I have a patient with severe anaphylaxis (tryptase 96) perioperative. In the recovery room he experienced severe bronchospasm without urticaria. During the surgery he received Tracrium (atracurium), propofol, cefazolin, neostingmin. All of the testing including ID were negative, even so also Latex. There was no use of gelatins. Did not test diclofenac because of the rarity of ig E mediated reactions. Summary: I have no clue on what happened. What is your policy? Can NSAID reactions (time course seems possibly) cause high tryptase concentrations?


Thank you for your inquiry.

I think you have done due diligence in regards to your pursuit of the cause of your patient’s anaphylactic episode, and I do not think there is anything else that you could do further to establish the cause unless you wished to pursue testing to diclofenac. However, as you mentioned, the existence of IgE-mediated reactions to diclofenac has been challenged, and certainly such reactions, as you said, are rare. However, should you wish to pursue diclofenac, I have copied for you below three references which would help you do so. The PLoS One 2010 reference by Harrer A, et al., would be especially helpful to you in this regard.

In addition, just for the sake of completeness, and to make sure the correct skin test concentrations were used in your evaluation of the patient, there is a previous entry to our website that you might find helpful.

Anaphylaxis during anesthesia” - posted 3/6/2013

I have also copied for you below references which will give you the correct skin test concentrations for neostigmine and atracurium.

However, assuming that the correct skin test concentrations were used and the reaction was not due to diclofenac, all reasonable conclusions, as mentioned, you have done due diligence. But there is one other point that should be made. Unexplained anaphylaxis during anesthesia documented by a markedly elevated tryptase suggests that the individual involved may have underlying mastocytosis. For your interest, I have also copied below a case report of a patient very similar to yours. Thus I think it is important that you evaluate your patient for mastocytosis. I would suggest obtaining a baseline (asymptomatic) serum tryptase, waiting at least six weeks after the event. If it is elevated, you should pursue the diagnosis further with a bone marrow.

Thank you again for your inquiry and we hope this response is helpful to you.

Clin Exp Allergy. 2010 Jan;40(1):15-31. doi: 10.1111/j.1365-2222.2009.03404.x.
BSACI guidelines for the investigation of suspected anaphylaxis during general anaesthesia.
Ewan PW, Dugué P, Mirakian R, Dixon TA, Harper JN, Nasser SM; BSACI.
Allergy Clinic, Cambridge University NHS Foundation Trust, Cambridge, UK.
Investigation of anaphylaxis during general anaesthesia requires an accurate record of events including information on timing of drug administration provided by the anaesthetist, as well as timed acute tryptase measurements. Referrals should be made to a centre with the experience and ability to investigate reactions to a range of drug classes/substances including neuromuscular blocking agents (NMBAs) intravenous (i.v.) anaesthetics, antibiotics, opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), local anaesthetics, colloids, latex and other agents. About a third of cases are due to allergy to NMBAs. Therefore, investigation should be carried out in a dedicated drug allergy clinic to allow seamless investigation of all suspected drug classes as a single day-case. This will often require skin prick tests, intra-dermal testing and/or drug challenge. Investigation must cover the agents administered, but should also include most other commonly used NMBAs and i.v. anaesthetics. The outcome should be to identify the cause and a range of drugs/agents likely to be safe for future use. The allergist is responsible for a detailed report to the referring anaesthetist and to the patient's GP as well as the surgeon/obstetrician. A shorter report should be provided to the patient, adding an allergy alert to the case notes and providing an application form for an alert-bracelet indicating the wording to be inscribed. The MHRA should be notified. Investigation of anaphylaxis during general anaesthesia should be focussed in major allergy centres with a high throughput of cases and with experience and ability as described above. We suggest this focus since there is a distinct lack of validated data for testing, thus requiring experience in interpreting tests and because of the serious consequences of diagnostic error.

Chem Immunol Allergy. 2010;95:180-9. doi: 10.1159/000315951. Epub 2010 Jun 1.
Anaphylaxis to general anesthetics.
Moneret-Vautrin DA, Mertes PM.
Department of Internal Medicine, Clinical Immunology and Allergology, Nancy, France.
The incidence of hypersensitivity reactions to anesthetics is estimated 1 in 13,000 anesthetics up to 1 in 3,180. The rate of mortality ranges between 3 and 9%. 90% of reactions appear at anesthesia induction. Cardiovascular collapse and bronchospasm are more frequent in IgE-dependent reactions. The leading causes are neuromuscular blocking agents (50-70% of cases). IgE-dependent reactions are predominant. Previous sensitization by other compounds containing quaternary ions is suspected. Cross-reactions are frequent. Latex allergy is the second cause, followed by antibiotics and beta-lactams in general. The incidence of anaphylaxis to vital dyes and chlorhexidine increases. Anaphylaxis to intravenous hypnotics, plasma substitutes, aprotinin, protamine and other drugs can occur. Any suspected hypersensitivity reaction during anesthesia must be extensively investigated to confirm the nature of the reaction, to identify the responsible drug, to study cross-reactivity in cases of anaphylaxis to a neuromuscular blocking agent and to provide recommendations for future anesthetic procedures. Tryptase assay at the time of the reaction has to be implemented by thorough investigations carried out weeks later: prick tests and intradermal tests, quantification of specific IgE to compounds containing quaternary ammonium ions, histamine release test or cytometric analysis of basophile activation.

Anesthesiology. 2007 Aug;107(2):245-52.
Skin reactions to intradermal neuromuscular blocking agent injections: a randomized multicenter trial in healthy volunteers.
Mertes PM, Moneret-Vautrin DA, Leynadier F, Laxenaire MC.
Department of Anesthesiology, Service d'Anesthésie-Réanimation, Hôpital Central, Centre Hospitalier Universitaire de Nancy, Unité Inserm 684, Faculté de Médecine de Nancy, France.
Background: Numerous reports confirm the performance of intradermal tests for the diagnosis of anaphylaxis during anesthesia; however, there is controversy over their diagnostic value regarding the newer neuromuscular blocking agents (NMBAs).
Methods: One hundred eleven healthy volunteers were randomly assigned to receive intradermal injections of two NMBAs, at five increasing concentrations. A concentration was considered as a reactive concentration when it led to a positive reaction in more than 5% of the subjects. These concentrations were compared with the maximal concentration recommended for the diagnosis of sensitization to NMBAs.
Results: The maximal nonreactive concentrations were 10 m for suxamethonium; 10 m for pancuronium, vecuronium, rocuronium, and cisatracurium; and 10 m for atracurium and mivacurium. Except for mivacurium, these nonreactive concentrations were close to the maximal concentrations used for the diagnosis of sensitization against NMBAs. For mivacurium, the nonreactive concentrations were higher than the maximal concentration currently recommended in clinical practice.
Conclusion: The aminosteroidal NMBAs pancuronium, vecuronium, and rocuronium and the benzylisoquinoline cisatracurium have a similar potency to induce a nonspecific skin reactivity. If the criteria for positivity and the maximal concentrations of the commercially available compounds recommended by French practice guidelines are used, the risk of false-positive results is limited, and only minor modifications of these recommendations could be suggested. A slight reduction in the maximal concentration used for rocuronium from 1:100 to 1:200 and an increase from 1:1,000 to 1:200 for mivacurium can be proposed.

Anaesthesia. 2000 Jun;55(6):574-5.
Anaphylaxis caused by neostigmine.
Seed MJ, Ewan PW.
Clinic 2A, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
A patient developed anaphylaxis during anaesthesia, towards the end of surgery, 30 s after intravenous administration of neostigmine. Anaphylaxis to neostigmine was confirmed by demonstrating an elevated mast cell tryptase and a strongly/positive skin prick test, showing the presence of drug-specific IgE (skin prick tests to neostigmine were negative in normal subjects). This is a rare cause of anaphylaxis during anaesthesia.

Indian J Crit Care Med. 2011 Jan;15(1):37-9. doi: 10.4103/0972-5229.78222.
Anaphylactic reaction to intravenous diclofenac.
Singh R, Bansal D, Baduni N, Vajifdar H.
Department of Anesthesiology and Critical Care, Lady Hardinge Medical College & Associated Hospitals, New Delhi - 110 001, India.
Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used as an opioid sparing agent for postoperative analgesia. Anaphylaxis due to intravenous diclofenac sodium is very rare. We report a case of anaphylactic reaction to IV diclofenac sodium, occurring postoperatively in a 25-year-old primigravida, the clinical features of which mimicked pulmonary embolism. The rarity, clinical importance and the diagnostic dilemma associated prompted us to report this case.

Anadolu Kardiyol Derg. 2011 Feb;11(1):88-9. doi: 10.5152/akd.2011.017. Epub 2011 Jan 11.
Acute coronary syndrome due to diclofenac potassium induced anaphylaxis: two Kounis syndrome variants in the same patient.

Cakar MA, Gündüz H, Kocayiðit I, Binak DF, Vatan MB, Tamer A
PLoS One. 2010 Oct 28;5(10):e13707. doi: 10.1371/journal.pone.0013707.

Diclofenac hypersensitivity: antibody responses to the parent drug and relevant metabolites.
Harrer A, Lang R, Grims R, Braitsch M, Hawranek T, Aberer W, Vogel L, Schmid W, Ferreira F, Himly M.
Division of Allergy and Immunology, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
Background: Hypersensitivity reactions against nonsteroidal antiinflammatory drugs (NSAIDs) like diclofenac (DF) can manifest as Type I-like allergic reactions including systemic anaphylaxis. However, except for isolated case studies experimental evidence for an IgE-mediated pathomechanism of DF hypersensitivity is lacking. In this study we aimed to investigate the possible involvement of drug- and/or metabolite-specific antibodies in selective DF hypersensitivity.
Methodology/Principal Findings: DF, an organochemically synthesized linkage variant, and five major Phase I metabolites were covalently coupled to carrier proteins. Drug conjugates were analyzed for coupling degree and capacity to crosslink receptor-bound IgE antibodies from drug-sensitized mice. With these conjugates, the presence of hapten-specific IgE antibodies was investigated in patients' samples by ELISA, mediator release assay, and basophil activation test. Production of sulfidoleukotrienes by drug conjugates was determined in PBMCs from DF-hypersensitive patients. All conjugates were shown to carry more than two haptens per carrier molecule. Immunization of mice with drug conjugates induced drug-specific IgE antibodies capable of triggering mediator release. Therefore, the conjugates are suitable tools for detection of drug-specific antibodies and for determination of their anaphylactic activity. Fifty-nine patients were enrolled and categorized as hypersensitive either selectively to DF or to multiple NSAIDs. In none of the patients' samples evidence for drug/metabolite-specific IgE in serum or bound to allergic effector cells was found. In contrast, a small group of patients (8/59, 14%) displayed drug/metabolite-specific IgG.
Conclusions/Significance: We found no evidence for an IgE-mediated effector mechanism based on haptenation of protein carriers in DF-hypersensitive patients. Furthermore, a potential involvement of the most relevant metabolites in DF hypersensitivity reactions could be excluded.

Can J Anaesth. 2011 May;58(5):456-9. doi: 10.1007/s12630-011-9472-z. Epub 2011 Feb 24.
Case Report: perioperative immediate hypersensitivity involves not only allergy but also mastocytosis.
Renauld V, Goudet V, Mouton-Faivre C, Debaene B, Dewachter P.
Department of Anesthesia and Intensive Care, University Hospital, Poitiers, France.
Purpose: We report a case of drug-induced immediate hypersensitivity occurring after atracurium injection in a patient with cutaneous mastocytosis.
Clinical Features: A 69-yr-old woman was scheduled for hysterectomy. She was premedicated with hydroxyzine, and anesthesia was induced with sufentanil, propofol, and atracurium. Within two to three minutes following the injection of atracurium, the patient experienced an episode of generalized erythema and arterial hypotension associated with tachycardia. No bronchospasm was observed. Her cardiovascular signs resolved spontaneously within five minutes, while her cutaneous signs disappeared within 30 min. Anesthesia and surgery remained uneventful. The patient's serum tryptase levels were measured at different time points following the clinical reaction. An in vitro flow cytometry-based basophil activation test was performed with atracurium, and in vivo skin tests to latex and all drugs which were administered just before the clinical reaction were also done. The serum tryptase showed increased concentrations that remained elevated for 24 hr, 48 hr, and even four weeks after the clinical reaction. Atracurium did not induce either CD63 or CD203c upregulation, and the skin tests were negative in response to the medications received (propofol, sufentanil, and atracurium) as well as to latex.
Conclusions: Allergic hypersensitivity to atracurium was ruled out. Increased tryptase concentrations following the clinical reaction, persistent increased levels of basal serum tryptase, and negative skin tests suggested the onset of mast cell degranulation in a patient with mastocytosis. Immediate reaction occurring in patients with mastocytosis should be investigated in order to identify the mechanism of the reaction, either histamine release due to the disease itself or due to a concurrent drug/agent-induced IgE-mediated mechanism.

Phil Lieberman, M.D.

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