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Lidocaine as a Rare and Hidden Allergen in the Perioperative Setting: A Case Report

Kvisselgaard, Ask D. BSc*; Melchiors, Birgitte B. MD*,†; Krøigaard, Mogens MD*; Garvey, Lene H. PhD, MD*,‡

doi: 10.1213/XAA.0000000000000955
Case Reports

Local anesthetics are used throughout the health care system. In the perioperative setting and in other settings of exposure to local anesthetics, true allergy is reported very rarely. We present an unusual case of immediate-type perioperative hypersensitivity to lidocaine with cross-reaction to mepivacaine, which was missed on initial investigation. This case illustrates that lidocaine may be a “hidden allergen” in the perioperative setting and should always be considered a potential culprit in cases of suspected perioperative hypersensitivity. The case also demonstrates that suspected perioperative hypersensitivity requires highly specialized investigation and close collaboration between allergists and anesthesiologists.

From the *Danish Anaesthesia Allergy Centre, Allergy Clinic, Department of Dermatology and Allergology, Herlev and Gentofte Hospital, University of Copenhagen, Denmark

Department of Neuroanaesthesia, Rigshospitalet, University of Copenhagen, Denmark

Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Accepted for publication November 19, 2018.

Funding: Departmental.

The authors declare no conflicts of interest.

Address correspondence to Ask D. Kvisselgaard, BSc, Allergy Clinic UA-816GE, Gentofte Hospital, Kildegårdsvej 28, DK-2900 Hellerup, Denmark. Address e-mail to

Perioperative hypersensitivity is very rare and estimated to occur in the range of 1:353 to 1:18,600 anesthetics.1 The prevalence of immediate-type allergy to local anesthetics is also very low, reported to be <1% of suspected allergic reactions to local anesthetics.2 A recent study of patients with suspected perioperative hypersensitivity exposed to local anesthetics failed to identify any cases of local anesthetics allergy over a 10-year period.3 Local anesthetics are used throughout the health care system in many different formulations. Lubricating gels and sprays often contain local anesthetics, but use is rarely documented in the medical charts, making local anesthetics potential “hidden allergens.” Adverse drug reactions to local anesthetics are most commonly associated with nonallergic causes such as relative overdose, vasovagal reactions, or symptoms elicited by the vasoconstrictor.4

We present a rare case of perioperative hypersensitivity to lidocaine, which was missed on initial investigation due to undocumented exposure. Written consent was obtained from the patient before the investigation and submission of the case report.

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A 63-year-old woman was referred to the Danish Anaesthesia Allergy Centre for investigation after anaphylaxis during computer-assisted functional endoscopic sinus surgery. Previous surgery and anesthesia had been uneventful. Her past medical history included hypothyroidism, hypertension, and aspirin-induced asthma with concomitant rhinosinusitis and nasal polyps giving the indication for sinus surgery. Past allergy history included urticaria, pruritus, and respiratory distress in connection with chemotherapy with docetaxel and asymptomatic sensitization to grass pollen. On the day of computer-assisted functional endoscopic sinus surgery, anesthesia was induced with propofol, fentanyl, and rocuronium, and she developed moderate bronchospasm within minutes of induction. Symptoms were initially attributed to inadequate depth of anesthesia and hyperreactive airways. Dexamethasone was administered together with bolus doses of propofol and alfentanil, and she was intubated uneventfully. Shortly after intubation, she developed severe hypotension (40/25 mm Hg), tachycardia (120 beats/minute), increased peak airway pressures (37 cm H2O), and generalized erythema. There was no decrease in the peripheral oxygen saturation during the procedure. Phenylephrine 0.5 mg IV and inhaled terbutaline 10 mg were administered without effect. Anaphylaxis was suspected, and the patient improved after treatment with epinephrine 20 μg × 2 IV + 0.5 mg intramuscular and isotonic saline 1500 mL followed by clemastine 2 mg IV. The surgical procedure was canceled, and neuromuscular blockade was reversed. There were no further complications, and she was discharged the following day.

Anaphylaxis was considered likely because serum tryptase was 8.63 μg/L 2 hours after the reaction, a relevant increase when compared to a later baseline serum tryptase of 1.61 μg/L. A clinically relevant increase in tryptase is confirmed when reaction tryptase >(baseline tryptase × 1.2) + 2.5

She was referred for investigation at the Danish Anaesthesia Allergy Centre, the Danish national reference center for the investigation of perioperative hypersensitivity. The standardized investigations in the Danish Anaesthesia Allergy Centre comprise skin tests (skin prick test and intradermal test), in vitro tests (specific immunoglobulin E and histamine release test), and drug provocation tests. All drugs and substances reported to be used before the reaction are investigated. All patients are tested with chlorhexidine, latex, ethylene oxide, and excipients (macrogols/methyl celluloses) because exposure to these substances is highly likely in the perioperative setting in Denmark. Drugs are investigated if given intravenously within an hour before the reaction and if given within 2 hours before the reaction for all other administration routes.6–8

The referral letter reported use of alfentanil, fentanyl, propofol, and rocuronium before the reaction. Initial investigations in the Danish Anaesthesia Allergy Centre were all negative. They included specific immunoglobulin E for chlorhexidine, ethylene oxide, latex, and rocuronium; skin prick test with latex and macrogols; skin prick test and intradermal test with alfentanil, fentanyl, propofol, and rocuronium; and drug provocation test with alfentanil, fentanyl, propofol, and rocuronium (see Table 1 for details).

Table 1.

Table 1.

However, the patient presented with clinical anaphylaxis and elevated tryptase at the time of reaction, suggestive of an immunoglobulin E-mediated immediate-type allergy. It was therefore suspected that an allergen had been overlooked.

The anesthesiologist who had performed the anesthetic was contacted and asked to report all possible exposures, including any not documented in the charts. The following additional exposures were reported to have occurred before the anaphylactic reaction: dexamethasone IV, eye ointment with paraffin oil, nasal administration of lidocaine/phenylephrine drops, and use of the lidocaine-containing product Instillagel for lubrication of the endotracheal tube before intubation. Investigations were extended to include testing with these potential culprits, that is, dexamethasone, lidocaine, eye ointment, lidocaine/phenylephrine nasal drops, Instillagel, phenylephrine, and their excipients povidone, mannitol, and benzalkonium chloride.

As shown in Table 1, all tests for dexamethasone, phenylephrine, eye ointment, and excipients were negative. However, skin prick test with lidocaine/phenylephrine nasal drops and with Instillagel, containing lidocaine, yielded clearly positive results. Undiluted lidocaine also showed clearly positive skin prick test (6 × 6 mm) and intradermal test with a 1:100 diluted lidocaine induced a 10 × 10 mm wheal. Due to the risk of a systemic reaction, intradermal test with 1:10 dilution and undiluted lidocaine was not performed (see Table 2).

Table 2.

Table 2.

Because the patient needed to be rescheduled for computer-assisted functional endoscopic sinus surgery, cross-reactivity testing was conducted to find safe alternative local anesthetics. All skin tests and subcutaneous drug provocation tests were negative for bupivacaine, ropivacaine, articaine, prilocaine, and cocaine. Skin prick test with undiluted mepivacaine induced a 4 × 5 mm wheal, and intradermal test with 1:10 dilution induced a 10 × 11 mm wheal; thus, cross-reactivity to mepivacaine was concluded.

In the Danish Anaesthesia Allergy Centre, an allergy is confirmed when the clinical history suggests perioperative hypersensitivity with or without an elevated serum tryptase, the timing of administration of the drug is consistent with the reaction, all other drug tests are negative, and ≥2 tests are positive for the suspected drug.7,8 In this case, skin prick test and intradermal test were clearly positive for lidocaine and mepivacaine, and subcutaneous provocation was deemed unnecessary.

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We present a very rare case of immediate-type perioperative allergy to lidocaine with cross-reaction to mepivacaine. Recent studies have pointed out that allergy to local anesthetics is extremely rare in the perioperative setting and in other settings of exposure to local anesthetics.3,9 A literature search identified 23 case reports worldwide since 1993, and of those, only 7 report convincing evidence of immediate-type allergy to local anesthetics on testing.10–16 Due to the rarity of these cases, cross-reactivity in immediate-type allergy to local anesthetics is not well characterized. Two case reports identified mepivacaine as the culprit drug with cross-reactivity on intradermal test to lidocaine and bupivacaine or lidocaine and ropivacaine, respectively.10,17 Cuesta-Herranz et al12 also showed cross-reactivity between lidocaine and mepivacaine confirmed by skin tests and subcutaneous provocation. This suggests that cross-reactions can occur within the amide local anesthetics group, while all patients tolerated testing with local anesthetics from the ester group. Cross-reactivity between the ester and amide subgroups has not been described for immediate-type allergy, and this may be due to differences in metabolism.18

The importance of testing for other simultaneous exposures in patients with suspected allergic reactions during procedures in local anesthetics has been emphasized.4 Other drugs and substances, for example, antibiotics or “hidden allergens” such as chlorhexidine, latex, and excipients are in fact more likely culprits.9,19 In this case, the local anesthetics presented as the “hidden allergen” due to undocumented exposures being overlooked during initial investigations. Local anesthetic is present in many lubricating gels or sprays used for endoscopy, catheterization, or endotracheal intubation. These substances are thus used very frequently in the health care setting, but rarely documented on charts.

The perioperative setting is extremely complex with a combination of the effects of anesthetic drugs, the surgical procedure, and multiple exposures to drugs and other substances, some of which unfortunately go undocumented. This case illustrates the need for documentation of all perioperative exposures, however small, especially in cases of perioperative anaphylaxis. In addition, it illustrates the need for highly specialized investigations of suspected perioperative anaphylaxis in allergy centers with close collaboration between allergists and anesthesiologists.20 Substandard investigations, overlooking allergens or guessing the culprit, may put the patient’s life at risk through unfortunate reexposures to the allergen.

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Name: Ask D. Kvisselgaard, BSc.

Contribution: This author helped write the manuscript.

Name: Birgitte B. Melchiors, MD.

Contribution: This author helped care for the patient and review the manuscript.

Name: Mogens Krøigaard, MD.

Contribution: This author helped care for the patient and review the manuscript.

Name: Lene H. Garvey, PhD, MD.

Contribution: This author helped care for the patient and review the manuscript.

This manuscript was handled by: BobbieJean Sweitzer, MD, FACP.

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