Research Article
Anaphylactic Reactions to Isosulfan Blue Dye during Sentinel Lymph Node Biopsy for Breast Cancer
Tao Wang1#, De-bin Xu2# and Zhen Liao3*
1Departmentsof Otolaryngology-Head & Neck Surgery, Sun Yat-sen University, China
2Departments of Thyroid and Neck Surgery, Nan Chang University, China
3Department of Operation Theater Services, Sun Yat-Sen University Cancer Center, China
#Both authors contributed equally
*Corresponding author: Zhen Liao, Department of Operation Theater Services, Sun Yat-Sen University Cancer Center, China
Published: 14 Sep, 2018
Cite this article as: Wang T, Xu D-B, Liao Z. Anaphylactic
Reactions to Isosulfan Blue Dye during
Sentinel Lymph Node Biopsy for Breast
Cancer. Clin Surg. 2018; 3: 2104.
Abstract
Background: The sentinel lymph node biopsy is an alternative to axillary dissection for many
breast cancer patients. Cases of anaphylactic reaction to the isosulfan blue dye used during sentinel
lymph node biopsy have recently been reported. A retrospective study the incidence and severity of
adverse reactions to isosulfan blue dye, we evaluated the incidence of severe anaphylactic reactions
to isosulfan blue dye during the performance of sentinel lymph node biopsy for breast cancer at our
institution.
Methods: A retrospective chart review study was enrolled consecutive 1456 patients for breast cancer
performed at our institution. Sentinel lymph node biopsy was performed using both isosulfan blue
dye and technetium-99m sulfur colloid. Cases of anaphylaxis were reviewed in detail.
Results: Overall, 12(0.8%) of the 1456 patients had severe anaphylactic reactions. All 12 patients
experienced cardiovascular collapse (profound hypotension and tachycardia) and skin reactions
and patients required admission to an intensive care unit bed or equivalent setting for postoperative
monitoring. No deaths or permanent disability occurred.
Conclusions: Prompt recognition and aggressive treatment of anaphylactic reactions to isosulfan
blue are critical to prevent an adverse outcome. Lymphatic mapping with blue dye should be
performed in a setting where personnel are trained to recognize and treat anaphylaxis.
Keywords: Sentinel lymph node; Biopsy; Anaphylaxis
Introduction
The Sentinel Lymph Node (SLN) biopsy has replaced Axillary Lymph Node Dissection (ALND) as the new standard of care in early breast cancer. Although dissection of the level I and II axillary lymph nodes is the gold standard for axillary staging, there are significant acute and chronic complications associated with the procedure [1,2]. Lymphatic mapping and SLN biopsy are now routinely used for staging of clinically lymph node negative patients with breast cancer. The SLN can be located by intra parenchymal injection of blue dye, either alone or in combination with a radiotracer. Isosulfan Blue (IB) is a patent dye, which, after subcutaneous or intra parenchymal injection, is absorbed by lymphoid tissue. It has been increasingly used for lymphatic mapping and for identification of sentinel lymph nodes [3]. Allergic or adverse reactions to IB dye have been reported in 0.06 and 2.7% of patients undergoing SLN biopsy in 11 single-institution studies representing 22803 patients, with a mean value of 0.71% [4]. Symptoms may range from mild (urticaria, erythema) to severe (pulmonary edema, hypotension, vascular collapse). Data on the incidence of severe anaphylactic reactions during the course of SLN biopsy for breast cancer are lacking. Given the substantial number of SLN biopsy currently being performed, even such a small risk of adverse reactions means that a significant number of individuals are at risk. To prospectively reduce the incidence and severity of adverse reactions to IB dye, we evaluated the incidence of severe anaphylactic reactions to IB dye during the performance of SLN biopsy for breast cancer at our institution.
Patient and Methods
Patient data
A retrospective chart review study was enrolled consecutive patients who were admitted to our
institution between January 2010 and December 2015 with initial
diagnoses of breast cancer without any other previous treatment.
Ethics approval was obtained from the Institutional Research Ethics
Committee of the Medical Center. In total, 1456 patients with breast
cancer were eligible for our study received a peritumoral injection
with a 99mTc-labeled filtered sulfur colloid. All patients scheduled to
receive IB dye. Lymphatic mapping and SLN biopsy were performed
as previously described [5].
Results
Between January 1, 2010 and December 31, 2015, 1456 patients underwent lymphatic mapping and SLN biopsy. Overall, 12(0.8%) of the 1456 patients had severe anaphylactic reactions. All 12 patients experienced cardiovascular collapse (profound hypotension and tachycardia) and skin reactions. In each case, symptoms developed 15 to 30 minutes after injection of IB dye. All 12 patients required vigorous resuscitation with phenylephrine infusion, antihistamines, steroids, and rapid fluid administration. All 12 patients required admission to an intensive care unit bed or equivalent setting for postoperative monitoring. Three patients had second episodes of anaphylaxis during postoperative monitoring. These allergic reactions consisted of nausea and vomiting, symptoms more consistent with known side effects of narcotic medications than with true allergic reactions. Two patients had a history of true drug allergies: one had a history of mild allergic reactions to penicillin and sulfa drugs, with symptoms including urticaria and itching, and the other had a history of severe anaphylaxis upon exposure to intravenous iodine, with symptoms including bronchospasm and hypotension. No previous exposure to IB dye was reported by any of the 12 patients. No perioperative complications occurred in any of these patients.
Discussion
Lymphatic mapping and SLN biopsy are now routinely used for
staging of clinically node-negative patients with breast cancer. IB is
commonly used for lymph node dissection. As experience with SLN
biopsy has expanded, reports of adverse reactions to IB dye used in
mapping have increased. The incidence of allergic reactions to IB dye
ranges from 0.06% to 2.7% [4]. Although anaphylaxis was reported
with administration of a related dye as early as 1966, anaphylactic
reaction to IB has been reported [7]. Montgomery identified three
distinct patterns or grades of allergic reaction to the dye [6]. Grade
1 reactions were defined as urticaria or blue hives, pruritis, and/
or a generalized rash. Grade 2 reactions were defined as transient
hypotension (systolic blood pressure ≥ 70 mmHg) not requiring
vasopressors. Grade 3 reactions were defined as hypotension
(systolic blood pressure <70 mmHg) requiring vasopressor support.
Montgomery reported 39 adverse reactions to IB dye in a series of
2392 patients (1.6%) undergoing mapping for breast carcinoma.
Nine (23%) of the adverse reactions were Grade 3 and 3(8%) were
Grade 2 reactions [5]. In a previous report 7 (1.1%) of 639 patients
injected with IB dye during lymphatic mapping for breast carcinoma
had severe anaphylactoid reactions to the dye that required vigorous
resuscitation [6]. All 7 had Grade 3 reactions characterized by
cardiovascular collapse requiring vasopressors and admission to an
intensive care unit or equivalent setting.
Our patient developed severe anaphylaxis after injection
of IB. Low blood pressure required large doses of vasopressors
over the first several hours after the event. All patients required
vigorous resuscitation with phenylephrine infusion, antihistamines,
steroids, and rapid fluid administration. 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. 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 [5]. Therefore,
previous exposure to any of these products may have sensitized our
patient.
There have been no deaths reported as a result of these systemic
reactions. The majority of affected patients stay 24 hours after
the procedure. Series have been reported on the use of methylene
blue as a substitute for IB [8]. Methylene blue may prove to be less
allergenic than IB and therefore remains an intriguing possibility that
warrants clinical investigation. Several studies have compared the
efficacy of identification of the sentinel node using blue dye to the
combination of blue dye and lymphoscintigraphy. In the literature
reviewed, no study compared lymphoscintigraphy alone to blue dye,
or to a combination of the two. To date there have been no reported
allergic complications related to the injection of radioactive isotopes
in lymphatic mapping. A well-designed prospective study comparing
lymphoscintigraphy alone to the combination may provide evidence
on the costs and benefits of using IB. As without any perioperative
complication, prevention is often the best management. Perhaps skin
testing in these patients will elicit a common antigen or substance that
can be eliminated or avoided. Also, identification of people sensitive
to the IB dye would allow proper preparation and precautions in
these patients to eliminate or limit the extent of their response. Even
if we are unable to prevent or eliminate this problem, knowledge of
this complication can provide patients with better informed consent
and allow breast physicians to be more prepared for these potentially
serious reactions.
As its use permeates medicine, more of these allergic reactions
should be expected. Although no deaths have been reported and
the symptoms and manifestations are reversible, in our study
0.8% is a significant risk of occurrence. Until a better alternative is
proven, high suspicion, early recognition, and appropriate clinical
management are recommended. The first line of therapy involves
the discontinuation of all anesthetic agents, administration of 100%
oxygen, rapid infusion of large amounts of intravenous fluids, and
prompt administration of phenylephrine (0.1 to 0.3 mg intravenously
given over 10 minutes). The second line of therapy includes H1-
blockers (diphenhydramine hydrochloride 50 mg intravenously)
and corticosteroids (methylprednisolone 125 mg intravenously). For
refractory hypotension in patients receiving beta blockers, glucagon
(1-mg ampule) constitutes a third line of treatment.
We chose to use a phenylephrine infusion instead of an
epinephrine infusion because of the absence of any changes in airway
pressure and because of the presence of sinus tachycardia (which
improved after initiating phenylephrine). It is worthwhile mentioning
that the stress dose of steroids failed to prevent the anaphylactic
response to isosulfan. However, preoperative prophylaxis may be
reduced the severity but not the overall incidence of adverse reactions
to IB dye [9].
In breast cancer, the combination of IB dye and a radiotracer has
been shown to markedly increase the sensitivity of this procedure.
Therefore, we currently advocate the use of IB dye in lymphatic
mapping for breast cancer.
Conclusion
As SLN biopsy rapidly becomes the standard of care for identifying nodal metastases in women with breast cancer, the questions that now face surgeons relate to optimal technique and safety. Nonetheless, anaphylactic reactions to IB dye during the course of SLN biopsy for breast cancer, although their incidence is relatively low, could have serious consequences. As part of the informed consent process, patients should be informed of this potentially life-threatening allergic reaction. At a time when so called minimally invasive procedures such as SLN biopsy are shifting towards more cost-effective ambulatory settings, it becomes paramount that the personnel involved in the performance of these procedures be familiar with potential reactions and be prepared to immediately recognize and treat anaphylaxis. Surgeons must know that severe reactions to IB may occur, recognize them early, and be prepared to treat anaphylaxis. However, a largerscale study on similar lines should be carried out investigating the molecular basis of these adverse reactions.
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