IDENTIFICATION of the sentinel lymph node, a marker for metastatic disease, is used increasingly for the surgical management of melanomas and tumors of the head and neck, breast, thyroid, and genitourinary and gastrointestinal tracts. 1Isosulfan blue (Lymphazurin; Ben Venue Laboratories, Bedford, OH) is the agent most commonly used, occasionally in conjunction with technetium sulfur colloid. Allergic reactions to this dye were reported previously during lymphangiography. 2,3We report a systemic reaction associated with use of isosulfan blue for detection of the axillary sentinel node in breast cancer.
A 48-yr-old woman was scheduled to undergo excision of a ductal carcinoma of the left breast and sentinel node biopsy. She had no history of drug or food allergies, hay fever, or bronchial asthma. Two hours before surgery, 1 mCi technetium sulfur colloid was injected near the lump. Two milligrams midazolam was administered intravenously for premedication.
Anesthesia was induced using 100 mg propofol, 20 μg sufentanil, and 30 mg rocuronium and maintained using isoflurane in nitrous oxide and oxygen after tracheal intubation. Vital signs were stable, with a blood pressure of 120/60 mmHg, a heart rate of 80 beats/min, and a pulse oxygen saturation (Spo2) of 99%. Five milliliters of isosulfan blue, 1%, was injected in 4 quadrants around the mass. Five minutes later, blood pressure decreased to 75/30 mmHg, with a heart rate of 85 beats/min and an Spo2of 94 or 95%. The inspired gases were changed to 100% oxygen, and isoflurane was temporarily discontinued. One liter of lactated Ringer’s solution was rapidly infused. A total of 50 mg ephedrine was administered, with little effect on the blood pressure but with a significant increase in heart rate and the occurrence of ventricular extrasystoles. The breath sounds were bilateral with no evidence of wheezing. When the drapes covering the face were lifted, marked swelling of the eyelids and lips was seen. Urticaria and erythema were not apparent at the site of dye injection or in the axilla. Fifty milligrams diphenhydramine, 1 g methylprednisolone, and 20 mg famotidine were administered. Blood pressure was maintained at 85–90/40–50 mmHg with subsequent doses of phenylephrine. The extrasystoles disappeared. After 15 min, blood pressure increased to 160/90 mmHg and then settled at 100–110/50 mmHg, with a heart rate of 100 beats/min and an Spo2of 99%. Axillary lymph node dissection was performed because the sentinel node showed metastases. At the end of the procedure, swelling of the eyelids and lips still were present. Direct laryngoscopy showed that the upper airway and vocal cords, however, appeared to be normal. The airway remained clear after extubation.
The facial swelling was absent by the following morning (18 h after the event). The plasma histamine concentration was 0.92 ng/ml (normal, ≤1.0 ng/ml). At the time of the reaction, the plasma histamine concentration was 11.2 ng/ml, and the serum complement levels were as follows: C3, 90 mg/dl (normal, 86–184 mg/dl); C4, 17 mg/dl (normal, 20–59 mg/dl). The immunoglobulin E level then was 38 IU/ml (normal, 0–160 IU/ml).
Four weeks later, intradermal testing with a dose of 0.02 ml isosulfan blue, 0.1%, yielded a pruritic 5-mm wheal with a surrounding 2.5-cm flare within 20 min. No reaction was seen in five healthy control subjects. Intradermal testing with use of 0.02-ml doses of propofol, 0.1 mg/ml; sufentanil, 0.05 μg/ml; midazolam, 0.01 mg/ml; and rocuronium, 0.01 mg/ml, yielded negative results. Subsequent anesthesia with use of these agents was uneventful. It was recommended that future use of the dye either be avoided or be covered by pretreatment if no alternative was available.
Isosulfan blue is a 2,5-disulfonated member of the triphenylmethane group of dyes, with a molecular weight of 563.13 d. Binding to serum proteins that leak into the interstitium causes it to enter the regional lymphatics, which become colored. 4Therefore, surgical exposure is facilitated. The incidence of adverse reactions is 1.5%. Many of these reactions are mild, with localized wheals and urticaria, but systemic anaphylaxis has also been reported. 3The reactions are mediated by histamine that is released either directly or through complement activation from mast cells or basophils. 3Serum tryptase measurement is advocated to confirm that the high plasma histamine level is because of its release from mast cells. However, serum tryptase does not signal histamine release from basophils, and therefore its level may be in the normal range during a systemic reaction mediated by these cells. 5
The temporal sequence of events and the positive skin test results with use of 0.1% isosulfan blue suggest that this substance was the cause of the systemic reaction. A false-positive wheal and flare response is possible at this dilution because the dye has anionic activity. However, at this dilution in control subjects, no reactions were seen with this agent in our case, or with other triphenylmethane dyes in a previous report. 6In our patient, the reaction resembled that which was considered positive for an allergic response to patent blue, the counterpart to isosulfan blue (4-mm wheal with surrounding 2.5-cm flare). 7Latex allergy is an unlikely cause of anaphylaxis in this patient because previous and subsequent anesthesia administrations with latex-containing equipment were uneventful.
This case highlights the need to suspect anaphylaxis when hemodynamic instability occurs after the injection of isosulfan blue. Further studies are needed to standardize the criteria for skin testing and reactivity because the reported values are based on only a few studies. In addition, the effectiveness of steroids and H1- and H2-receptor blocking agents for prevention of reactions in susceptible individuals remains to be determined.
The authors thank M. Castresana, M.D., Professor, and A. Cancel, M.D., Associate Professor, Department of Anesthesiology, Mercer University School of Medicine, Macon, Georgia, for their editorial assistance.