The paper presented during the 8th Polish ESRA Zonal Symposium, Wisła 27-29 May 2010

Adverse effects of local anaesthetics (LAs) are observed in everyday practice of anaesthesiologists, dentists, laryngologists and surgeons, which is associated with their common use and lack of standards of diagnostic management (particularly of prognostic nature) and effective monitoring of post-drug reactions.

Due to the nomenclature-related differences, any unanticipated reaction to LA is defined as an allergy. According to the European Academy of Allergology and Clinical Immunology (EAACI), objectively reproducible symptoms, initiated by exposure to a stimulus in the dose tolerated by healthy individuals, should be considered as hypersensitivity [1] whereas the term “allergy” confined to hypersensitivity reactions triggered by specific immune mechanisms, as opposed to non-allergic hypersensitivity, which develops due to other non-immune causes (Fig.1) [1]. 

The most severe form of hypersensitivity is anaphylaxis − severe, life-threatening generalized or systemic reaction which is divided into allergic (documented involvement of immune mechanisms) and non-allergic (earlier defined as anaphylactoid reaction) [1].

Allergic hypersensitivity constitutes less than 1% of all adverse reactions to LAs [2]. It can be immediate − initiated by IgE (type 1) and delayed − T cell-mediated reactions (type 4). To date, involvement of type 2 and 3 immune reactions in the development of LA hypersensitivity, according to Gell and Coombs, has not been described [2, 3, 4].

The first symptoms of IgE-dependent reaction occur within 30 min after LA administration and most commonly include skin symptoms accompanied by respiratory, gastrointestinal and cardiovascular symptoms leading to the life-threatening condition – anaphylactic shock [5]. Moreover, the late phase of immediate reaction in IgE allergy has been described, which develops several hours after exposure [2].

Cell-mediated mechanisms are triggered by direct contact of LAs with the skin surface or mucous membranes. Single cases of such reactions have also been reported after subcutaneous or submucosal administration of LAs. They cause contact skin inflammation, exceptionally oedema at the injection site [4, 6, 7]. These are delayed reactions; clinical symptoms develop after 48 h, although in cases of LAs they may occur earlier, even after 2 h [2].

Local anaesthesia is associated with hypersensitivity not only to the anaesthetics themselves but also to the preservatives in them – parabens, sulphites, latex and nickel or antiseptic agents [2, 8]. Nickel may be released from the needles whereas the potential sources of latex are mainly vials and cartridges with local anaesthetics, syringe knobs and gloves.

The aim of the study was to determine the cause and to optimize diagnostic management in patients referred for allergologic consultation due to suspected allergy to local anaesthetics. 

METHODS

The study involved patients with LA-related adverse reactions tested. In all patients history and comprehensive allergologic evaluation were carried out (Fig. 2). 

Skin tests and their interpretation were carried out according to the EAACI recommendations; in patch tests, the guidelines of the Standardization Group of the International Society for Contact Dermatitis were additionally considered.

Prick tests were performed first. If their results were negative or doubtful, intradermal and epidermal patch tests were carried out. The results of prick tests were read after 15 and 30 min, of intradermal tests after 30 min and 24 h (possible delayed reactions). Epidermal patch test findings were assessed after 24, 48 and 72 h. The suspicion of LA hypersensitivity was finally excluded based on negative results of provocative tests. In all patients, concentrations of serum IgE against latex proteins were determined using ELISA.

The diagnostics was carried out between 4 weeks and 5 months after the occurrence of post-drug reactions.

RESULTS

The study involved 32 patients (24 females and 8 males) aged 22-56 years. In all cases, the referring physician diagnosed or suspected the LA allergy. No detailed descriptions of the post-drug adverse reactions or treatment were available. Only in 1 case, the proprietary name of the drug was mentioned, in 25 cases, the international name was given; in the remaining cases, the cause was generally defined as LA (thus analysis of effects of preservatives or additional drugs, e.g. adrenaline, was not possible).

In 29 patients, adverse effects occurred immediately after administration of the agent (skin redness, palpitations, dyspnoea, sudden elevation or drop in blood pressure, fainting). The skin symptoms (pruritus, urticaria and vasculomotor oedema), typical of anaphylaxis, developed in 4 patients. Three patients reported late symptoms, i.e. pruritus, urticaria and vasomotor  angioneurotic oedema, several hours after LA administration

The diagnostic procedures enabled to detect allergic hypersensitivity only in 3 patients. In one, IgE-dependent allergic hypersensitivity to lignocaine was found: prick skin tests showed the wheal, 3 mm in diameter whereas intradermal tests revealed extensive irregular oedema (“pseudopodlia”) accompanied by skin pruritus and urticaria; the results of skin tests for bupivacaine and mepivacaine were negative. The lack of hypersensitivity to the drugs mentioned was confirmed by negative results of provocative tests. In this patient, symptoms of generalized urticaria with intensive pruritus and decreased arterial pressure were already observed during lignocaine block anaesthesia, which resulted in discontinuation of drug administration.

In 2 patients, positive patch tests were found. In one of them, a strong response to lignocaine and extremely strong response to nickel were observed. The patient reported face angioneurotic oedema and palm pruritus several hours after LA administration. The symptoms occurred twice, each time after anaesthesia; moreover, the patient complained of recurrent urticaria after the intake of nickel-containing foods. The second case revealed late hypersensitivity to preservatives – a strong reaction to parabens. In this patient, redness and intensified skin pruritus developed immediately after anaesthesia whereas the symptoms of urticaria occurred on day 2. In the past, the patient underwent several consultations due to skin lesions whose increase was observed after the intake of preserved or long-life food products.

In one patient, the provocative test was positive: 24 h after subcutaneous administration of lignocaine the symptoms of urticaria were observed despite negative results of skin tests.

IgE specific antibodies against latex allergens were not found in any of the patients.

DISCUSSION

Allergy to LAs is rare. Adverse effects related to their use are much more commonly caused by other factors. The majority of publications addressing allergy to local anaesthetics emphasize that diagnostics of adverse reactions is mainly to exclude rather than confirm the allergy [9]. Low incidence rates of allergies should incline to use the term “hypersensitivity to local anaesthetics”. The terminology suggested by EAACI is useful in everyday practice, as the physician diagnosing LA hypersensitivity does not have to decide whether the symptoms are caused by immune mechanisms until allergologic diagnostics has been carried out.

The assessment of side effects developing during local anaesthesia should also include some other factors, which are likely to mimic the hypersensitivity reaction (toxic actions, effects of simultaneous administration of adrenaline, vasovagal syncope, anxiety reactions or hyperventilation syndrome). In uncertain cases, the serum sample should be collected for tryptase determinations (preferably within 2 h after the onset of symptoms). Increased tryptase level may help in retrospective diagnosis of anaphylaxis, without differentiation of allergic and non-allergic hypersensitivity, as tryptase is the marker of mast-cell degranulation activated immunologically or non-immunologically.

Hypersensitivity should also be differentiated from the toxic reaction developing once the tolerated dose is exceeded (relative and absolute overdose) or resulting from pharmacological properties of the drug.

Medical history is essential for hypersensitivity diagnostics. The relation between anaphylactic symptoms and a given substance may be so explicit that diagnostic tests will be unnecessary (in many cases even dangerous) [10]. The retrospective evaluation based only on the history data, however, may be associated with subjective errors resulting from the anxiety accompanying patients in such situations. The access to medical records is extremely helpful for a consulting allergologist as they contain objective evaluation of clinical symptoms of the post-drug reaction and basic vital parameters of patients with abnormal reactions to local anaesthetics.

Our study findings indicate that delayed allergic reactions are likely to develop. In some patients, such reactions did not result from the exposure to local anaesthetics themselves but were caused by other factors (nickel and preservatives contained in them). The positive result of provocative test in the patients with negative skin test results has to be explained.  It is known that provocative tests are a ”golden standard” in the diagnostics of hypersensitivity to local anaesthetics; however, they do not differentiate allergic and non-allergic reactions. Therefore, it may be assumed that in the case in question, the development of symptoms resulted from non-immune mechanisms, which might have been initiated by non-allergic hypersensitivity to preservatives, more so as the patients had the history of skin changes after wine and dry fruits and preservatives might have acted immunologically and non-immunologically. The cases described justify the pre-LA administration questions concerning tolerance to food products rich in preservatives.

In our material, skin symptoms, the most characteristic of anaphylaxis, were observed in 7 patients, in 4 of them allergic hypersensitivity was demonstrated. In the remaining cases, allergic and non-allergic hypersensitivity was excluded based on provocative tests (which were likely to be carried out using the agent the patient did not receive in the past - no suitable information in the referral). Moreover, in some cases the development of anaphylactic symptoms might have resulted from simultaneous action of two factors [8]. The experiences with other drugs also demonstrate that T lymphocyte-dependent reactions do not always recur due to lack of appropriate co-stimulation during re-exposure [11].

The diagnostic management of post-drug reactions should also consider the allergy to latex. The particularly high-risk group includes health care and gum industry workers as well as patients undergoing numerous medical procedures. In our material, no such cases were found.

Although LA allergies are extremely rare, once adverse effects occur they should be meticulously diagnosed. Thanks to that, the development of generalized life-threatening anaphylactic reaction can be avoided and a given method of anaesthesia does not have to be unnecessarily abandoned. The recognition of some other causes of allergic hypersensitivity (e.g. to sulphites or parabens) suggests the use of a local anaesthetic without a particular preservative.

In future, the incidence of LA reactions is likely to increase due to increasingly wide use of local anaesthetics and more frequent re-exposure to agents of similar chemical structures.    

CONCLUSION

Full diagnostics of hypersensitivity to local anaesthetics should involve reviews of  medical records and tests assessing immediate and delayed reactions to the preparation itself, its components and other agents of the anaesthetic procedure.

..............................................................................................................................................................

REFERENCES

1.    Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haahtela T, Kowalski ML, Mygind N, Ring J, van Cauwenberge P, van Hage-Hamsten M, Wüthrich B: A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy 2001; 56: 813-824.

2.    Thyssen JP, Menné T, Elberling J, Plaschke P, Johansen JD: Hypersensitivity to local anaesthetics – update and proposal of evaluation algorithm. Contact Dermatitis 2008; 59: 69-78.

3.    Khan DA, Solensky R: Drug allergy. J Allergy Clin Immunol 2010; 125: 126-137.

4.    Redfern DC: Contact sensitivity to multiple local anesthetics. J Allergy Clin Immunol 1999; 104: 890-891.

5.     Węgrzyn D. Kolasa A, Kutwin-Chojnacka A, Węgrzyn W, Przybylski W: Znieczulenie podpajeczynówkowe do cięcia cesarskiego powikłane wstrząsem neurogennym – opis przypadku. Anest Inten Terap 2006; 38: 80-82.

6.    Breit S, Ruëff F, Przybilla B: ‘Deep impact’ contact allergy after subcutaneous injection of local anesthetics. Contact Dermatitis 2001; 45: 296-297.

7.    Whalen JD, Dufresne RG Jr: Delayed-type hypersensitivity after subcutaneous administration of amide anesthetic. Arch Dermatol 1996; 132: 1256-1257.

8.    Parkes AW, Harper N, Herwadkar A, Pumphrey R: Anaphylaxis to the chlorhexidine component of Instillagel(R): a case series. Br J Anaesth 2009; 102: 65-68.

9.    Brockow K, Romano A, Blanca M, Ring J, Pichler W, Demoly P: General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 2002; 57: 45-51.

10.    Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, Bernstein JA, Burks AW, Feldweg AM, Fink JN, Greenberger PA, Golden DB, James JM, Kemp SF, Ledford DK, Lieberman P, Sheffer AL, Bernstein D, Blessing-Moore J, Cox L, Khan DA, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph C, Schuller DE, Spector SL, Tilles S, Wallace D: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126: 477-480.

11.    Schnyder B, Frutig K, Mauri-Hellweg D, Limat A, Yawalkar N, Pichler WJ: T-cell-mediated cytotoxicity against keratinocytes in sulfamethoxazol-induced skin reaction. Clin Exp Allergy 1998; 28: 1412-7.
..............................................................................................................................................................

address:

*Alicja Grzanka
Katedra i Oddział Kliniczny Chorób Wewnętrznych,
Dermatologii i Alergologii w Zabrzu
Śląski Uniwersytet Medyczny w Katowicach
ul. M. Curie-Skłodowskiej 10, 41-800 Zabrze,
tel. +48 32 271 31 65,
e-mail: alicjag@mp.pl

received: 27.08.2010
accepted: 01.10.2010