for clinical symptoms, skin eruption was recorded in
Spain). All drugs and/or substances suspected of being involved 40 cases (83%), cardiovascular involvement (hypotension,
in the reaction were also tested. Histamine 10 mg/mL and tachycardia) in 13 cases (27%), and respiratory symptoms
physiologic saline solution were used as positive and negative (bronchospasm, increased airway resistance, breathlessness)
controls, respectively, for skin prick tests. The concentrations in 11 cases (23%). Thirty-seven out of 48 patients presented
used are shown in Table 1. Skin tests involved 2 different steps: only 1 type of symptom: 31 were skin-related, 3 cardiovascular,
a prick test and, if this was negative, intradermal tests using and 3 respiratory. Although cutaneous manifestations were
increasing concentrations of the drugs. Readings were taken after predominant in all phases of anesthesia, as usually occurs in
15 minutes and assessed according to the criteria of the EAACI drug allergy, respiratory and cardiovascular manifestations show
[10]. When skin tests were positive with any of the NMBA equal ratios in the maintenance phase. During the induction and/
tested, a study with monovalent haptens, etamsylate (Hemo 141, or premedication phase, the most frequent type of reaction was
Esteve SA, Barcelona, Spain), or cytidine 5-diphosphocholine cutaneous (generalized erythema, rash, or urticaria/angioedema
choline (SOMAZINA, Almirall Prodesfarma SA, Barcelona, in 26 out of 31 patients). During the recovery phase, cutaneous
Spain) was carried out. The shift to a negative result in the symptoms were once again predominant.
intradermal test by mixing the muscle relaxant (which had been Tryptase was determined in 22 patients and high values
positive alone) at the same concentration with the monovalent were detected in 4. In 3, a sensitizing agent was confirmed
hapten 50:50 was considered to be confirmation of an IgE- (amoxicillin, latex, and dipyrone).
mediated mechanism [11]. An allergic IgE-mediated mechanism was confirmed in
27 cases (56%): 1 Echinococcus, 2 pyrazolones (dipyrone),
Other Determinations 2 latex, 12 antibiotics (6 cephalosporins, 4 penicillins, 1
vancomycin, 1 ciprofloxacin), 10 NMBA (5 rocuronium, 3
When other substances were involved, we also carried out an pancuronium, 3 mivacurium, 3 vecuronium, 2 suxamethonium,
IgE determination (penicillin, latex), if possible, and controlled and 1 gallamine). The 17 positive skin tests found in 10 patients
challenge tests to rule out sensitization to those drugs. were due to cross-reactivity between the NMBA (Tables
The patient signed a written informed consent form before 2, 3, and 4). Only 2 patients refused to finish the skin test
the controlled challenge test was performed. This was a single- (patients number 10 and 13).
blind subcutaneous or oral challenge with the suspect drug: oral All allergic reactions were analyzed in relation to the
challenge was performed with nonsteroidal anti-inflammatory phase when the reaction was induced, and differences can be

© 2008 Esmon Publicidad J Investig Allergol Clin Immunol 2008; Vol. 18(5): 350-356
353 T Lobera, et al

Table 2. Thirty-one Cases of Adverse Reaction Induced During the First Phase: Premedication and Induction

Case Sex Age Previous Reaction Phase Type Of Tryptase Confirmed Allergic
Surgery Reactiona Reaction
2 F 45 1 Induction 2,3 NT Yes (Echinococcus)
5 F 49 2 Induction 1 (-) Yes (penicillin)
6 F 37 1 Premedication 1 NT No
7 F 31 1 Induction 1,2,3 (-) Yes (cefuroxime)
8 M 49 2 Induction 1,2 NT No
9 F 39 0 Induction 1 (-) No

10 F 60 2 Induction 1 (-) NT

12 M 57 2 Premedication 1 (-) Yes (cefazolin)

15 F 51 2 Induction 1 (-) Yes (muscle relaxants)

16 M 51 0 Premedication 3 (-) Yes (cefazolin)

17 F 49 0 Induction 1 (-) No

18 M 28 2 Premedication 3 (-) Yes (cefazolin)

19 F 46 2 Induction 1 NT Yes (muscle relaxants)

24 F 81 1 Induction 2 NT No

29 F 60 3 Induction 1 (-) No

30 F 67 1 Induction 1 (-) No

32 M 34 2 Induction 1 NT Yes (ceftriaxone)

33 F 64 3 Induction 1 NT Yes (muscle relaxants)

34 F 54 2 Induction 1 (-) Yes (muscle relaxants)

35 F 74 1 Induction 1 NT Yes (latex)

36 F 64 0 Induction 1 (-) No

37 F 19 2 Induction 1 (-) Yes (muscle relaxants)

38 F 40 1 Induction 1 NT Yes (amoxicillin)

39 M 18 0 Induction 1,2 NT No

41 M 32 1 Induction 1 NT Yes (vancomycin)

42 M 70 1 Induction 1 NT No

43 F 41 3 Induction 1 NT Yes (ciprofloxacin)

44 F 69 3 Induction 2,3 NT Yes (muscle relaxants)

45 M 33 1 Induction 1 NT Yes (amoxicillin)

46 F 13 1 Induction 1 (-) No

48 M 57 0 Induction 1,2,3 (+) Yes (amoxicillin)

Abbreviation: NT, not tested

a
Type of reaction: 1, cutaneous (erythema, rash, urticaria/angioedema); 2, cardiovascular (hypotension, tachycardia); 3, respiratory (bronchospasm,
increased airway resistance, breathlessness).

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 Perianesthetic Hypersensitivity Reactions 354

Table 3. Six Cases of Adverse Reaction Induced During the Maintenance Phase

Case Sex Age Previous Reaction Phase Type Of Tryptase Confirmed Allergic
Surgery Reactiona Reaction
1 F 57 2 Maintenance 1,2,3 (-) No
3 F 65 1 Maintenance 1 NT No
13 M 51 3 Maintenance 2 (-) Not tested
20 M 9 0 Maintenance 1 NT Yes (muscle relaxants)
21 F 50 0 Maintenance 2 NT No
26 F 43 1 Maintenance 1,2,3 (+) Yes (latex)

Abbreviation: NT, not tested

a
Type of reaction: 1, cutaneous (erythema, rash, urticaria/angioedema); 2, cardiovascular (hypotension, tachycardia); 3, respiratory (bronchospasm,
increased airway resistance, breathlessness).

Table 4. Eleven Cases of Adverse Reaction Induced During the Recovery Phase

Case Sex Age Previous Reaction Phase Type Of Tryptase Confirmed Allergic
Surgery Reactiona Reaction
4 M 20 1 Recovery 1 NT No
11 M 86 2 Recovery 3 (+) No
14 M 82 0 Recovery 1 (-) No
22 F 20 1 Recovery 1 NT No
23 M 22 0 Recovery 1 NT No
25 F 7 0 Recovery 1 NT Yes (muscle relaxants)
27 M 36 1 Recovery 1,2 NT Yes (cefazolin)
28 M 42 1 Recovery 1,2,3 (+) Yes (dipyrone)
31 F 29 1 Recovery 1 NT Yes (muscle relaxants)
40 F 35 1 Recovery 1,3 NT Yes (muscle relaxants)
47 F 45 1 Recovery 1 NT Yes (dipyrone)

Abbreviation: NT, not tested

a
Type of reaction: 1, cutaneous (erythema, rash, urticaria/angioedema); 2, cardiovascular (hypotension, tachycardia); 3, respiratory (bronchospasm,
increased airway resistance, breathlessness).

observed regarding the type of allergy and its etiology. During 7 had had at least 2 previous operations, 1 had had 1 operation,
the induction phase, the allergic mechanism was confirmed and 2 (numbers 20 and 25 in Tables 3 and 4) had never
in 19 out of 30 cases, which is slightly higher than the global undergone surgery. Interestingly, these last 2 cases were
mean (63% vs. 56%), although not statistically significant. Skin children, a girl aged 7 and a boy aged 9.
testing confirmed that allergic reactions to antibiotics were
predominant (11/19), followed by NMBA (6/19), and 2 isolated
cases of latex and Echinococcus. During the maintenance Discussion
phase, the allergic mechanism was only confirmed in 2 patients
(latex and NMBA) out of 5 studied cases (40%). During the Few studies have analyzed adverse reactions to general
recovery phase, the number rose to 6 out of 11 (54%) and anesthetics in Spain [8] and the incidence is currently
the drugs were NMBA (3), dipyrone (2), and cefazolin (1). unknown.
Interestingly, 2 of these reactions were caused by an NSAID, Previous studies have demonstrated the usefulness of skin tests
namely, magnesium dipyrone. to confirm allergy to NMBA, antibiotics, and other drugs [12,13].
Allergy to antibiotics was confirmed in 12 out of 48 In our study, the diagnosis of an allergic or nonallergic reaction
cases: 10 with betalactams, 6 with cephalosporins, and 4 with was made by skin tests, IgE determination, or both.
penicillins. The age range of the present series is wide (7-86 years),
Of the 10 patients with confirmed allergy to NMBA (21%), with a higher percentage of females (63%), which is consistent

© 2008 Esmon Publicidad J Investig Allergol Clin Immunol 2008; Vol. 18(5): 350-356
355 T Lobera, et al

with previous reports [3,4]. An IgE-mediated allergic reaction If we look at those cases with 3 or more previous operations
was confirmed in 56% of patients, also consistent with previous separately, a higher proportion of allergy is detected than in the
reports [7,8,14]. rest of the cases (3 out of 4 studied were positive). These results
Generally, reactions were predominant in the induction and coincide with previous reports [7] regarding the number of
recovery phases, and manifested mainly as cutaneous symptoms. operations as a risk factor for allergy. In children, drug allergy
Reactions to drugs coincide with the phases when they were is not common [27], although we found 2 cases of skin allergic
administered. Reactions to antibiotics were more frequent in reaction to NMBAs. These results agree with the results of a
the induction phase, NMBA in the initiation and maintenance 12-year survey at a French pediatric center [28]. However, these
phases, and the NSAID (dipyrone) in the recovery phase. 2 cases had no previous history of surgical intervention.
We found differences regarding the etiological agents: NSAIDs, and more specifically pyrazolone derivatives, are
in most studies, NMBA are the most frequent followed by uncommonly reported as causal agents of anaphylaxis during
latex [7,15-17]; however, in our study, betalactam antibiotics surgery. We found 2 cases, both during the recovery phase;
caused 44% of allergic reactions and NMBA caused 37% of this is consistent with the high consumption of pyrazolones in
allergic reactions. In previous case studies, reactions to antibiotics Spanish hospitals. These 2 patients tolerated oral challenge tests
could have been underdiagnosed, since prophylaxis was with other nonpyrazolone-derivative NSAIDs (indomethacin
administered in the patient’s room immediately before the patient and aspirin). The use of dipyrone is controversial.
was taken to the operating room, where the reaction developed. Another unusual finding is IgE-mediated anaphylaxis
The most frequently involved antibiotics were within the context of a hydatid cyst operation due to
cephalosporins. We believe that the predominance of sensitization to Echinococcus. It is known that this condition
cephalosporin allergy is due to their widespread use in the is highly dependent on the geographic origin of the patient and
context of general anesthesia. In the general population in Spain, it is endemic in some areas of Spain [29,30].
however, allergy to aminopenicillins is predominant [18]. Finally, we were unable to confirm a high yield for serum
Penicillin and other betalactams are also considered to be tryptase determination, which was only positive in 4 out of 22
emerging antigens [19], and antibiotic therapy occupies the patients who underwent testing. An allergic cause of the reaction
third cause of anaphylaxis and could increase [7,20]. was confirmed in 3. The low sensitivity of the test in this series
Latex caused allergic reactions in only 2 cases. In 2003, may be due to the fact that in 19 out of 22 cases, only a single
Dybendal et al [21] reported 1 out of 18 cases induced by latex. first determination was performed, at the time of the reaction.
This and other reports show that the incidence of latex allergy Therefore, levels were still low. Unfortunately, in most cases, the
is decreasing [3,7]. second extraction was not performed, due to lack of coordination
As for curare derivative drugs (NMBA), some intradermal between the different departments of the hospital.
tests could be irritative due to nonspecific histamine release To conclude, we would like to stress the importance of
or a result of the direct vasodilating effects [22], so that the carrying out an allergy study to detect an allergic cause in
interpretation of the cutaneous response could be difficult. more than 50% of the perioperative reactions studied. This
Although some studies note that a high percentage of is of paramount importance, since allergic reactions are the
the control subjects had a positive prick test to undiluted main causes of morbidity and mortality during anesthesia
NMBA [23], our previous controls did not react to undiluted and the postoperative period [6]. Our study also highlights the
NMBA, except for mivacurium and atracurium, which were importance of drugs such as antibiotics and NSAIDs, which
tested at a dilution of 1:10. The highest concentration used for play a vital role in perianesthetic allergic reactions and can be
our intradermal tests is similar to that suggested elsewhere [22]. used again outside the operation room.
None of our patients diagnosed as allergic to NMBA reacted
to the prick test, although they all reacted at different
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