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Anaphylactoid Reactions to Isosulfan Blue Dye During Breast Cancer Lymphatic Mapping in Patients Given Preoperative Prophylaxis

Departments of Surgical Oncology and Anesthesia, University of Texas M.D. Anderson Cancer Center and the Division of Allergy and Clinical Immunology, University of Texas—Houston Medical School, Houston, TX

To the Editor:

Lymphatic mapping and sentinel lymph node (SLN) biopsy are now routinely used for staging of clinically node-negative patients with breast cancer. Currently, technetium-99m-labeled sulfur colloid and 1% isosulfan blue dye, either alone or in combination, are used to trace the lymphatic drainage of a neoplasm to its SLN. However, allergic or adverse reactions to isosulfan blue dye have been reported in 0.7% to 1.9% of patients undergoing SLN biopsy in five single-institution studies representing 4,247 patients [1-5]. Three distinct patterns of allergic reactions to the dye have been identified and have been defined as grade 1 (urticaria or blue hives, pruritis, or a generalized rash), grade 2 (hypotension not requiring vasopressors), or grade 3 (hypotension requiring pressor support) [5]. Given the large number of patients who undergo SLN biopsy, even such a small risk of adverse reactions means that a significant number of individuals are at risk.

In an effort to reduce the incidence and severity of adverse reactions to isosulfan blue dye, we instituted a clinical practice protocol employing preoperative prophylaxis in December 2001. All patients were mapped with peritumoral injection of technetium-99m-labeled filtered sulfur colloid (2.5 mCi injected 24 hours before surgery or 0.5 mCi injected 1 to 4 hours before surgery). When blue dye was used, 5 mL of the 1% dye (Lymphazurin, US Surgical Corp, Norwalk, CT) was injected into the breast parenchyma around the primary tumor, and then the breast was massaged for 5 minutes. Those receiving isosulfan blue dye received 100 mg of hydrocortisone (or 4 mg of dexamethasone), 50 mg of diphenhydramine, and 20 mg of famotidine intravenously just before or at induction of anesthesia. Lymphatic mapping and SLN biopsy were performed as previously described [1]. We analyzed the type of surgery, adverse reactions occurring at the time of surgery, and wound complications presenting within 90 days after surgery in patients who underwent lymphatic mapping and SLN biopsy for breast cancer at our institution between December 2001 and January 2003. Groups were compared using the Fisher’s exact test.

Between December 2001 and January 2003, 654 consecutive patients underwent sentinel lymphadenectomy for breast cancer. Four hundred forty-eight patients (68.5%) received prophylaxis and isosulfan blue dye, 199 patients (30.4%) received no prophylaxis or dye, six patients (0.9%) received prophylaxis but no dye, and one patient (0.2%) received dye but no prophylaxis. Grade 1 adverse reactions to blue dye (blue urticaria, facial edema) were observed in three (0.7%) of 448 patients receiving prophylaxis and dye. There were no episodes of hypotension, and no patients required vasopressors, ventilatory support, or intensive care observation. Reactions to agents other than blue dye were observed in two (0.5%) of 448 patients receiving prophylaxis and dye and in two (1.0%) of 199 patients receiving no prophylaxis and no dye (P = .5905). In the two patients receiving prophylaxis and dye, the reactions were attributed to clindamycin and to a heat rash or contact dermatitis; neither patient had cardiovascular collapse or respiratory compromise. In one of the two patients receiving no prophylaxis or dye, the reaction was attributed to clindamycin or ondansetron and resulted in angioedema requiring reintubation. In the other patient without prophylaxis or dye, the reaction was a contact dermatitis. The overall incidence of wound complications potentially attributable to the use of one preoperative dose of corticosteroid, including all infectious complications and wound dehiscences, was 9.2% (41 of 448) in patients who received prophylaxis and dye. The incidence of similar complications in patients receiving neither prophylaxis nor dye was 4.5% (nine of 199; P = .0543). Infectious wound complications, including cellulitis requiring antibiotics and abscess requiring drainage, were observed in 38 (8.5%) of the 448 patients who received prophylaxis and dye and in nine (4.5%) of the 199 patients who received neither prophylaxis nor dye (P = .0994). Wound dehiscence was observed in three (0.7%) of the 448 patients who received prophylaxis and dye and in none of the 199 patients who received neither prophylaxis nor dye (P = .5565).

In our experience before the use of preoperative prophylaxis, seven (1.1%) of 639 patients injected with isosulfan blue dye during lymphatic mapping for breast cancer had grade 3 anaphylactoid reactions to the dye requiring vigorous resuscitation [1]. In comparison, in this study, we found that three (0.7%) of 448 patients who received prophylaxis and isosulfan blue dye had grade 1 adverse reactions directly attributable to the dye; none had grade 2 or 3 reactions. This incidence is not significantly different from the incidence before the initiation of our clinical practice protocol with the prophylaxis regimen (0.7% v 1.1%; P = .3515). Thus, preoperative prophylaxis reduced the severity but not the overall incidence of adverse reactions to isosulfan blue dye. No life-threatening reactions were noted in patients treated with preoperative prophylaxis. Because the prophylaxis regimen included a corticosteroid, we monitored our outcomes for wound complications. Although the complication rate was two-fold greater in patients receiving prophylaxis and dye compared with those receiving neither, this was not statistically significant. Several mechanisms of action behind adverse reactions to isosulfan blue dye have been postulated, but none have been confirmed. We are currently investigating the molecular basis of these adverse reactions.

Authors’ Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Albo D, Wayne JD, Hunt KK, et al: Anaphylactic reactions to isosulfan blue dye during sentinel lymph node biopsy for breast cancer. Am J Surg 182: 393-398, 2001[CrossRef][Medline]

2. Cimmino VM, Brown AC, Szocik JF, et al: Allergic reactions to isosulfan blue during sentinel node biopsy: A common event. Surgery 130: 439-442, 2001[CrossRef][Medline]

3. Hirsch JI, Tisnado J, Cho SR, et al: Use of isosulfan blue for identification of lymphatic vessels: Experimental and clinical evaluation. AJR Am J Roentgenol 139: 1061-1064, 1982[Abstract/Free Full Text]

4. Leong SP, Donegan E, Heffernon W, et al: Adverse reactions to isosulfan blue during selective sentinel lymph node dissection in melanoma. Ann Surg Oncol 7: 361-366, 2000[Abstract/Free Full Text]

5. Montgomery LL, Thorne AC, Van Zee KJ, et al: Isosulfan blue dye reactions during sentinel lymph node mapping for breast cancer. Anesth Analg 95: 385-388, 2002[Abstract/Free Full Text]

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