Anaphylaxis to isosulfan blue and cross-reactivity to patent blue v

Case report
Anaphylaxis to isosulfan blue and cross-
reactivity to patent blue V: case report and
review of the nomenclature of vital blue dyes
Kathrin Scherer, MD*; Wolfgang Studer, MD†; Verena Figueiredo‡; and Andreas J. Bircher, MD*
Background: Blue dyes used for lymphatic mapping in sentinel lymph node biopsy cause intraoperative anaphylactic
reactions in up to 2.7% of patients. With increasing implementation of this technique, the incidence of anaphylaxis to these dyescan be expected to increase. In the literature, the chemically often unrelated and inconsistently designated dyes have beenconfused, adding to other inconsistencies in the nomenclature.
Objective: To demonstrate the nomenclature, chemical and physiologic differences, and allergenicity of the various blue dyes
Methods: We describe a patient with an intraoperative grade IV anaphylactic reaction to isosulfan blue. Immediate-type
hypersensitivity was proved by positive skin test reactions and CD63 expression to isosulfan blue and cross-reactivity to patentblue V.
Results: A review of the literature clarified the exact nomenclature of the blue dyes and the possible pitfalls of confusing
nomenclature in the context of structurally closely related dyes with different allergenic properties. For the detection of type Ihypersensitivity, intracutaneous tests are valuable tools. An IgE-mediated mechanism has been shown recently. In most cases,sensitization exists without known previous exposure in a medical context. This may be due to the widespread use of such dyesin objects of everyday life. Preoperative antiallergic medication use does not prevent anaphylactic reactions but apparentlyreduces their severity.
Conclusion: For better comparison and precision, the Chemical Abstracts Service number of the respective dye should always
Ann Allergy Asthma Immunol. 2006;96:497–500.
laxants and opiates, may cause anaphylactoid reactions owing Anaphylactic and anaphylactoid reactions are rare events during to their strong histamine-liberating capacity, in addition to the anesthesia, although the true incidence of anaphylactic reactions possibility of an IgE-mediated reaction. Skin tests, which are and their morbidity and mortality remain poorly defined. These usually a valuable diagnostic tool, may yield misleading reactions may lead to death, even when appropriately treated, results owing to uncertainties in distinguishing irritant from with a mortality of 3.5% to 4.7%. Incidence rates are known to allergic skin reactions. Blue dyes, used for lymphatic map- be 0.5 to 1 in 10,000 (in Australia in 1993) to 1 in 13,000 (in ping in the context of sentinel lymph node biopsy (SLNB) in France in 1996)1,2 in countries with well-organized documenta- cancer surgery, are rare causes of anaphylactic reactions.
tion systems. Of the drugs most liable for inducing anaphylac- Because of the increasing implementation of this technique toid or anaphylactic reactions during anesthesia, myorelaxants for new indications, eg, melanoma, breast carcinoma, bladder account for approximately 50%,3 followed by latex sensitization cancer, and cervical and endometrial cancer, the incidence of anaphylaxis to these blue dyes can be expected to increase.
Allergologic diagnostic approaches to these events are By means of this case report of intraoperative anaphylaxis challenging for multiple reasons.4 Usually more than 1 pos- to isosulfan blue and an overview of the literature, we attempt sible elicitor of anaphylaxis has been administered at the to draw attention to this increasingly important group of dyes same time. Some of the drugs in question, especially myore- and its potential to cause intraoperative anaphylaxis. In ad-dition, often these dyes are not correctly designated, and evenfrom a chemical point of view misleading designations have * Allergy Unit, Department of Dermatology, University Hospital, Basel, been used, resulting in a mix up of the dyes in the literature.
† Department of Anesthesia, Kantonsspital, Liestal, Switzerland.
‡ Institute of Hospital Pharmacy, University Hospital, Basel, Switzerland.
A 70-year-old woman was scheduled to undergo a lumpec- Received for publication March 18, 2005.
Accepted for publication in revised form July 26, 2005.
tomy of the left breast and SLNB for suspected breast cancer.
Hypertension was treated with enalapril. After the smooth Both dyes were injected in the upper back at 1:10 and 1:100 induction of general anesthesia, the patient developed, shortly dilutions. After 15 minutes, the resulting wheals were docu- after the start of surgery, generalized erythema, tachycardia, mented using a digital camera (Coolpix 5000; Nikon USA, a decline in blood pressure to 80/50 mm Hg, and conjuncti- Melville, NY) through an optical device with an integrated vitis. After the administration of vasoactive substances and scale. The wheal circumference was determined in triplicate, glucocorticosteroids and substitution of volume, her circula- and the area was then calculated using the freeware NIH tion returned to a stable condition and her shock symptoms Image/J software V 1.3Ø win32 (National Institutes of regressed. The postoperative course was uneventful.
Health). By statistical analysis, compared with a negative At the time of the anaphylactic reaction the patient had control (0.9% sodium chloride), a threshold dilution for in- previously received propofol, enflurane, and thiopental so- tracutaneous tests of 1:100 of the stock solution for isosulfan dium, as well as the muscle relaxant atracurium besylate for blue and patent blue V was established, separating toxic- the induction of anesthesia and cefazolin sodium (a first- irritant reactions from true allergic reactions.
generation cephalosporin) as a prophylactic antibiotic. Mast Specific IgE to isosulfan blue and patent blue V could not cell tryptase levels were elevated immediately after the inci- be detected using either ImmunoCAP (isosulfan blue) or dent to 113 ␮g/L (reference range, 1–13.5 ␮g/L), indicating radioallergosorbent test (patent blue V) techniques (Pharma- an allergic reaction. At that point, an anaphylactic reaction cia, Uppsala, Sweden). Investigation of specific IgE to iso- grade IV to cefazolin, atracurium, thiopental, or latex was sulfan blue using an enzyme-linked immunosorbent assay according to a recent publication5 was also negative. Results Results of skin prick and intracutaneous tests with propo- of sulfidoleukotriene release tests (CAST, Bu¨hlmann Inc, fol, thiopental, atracurium, benzylpenicillin, amoxicillin, and Allschwil, Switzerland) were negative; however, CD63 ex- cefazolin in several concentrations; skin prick tests with pression (Flow-CAST Basophil Activation Test, Bu¨hlmann latex-protein derivatives; and determination of specific IgE Inc) was positive for both substances. Therefore, the final against latex, penicillins, and aminopenicillins were negative.
diagnosis was an intraoperative anaphylactic reaction due to A lymphocyte transformation test to benzylpenicillin, amoxi- immediate-type hypersensitivity to isosulfan blue with cross- cillin, and cefazolin did not show any stimulation. A serum reactivity to patent blue V, possibly aggravated by enalapril.
sample from the patient was used for experimental determi-nation of specific IgE to thiopental, propofol, and cefaclor (another first-generation cephalosporin), and the findings The dyes commonly used for SLNB are isosulfan blue and were negative. The basal mast cell tryptase concentration was patent blue V, although other dyes, such as indocyanine green elevated to 25.4 ␮g/L, suggesting an increased mast cell and fluorescein, have been investigated and are used in spe- mass. However, no clinical symptoms of mastocytosis were cial situations.5 The chemical systematics of the standard present. The preliminary diagnosis was an anaphylactic reac- dyes isosulfan blue and patent blue V are complicated, and tion of unknown origin, possibly due to the suspected diag- the situation is aggravated by a misleading nomenclature that nosis of systemic mastocytosis. However, on repeated con- is sometimes contradictory even in the chemical expert liter- trols, serum mast cell tryptase levels ranged from 18 to 25 ature. Figure 1 shows the chemical structure of the 2 mole- ␮g/L, thereby not fulfilling the criterion for systemic masto- cules, which differ in the position of the substituted sulfonate.
cytosis of being constantly greater than 20 ␮g/L.
Both belong to the group of triarylmethane dyes and basically A new careful study of the anesthesia protocol and the share the same formula of C H N O S , with patent blue V surgical report and repeated questioning of the anesthesiolo- having an additional hydroxyl group.
gist revealed that immediately before the start of surgery the The sodium salt of patent blue (Chemical Abstracts Service patient was injected with several milliliters of isosulfan blue [CAS] No. 129-17-9) is, among many other names, also perilesionally as a marker for the lymphatic drainage system called sulfan blue, food blue 3, patent blue VF, and acid blue of the diseased tissue in preparation for the intended SLNB.
1. Isosulfan blue (CAS No. 68238-36-8) is the 2,5-disulfo- Skin prick and intracutaneous tests were then performed phenyl structural isomer of patent blue (not patent blue V) with isosulfan blue and patent blue V (concentration forintracutaneous tests: 1:1 to 1:106 of stock solution [1%]) andmethylene blue (1:1 to 1:104 of stock solution [1%]). Meth-ylene blue results were negative for all the tests, whereasisosulfan blue and patent blue V results were positive up todilutions of 1:105 of the stock solution, positive being definedas a wheal larger than the negative control after 15 minutes.
Informed consent was obtained from 9 healthy individuals who had never been exposed to isosulfan blue or patent blueV in a medical context and who served as controls for theintracutaneous tests. This testing was approved by the ethics Figure 1. Chemical structure of patent blue V (A) and isosulfan blue committee of the Medical Faculty of the University of Basel.
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY and is sold under the trade name Lymphazurine.6 Patent blue after injection of the drug indicate as much. The cause of V is predominantly provided as calcium-chelated dimer (CAS biphasic reactions is not yet understood completely. Sampson No. 3536-49-0) and can also be found under the name patent et al15 and Lee and Greenes16 discuss in studies of children blue violet, food blue 5, acid blue 3, and disulfine blue. It is and adolescents a relatively long time between initial ana- also known as E 131 and is still on the market as a food phylaxis and the administration of epinephrine and its corre- colorant, in contrast to the report by Quiliquini et al.7 Patent lation with the occurrence of a second anaphylactic (biphasic) blue V has a slightly different chemical structure containing episode. In a study17 of 639 patients who underwent SLNB an additional hydroxyl group at position 5.
for breast cancer using isosulfan blue, 7 anaphylactic reac- Because of the close structural relationship of these vital tions occurred, 2 of which were biphasic. The 2 patients had dyes, cross-reactivity may be assumed and could be shown recurrences during postoperative monitoring (6 and 8 hours clinically and in the Flow-CAST in our patient. Recently, after surgery) and again responded well to antiallergic treat- flow cytometric quantification of CD63-positive basophils ment.17 Quiliquini et al7 described a patient with a second has been shown to be a useful tool in the diagnosis of type I episode of severe anaphylaxis 3 hours after the first. In that sensitization to patent blue V.8 For most patients, the mode of case, patent blue V was the causative agent.
sensitization is not clear because almost all patients are ex- Raut et al18 investigated the use of preoperative prophy- posed only once to one of the dyes in the context of lym- laxis with 100 mg of hydrocortisone (4 mg of dexametha- phangiography or SLNB. Therefore, most patients have re- sone), 50 mg of diphenhydramine, and 20 mg of famotidine acted at their first known exposure to such a dye. An as-yet in 448 patients with SLNB using isosulfan blue. They ob- unproven hypothesis states that sensitization against the vital served allergic reactions in 0.7% of these patients, all of them dyes is facilitated by the common use of patent blue and other grade I. No episodes of hypotension were noted. They con- structurally closely related triarylmethane dyes in objects of cluded that preoperative prophylaxis reduced the severity but everyday life, such as color textiles, cosmetics, detergents, not the overall incidence of adverse reactions to isosulfan paints, inks, antifreeze, cold remedies, laxatives, and suppos- blue.18 The complication rate regarding wound healing dou- bled under this treatment, but it did not reach statistical In addition to a variety of case reports11,12 there are several significance. No biphasic anaphylaxis was seen with prophy- retrospective and prospective studies of large numbers of lactic therapy, perhaps because of the overall less severe patients on the frequency of allergic reactions to isosulfan reactions with prophylactic therapy. Severe reactions and blue and patent blue V. Montgomery et al10 calculated in their early onset after exposure to the allergen seem to be risk meta-analysis of several single-institution series, including their own of 2,392 patients, the incidence of allergic reactions Several incidences have been reported of transient, false to vital blue dyes in patients with breast cancer. For patent lowering of pulse oximetry findings. Coleman et al19 postu- blue, the incidence is 0.6% to 2.7%, with a mean of 1.8%. For lated that the absorption maximum of isosulfan blue at 646 isosulfan blue, the incidence is 0.9% to 1.9%, with a mean of nm interferes with measuring of the absorption of oxyhemo- 1.4%. The cumulative number of patients included in these globin at 660 nm using conventional pulse oximeters, indi- studies was 1,940 for patent blue and 4,247 for isosulfan blue.
Most of the patients reacted mildly, with anaphylactic reac- Skin tests, especially intracutaneous tests, are valuable tion grades I and II, with urticaria, blue hives, flush, and tools for diagnosing type I sensitization to isosulfan blue and pruritus; however, severe hypotensive reactions do occur.
patent blue V. We demonstrated that a 1:100 dilution of the The reactions are generally reported to respond rapidly to stock solution (1%) was not irritant after intracutaneous in- jection in 9 healthy individuals. This is in analogy to studies In our patient, the long-term use of the angiotensin-con- by Laurie et al,20 who reported negative intradermal test verting enzyme (ACE) inhibitor enalapril may have aggra- results in 8 healthy individuals and 1 patient with breast vated the situation. In a recent retrospective analysis of 1,149 cancer with 1:100 dilutions of the stock solution.
patients with anaphylaxis, Brown13 suggested that ACE in- Woehrl et al21 recently demonstrated specific IgE antibod- hibitors affect reaction severity, although it was not an inde- ies against isosulfan blue in patients with previous anaphy- pendent predictor of any severe reaction feature. Other re- lactic reactions to isosulfan blue. However, they did not searchers14 report that inhibition of the metabolism of succeed with the serum of our patient. Despite this, an IgE- angiotensin by ACE inhibitors and the following buildup of mediated mechanism can be assumed, although older publi- bradykinin and substance P might predispose some individ- cations suggest pseudoallergic mechanisms.22 Given the rel- uals to anaphylaxis and to being more refractory to treatment atively small molecular weight of isosulfan blue, it is likely to act as a hapten. Approximately 50% of the isosulfan blue in Biphasic courses of the reaction have sometimes been aqueous solutions is weakly bound to serum proteins, which described. They may be attributed to the slow release of the allows for its characteristic lymphatic tropism.19 dye from the subcutaneous tissue or the lymphatic tissue and Methylene blue is sometimes mentioned as another dye the half-life of the dye in the body of several hours. Blue or successfully used for lymphatic mapping.8,23 The methylene green serum, urine, or skin discoloration for up to 24 hours blue known under CAS No. 61-73-4 (anhydrous methylene blue) or CAS No. 7220-79-3 (methylene blue trihydrate), how- blue [letter]. Dermatology. 1998;197:400.
ever, is only approved for intravenous administration for the 8. Ebo DG, Wets RD, Spiessens TK, Bridts CH, Stevens WJ.
treatment of methemoglobinemia and hemolysis because it may Flow-assisted diagnosis of anaphylaxis to patent blue. Allergy.
cause necrosis on subcutaneous administration. It has the total 9. Leong SPL, Donegan E, Heffernon W, et al. Adverse reactions formula C H ClN S and is the trihydrate of the 3,7-bis(dim- to isosulfan blue during selective sentinel lymph node dissection ethylamino) phenazathionium chloride. According to Tsopelas in melanoma. Ann Surg Oncol. 2000;7:361–366.
and Sutton,24 methylene blue does not bind to plasma proteins, 10. Montgomery LL, Thorne AC, Van Zee KJ, et al. Isosulfan blue having no sulfonic acid groups, and, therefore, is not taken up by dye reactions during sentinel lymph node mapping for breast lymph but diffuses directly into blood capillaries. Unfortunately, cancer. Anesth Analg. 2002;95:385–388.
the exact name of the product used is not always given so that 11. Sprung J, Tully MJ, Ziser A. Anaphylactic reactions to isosulfan the question of possibly another nomenclature problem cannot blue dye during sentinel node lymphadenectomy for breast be answered. However, methylene blue is structurally not related cancer. Anesth Analg. 2003;96:1051–1053.
to isosulfan blue or patent blue V, and, therefore, cross-reactivity 12. Efron P, Knudsen E, Hirshorn S, Copeland EM III. Anaphylac- tic reaction to isosulfan blue used for sentinel node biopsy: casereport and literature review. Breast J. 2002;8:396 –399.
13. Brown SGA. Clinical features and severity grading of anaphy- CONCLUSION
laxis. J Allergy Clin Immunol. 2004;114:371–376.
Anaphylactic reactions are a dreaded intraoperative complica- 14. Ober AI, MacLean JA, Hannaway PJ. Life-threatening anaphy- tion. As SLNBs are increasingly performed in patients with laxis to venom immunotherapy in a patient taking an angioten- various malignant tumors, the likelihood of anaphylactic reac- sin-converting enzyme inhibitor. J Allergy Clin Immunol. 2003; tions to vital blue dyes increases. Incidences of 0.6% to 2.7% for anaphylactic reactions to either isosulfan blue or patent blue V 15. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal necessitate awareness of the risk on the part of the surgeon and anaphylactic reactions to food in children and adolescents.
the anesthesiologist. Preoperative antiallergic prophylaxis appar- N Engl J Med. 1992;327:380 –384.
ently reduces only the severity of the reactions and not the 16. Lee JM, Greenes DS. Biphasic anaphylactic reactions in pedi- atrics. Pediatrics. 2000;106:762–766.
number of adverse events, with a consecutive increase in post- 17. Albo D, Wayne JD, Hunt KK, et al. Anaphylactic reactions to operative wound problems. Preoperative intracutaneous testing, isosulfan blue dye during sentinel lymph node biopsy for breast which can easily be performed, should, therefore, be taken into cancer. Am J Surg. 2001;182:393–398.
consideration as a potential diagnostic procedure.
18. Raut CP, Daley MD, Hunt KK, et al. Anaphylactoid reactions to isosulfan blue dye during breast cancer lymphatic mapping in ACKNOWLEDGMENTS
patients given preoperative prophylaxis. J Clin Oncol. 2004;22: We thank Bu¨hlmann Inc, Allschwil, Switzerland, for per- forming CAST and Flow-CAST; Pharmacia for investigating 19. Coleman RL, Whitten CW, O’Boyle J, Sidhu B. Unexplained the serum for specific IgE to the dyes; Dr Focke-Tejkl (Vi- decrease in measured oxygen saturation by pulse oximetry enna, Austria) for attempting to detect specific IgE to isosul- following injection of lymphazurin 1% (isosulfan blue) during alymphatic mapping procedure. J Surg Oncol. 1999;70:126 –129.
fan blue; and J. L. Gue´ant (Nancy, France) for determining 20. Laurie SA, Khan DA, Gruchalla RS, Peters G. Anaphylaxis to specific IgE to thiopental, cefaclor, and propofol.
isosulfan blue. Ann Allergy Asthma Immunol. 2002;88:64 – 66.
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