Anesth Analg 2003;96:1051-1053
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Anaphylactic Reactions to Isosulfan Blue Dye During Sentinel Node Lymphadenectomy for Breast Cancer
Juraj Sprung, MD PhD*,
Michael J. Tully, MD*, and
Avishai Ziser, MD
*Department of Anesthesiology, Mayo Clinic, Rochester, MN; and
Rambam Medical Center, Haifa, Israel
Address correspondence and reprint requests to Juraj Sprung, MD, PhD, Mayo Medical School, Department of Anesthesiology, Saint Mary’s Hospital, MB 2–752, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Address e-mail to Sprung.juraj{at}mayo.edu
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Abstract
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IMPLICATIONS: Intraoperative use of isosulfan dye for lymphatic mapping may result in anaphylaxis. Furthermore, in some patients, intravascular absorption of isosulfan may induce serum discoloration causing interference with pulse oximetry function.
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Introduction
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Isosulfan blue (LymphazurinTM 1%, Surgical, a Division of Tyco Healthcare Group LP, Norwalk, CT) is an aniline dye (2,5-disulfonated isomer of patent blue dye) used to stain lymphatic channels before lymphangiography. Lymphatic mapping with isosulfan blue and sentinel lymphadenectomy was first described in 1990 and is being increasingly used in the management of patients with melanoma, breast cancer, and other solid tumors (1). The sentinel lymph node (SLN) hypothesis is based on the assumption that a tumor metastasis, if it exists, will travel on a direct path from the primary tumor through the efferent lymphatic channels to the first draining lymph node in the regional lymphatic basin, the sentinel node (1). This technique involves injection of 5 mL of isosulfan blue and 450 µCi of technetium-99m sulfur colloid around the primary malignancy (2). After either intradermal or intraparenchymal injection, isosulfan is selectively picked up by the lymphatic vessel, thus delineating the lymphatic system draining the area of injection making targeted surgical excision feasible. Although anaphylactic reactions to patent blue dyes have long been known (3), the first case of an anaphylactic reaction to isosulfan blue was reported in 1985 (4). Several authors (2,5,6) in the surgical literature reported an anaphylaxis to isosulfan blue; however, the first review of this topic in the anesthesia literature was recently published (7). Besides anaphylaxis, isosulfan blue dye may cause discoloration of a patient’s serum making the use of pulse oximetry useless by mimicking true intraoperative hypoxia (8). All these potential problems with isosulfan blue, as demonstrated by our case, can make an important impact on an anesthesiologist’s practice.
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Case Report
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A 53-yr-old woman (169 cm; 77 kg) was admitted for SLN biopsy and excision of breast carcinoma. Her medical history included Graves disease treated with radioactive iodine and hormone replacement therapy. The patient reported an allergy to penicillin (hives). Her preoperative blood pressure was 130/70 mm Hg, and an electrocardiogram showed a normal sinus rhythm of 60 bpm. After routine anesthesia, monitors were applied, propofol, vecuronium, and fentanyl were administered for the induction of general anesthesia, and the trachea was intubated. Anesthesia was maintained with N2O:O2, isoflurane, and fentanyl. After the induction of anesthesia, 1 g of cefazolin was administered IV. Before incision, the surgeon subcutaneously injected 4 mL of 1% isosulfan blue. One minute after the injection, the patient’s systolic blood pressure decreased to 55 mm Hg and then became undetectable with the noninvasive blood pressure monitor. The electrocardiogram showed a nodal rhythm at a rate of 40 bpm with frequent premature ventricular contractions. End-tidal CO2 acutely decreased to 12 mm Hg. Oxyhemoglobin saturation decreased to 81% and remained in the low 90% for the next 15 min. At the same time, arterial blood gases on the fraction of inspired oxygen = 1.0 were: PaO2 of 159 mm Hg (with SpO2 of 81%), PaCO2 of 61 mm Hg, base deficit of -9 mEq/L, and a pHa value of 7.15. A reddish macular rash was present throughout all the skin areas exposed to inspection. Epinephrine (300 µg sc and 30 µg IV), ephedrine (85 mg IV), and glycopyrrolate (0.4 mg IV) were administered, and the heart rate increased to 150 bpm, whereas the systolic blood pressure remained at 60 mm Hg. An epinephrine drip was initiated at 0.04 µg · kg-1 · min-1. An arterial line was placed, and systolic blood pressure remained between 60 and 70 mm Hg over the next 30 min despite infusion of epinephrine, dexamethasone (12 mg IV), and intravascular volume administration. At that point, it was decided to abort the surgery. Thirty minutes after the initial hypotension, the patient’s arterial blood pressure was stable at 90/70 mm Hg and the patient was transferred to the postanesthesia recovery room, with epinephrine infusion running at 0.35 µg · kg-1 · min-1, trachea being intubated, and lungs mechanically ventilated. A urinary catheter was placed. The patient’s urine was blue-green. At the same time, our laboratory informed us that the patient’s serum was green. Two and a half hours after the initial event, the patient was hemodynamically stable without epinephrine drip, and as she regained full alertness, her trachea was extubated. The diffuse rash gradually diminished, but her forearms and fingers became markedly swollen. This edema gradually receded over the next 24 h. In the recovery room, we measured the patient’s serum troponin T level, which was 0.04 ng/mL (normal <0.1 ng/mL). The serum tryptase (9,10) , drawn 2 h after the initial incident, was 38.2 ng/mL. The normal value is less than 11.5 ng/mL. Thirteen hours later, the serum tryptase was still increased at 14.1 ng/mL. The patient was discharged from the hospital on the following day. Ten days later, skin testing was performed for all the drugs she received during anesthesia. These tests demonstrated a severe positive reaction to isosulfan blue (the patient developed 7 x 8 mm skin wheal with pseudopod reaction to pinprick) but a negative reaction to penicillin, cefazolin, propofol, vecuronium, and latex.
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Discussion
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Selective SLN dissection is a relatively new method that can spare approximately 80% of patients with primary melanoma from radical lymph node dissection (5). Similarly, SLN biopsy is a good alternative to axillary dissection for patients with breast cancer. Combining the use of isosulfan blue dye with radioactive isotope optimizes SLN mapping in breast cancer patients (11). Local injection of isosulfan and technetium sulfur radiocolloid identifies the SLN both visually by staining the lymph nodes with dye and by detecting the hot spot with a hand-held 
probe. Whereas it is undoubtedly a useful method for detection of regional cancer spread, this approach is not without risks.
Our patient developed severe anaphylaxis after injection of isosulfan blue. Low blood pressure required large doses of vasopressors over the first several hours after the event. This protracted course of hemodynamic instability may be explained by a continuous systemic uptake of isosulfan dye from the injected site, as was demonstrated by green serum discoloration that lasted throughout the stay in the recovery room. In our patient, anaphylaxis was confirmed with both increases in serum tryptase concentrations (markers of mast-cell activation during systemic anaphylaxis) (9,10) and with markedly positive reaction to skin testing. Anaphylaxis represents an immediate type I hypersensitivity reaction, and isosulfan-induced hypersensitivity is an immunoglobulin E-mediated reaction. We could not detect that our patient had previous exposure to isosulfan antigen; however, isosulfan is triphenylmethane dye used in industry to color textiles, cosmetics, detergents, paints, and cold remedies (7). Therefore, previous exposure to any of these products may have sensitized our patient.
Several cases of anaphylaxis to isosulfan during SLN biopsy have been reported (2,4,5,12–14) . When isosulfan is used for SLN mapping, the incidence of anaphylaxis is between 0.7% and 1.1% (3 of 406 (5), 2 of 267 (2), and 7 of 639 (6)). The most recent report showed that the incidence of allergic reactions to isosulfan was 1.6%, whereas a severe hypotensive reaction occurred in 0.5% of patients (7). In this series, severe hypotensive reactions were rapidly responsive to antihistaminics, corticosteroids, and epinephrine (7).
Cimmino et al. (2) described another less severe form of allergic reaction. In a series of 267 patients undergoing intraoperative lymphatic mapping with isosulfan, they described three cases of blue hives, which transformed to blue patches during the course of the procedure (2). Other authors (1,15) have also reported blue hives during the use of isosulfan blue. Interestingly, although our patient had a diffuse rash, signs of excessive vascular permeability (swelling of her arms and fingers), and green-colored serum, she did not manifest signs of blue urticaria.
Another observation of interest for anesthesiologists is that isosulfan dye may interfere with pulse oximetry monitoring (8). Coleman et al. (8) described a profound decrease in oxyhemoglobin saturation, as measured with pulse oximetry, which occurred over a five-minute period after an injection of isosulfan. At the same time, arterial oxygenation, measured by arterial blood gases, was normal (8). Similarly, our patient had desaturation, as determined by pulse oximetry (SpO2 of 81%), whereas directly measured PaO2 was 159 mm Hg. This indicates a possible interaction of this drug’s absorptive spectroscopy and the wavelengths used to measure oxyhemoglobin saturation by commercial pulse oximetry devices. This interference is infrequently described (8), and we presume it occurs only in cases with intensive serum discoloration (i.e., when the injection is associated with large intravascular isosulfan absorption).
In conclusion, operating room personnel who participate in intraoperative lymphatic mapping with isosulfan blue must be aware of the relatively frequent incidence of anaphylaxis when this dye is used, and they should be prepared to recognize and treat it. Anesthesiologists must also be aware that pulse oximetry readings may occasionally be falsely low when isosulfan blue is used.
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References
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- Sadiq TS, Burns WW3rd, Taber DJ, et al. Blue urticaria: a previously unreported adverse event associated with isosulfan blue. Arch Surg 2001; 136: 1433–5.[Abstract/Free Full Text]
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Accepted for publication October 21, 2002.
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Abstract
Introduction
