Vol.:(0123456789)

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Breast Cancer

https://doi.org/10.1007/s12282-020-01129-5

CASE REPORT

Kounis syndrome afterpatent blue dye injection forsentinel lymph

node biopsy

MaximosFrountzas

· PanagiotisKarathanasis

· GavriellaZoiVrakopoulou

· CharalamposTheodoropoulos

·

ConstantinosG.Zografos

· DimitriosSchizas

· GeorgeC.Zografos

· NikolaosV.Michalopoulos

1,3

Received: 11 May 2020 / Accepted: 22 June 2020

Abstract

Background Kounis syndrome (KS) has been described as an acute coronary syndrome (ACS) associated with an anaphy-

lactic reaction. Several triggers have been identiﬁed and the diagnostic and treatment process can be challenging.

Case A 58-year-old, female patient diagnosed with breast cancer and no history of allergies had subcutaneous injection

of patent blue V dye for sentinel lymph node biopsy (SLNB). Intraoperatively, she developed anaphylactic shock and was

transferred to the intensive care unit (ICU). A few hours later, electrocardiographic alterations and elevation of blood troponin

were observed. Emergency coronary angiography revealed no occlusive lesions in coronary vessels. Further investigation in

the allergy department set the diagnosis of KS.

Conclusion There are just ten cases of perioperative KS in the literature so far and here we present the ﬁrst one triggered by

patent blue V dye for sentinel node biopsy.

Keywords Kounis syndrome· Patent blue· Sentinel node biopsy

Introduction

Sentinel lymph node biopsy (SLNB) has been considered as

the gold standard method for axillary staging in early breast

cancer. Surgeons traditionally utilize intra-parenchymal

injection of blue dye, either alone or in combination with

a radiotracer [1]. Patent blue violet (V) has been the most

commonly used blue dye outside the USA, despite its minor

allergic reaction risk, which is below 1% [2]. Patent blue V

allergic reactions could vary from simple cutaneous mani-

festations to cardiac arrest [3].

Kounis Syndrome (KS) is an extremely rare anaphylactic

reaction to various allergens, which is associated with acute

coronary syndrome [4]. KS leads to hypovolemic shock of

cardiogenic etiology, that actually should be treated as an

anaphylactic one. Herein we present the ﬁrst case in the

literature concerning KS after patent blue V injection for

SLNB in early-stage breast cancer.

Case report

A 58-year-old Caucasian woman with an invasive ductal car-

cinoma in the upper outer quadrant of the right breast was

scheduled for breast conserving operation and axillary sen-

tinel lymph node biopsy. Her past medical history included

only a mild dilatation of the thoracic aorta (4.2cm). No

allergies were reported. The preoperative echocardiogram

revealed no abnormalities with a left ventricular ejection

fraction of 55–60%. During the operation, 2ml of patent

blue V was administered subcutaneously in the periareolar

area of the right breast.

Approximately 15min after patent blue V dye injection,

the patient progressively developed tachycardia (110bpm)

followed by hypotension (blood pressure: 60/30mmHg).

* Maximos Frountzas

[email protected]

1st Department ofPropaedeutic Surgery, Medical School,

“Hippocratio” General Hospital, University ofAthens, 114

Vas. Sophias Av, 11527Athens, Greece

1st Department ofSurgery, Medical School, University

ofAthens, “Laiko” General Hospital, 17 Agiou Thoma St,

11527Athens, Greece

4th Dept. ofSurgery, Medical School, “Attikon” University

Hospital, University ofAthens, 1 Rimini St, 12462Chaidari,

Greece

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Pulse oximetry decreased from 100 to 95%. The patient

developed a rash initially in the face, which gradually

expanded in the whole body, and a systemic allergic reac-

tion was diagnosed. The patient immediately received

bolus doses of corticosteroids and dimetindene. In addi-

tion, ﬂuid resuscitation with 3L of crystalloids and doses

of norepinephrine were administered to maintain blood

pressure in normal values. High-sensitivity (HS) troponin-

I levels were normal (2.23mg/dl).

The patient was transferred to the intensive care unit

(ICU) for monitoring. 6h later, electrocardiogram abnor-

malities (depression of ST segment in leads II and III)

were observed (Fig.1). New blood samples for HS tro-

ponin-I were abnormal (2360mg/dl). She underwent a

new echocardiogram, which demonstrated a decrease of

ejection fraction (40%) and a hypokinetic left cardiac ven-

tricle. The patient was treated with dual antiplatelet ther-

apy (clopidogrel 300mg and acetylsalicylic acid 100mg)

and underwent emergent coronary angiography, which

revealed no occlusive lesions in the coronary arteries, but

conﬁrmed the low ejection fraction (40%). The follow-

ing 24h her condition gradually improved and she was

extubated the next day, being haemodynamically stable

and without need of vasopressor support. After Intensive

Care Unit discharge, the levels of HS troponin-I gradually

decreased until they became normal, and she was ﬁnally

discharged from hospital on the sixth postoperative day.

A month later, the patient was reviewed at the Allergy

and Immunology Department, where allergy to patent blue

V was conﬁrmed.

Discussion

Kounis syndrome (KS), or “allergic angina syndrome”,

is deﬁned as the co-incidental occurrence of an acute

coronary syndrome (ACS) associated with mast cell and

platelet activation in the setting of an allergic or anaphy-

lactic insult [5]. Its annual incidence is 4 to 10 cases per

100,000 inhabitants and its mortality rate is 0.0001% [6,

7]. Although KS could be presented in any age group,

68% of patients aﬀected are between 40 and 70years. Risk

factors of KS include history of allergy, hypertension,

smoking, diabetes and hyperlipidemia. The most common

triggers of KS are antibiotics (27.4%) followed by insect

bites (23.4%), even though more triggers are still under

investigation [8].

Three main types of KS have been described so far:

•

Type I (without coronary disease, 75%): patients with-

out previous history of coronary disease, who present

anaphylactic reaction that causes coronary vessels

spasm. Electrocardiographic changes cardiac enzymes

elevation could be present. Endothelial dysfunction

and/or microvascular angina have been proposed as

probable pathophysiological mechanisms of this type

of KS [9].

•

Type II (with coronary disease, 20%): patients with pre-

existing atheromatous disease, either symptomatic or

unknown, in which the hypersensitivity reaction causes

plaque erosion or rupture, leading to acute myocardial

infarction [10].

•

Type III (with stents, 5%): patients with previous cor-

onary artery disease and drug-eluting stents that get

thrombosed due to hypersensitivity vasculitis [11].

KS is characterized by the interaction between mast cells,

macrophages and T-lymphocytes, which activates an inﬂam-

mation cascade that is mediated by several molecules and

leads to coronary artery spasm and/or atheromatous plaque

erosion or rupture during an allergic reaction [12, 13]. Mast

cells are located in the areas of coronary plaque erosion or

rupture, whereas they act on the smooth muscle of the coro-

nary arteries [14]. The inﬂammation cascade is triggered

by antigen–antibody reaction on the surface of the mast and

basophil cells, or activation of the complement system (C3a,

C5a), which explains the rapid—less than 60min—manifes-

tation of KS after trigger exposure [15]. In addition, there is

a threshold beyond which the inﬂammation cascade is acti-

vated, that depends on the body site, where the antigen–anti-

body reaction occurs, the area of exposure, the mediators

release and the severity of the allergic reaction [16].

Therefore, it is understandable why KS is exacerbated

very quickly with high severity perioperatively, where the

Fig. 1 Electrocardiogram showing alterations (ST segment depres-

sion in leads II and III) developed during Intensive Care Unit stay

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potential triggers are administrated in the blood circula-

tion, either during general anesthesia induction or during

an operation. Only ten cases of perioperative KS have been

reported in the literature so far (Table1). In six of them,

KS was presented during general anesthesia induction or

immediately after that, but before skin incision. The rest

four cases were reported intraoperatively after skin inci-

sion by surgeons. Several triggers have been reported to

cause perioperative KS such as rocuronium, cefazoline,

gelofusine, midazolam, bupivacaine, latex and succi-

nylated gelatin. In 80% of the patients that experienced a

perioperative KS, there was no history of allergy or previ-

ous coronary disease (Type I).

Perioperative KS has presented as hypovolemic shock—

hypotension and tachycardia—during anesthesia induction

or within 60min after it. However, only in four out of ten

reported cases electrocardiographic alterations and rash were

initially manifested. In four more cases ACS was identiﬁed

by electrocardiographic alterations without clinical signs of

anaphylactic reaction. Finally, in two cases allergic reac-

tion was the ﬁrst manifestation with a rash, but no initially

clinical signs of a coronary syndrome. Simultaneous clinical

signs of ACS and allergic reaction impose a serious diagnos-

tic problem and one out of ten patients died due to periop-

erative KS. All cases were managed according to ACS and

anaphylactic reaction therapeutic protocols.

KS in the operating room may prove serious and usually

presents as a hypovolemic shock. The key for successful

management of such a shock in an intubated patient is recog-

nizing the cause. This may prove to be challenging, as only

40% of patients develop a combination of ACS and allergic

clinical signs. Similar to what happened in our case, 20% of

patients with perioperative KS initially manifest an anaphy-

lactic reaction without ACS. Therefore, they are generally

treated for anaphylactic shock, as the pathophysiologic basis

of coronary occlusion in KS is based on hypersensitivity

reactions, that are resolved by corticosteroids and antihis-

tamines [17]. The main problem, however, exists in 40% of

patients with perioperative KS, that present ACS without

an initial anaphylactic reaction. These patients are treated

according to an ACS therapeutic protocol that is usually

not eﬀective, because it actually does not deal with the real

cause of coronary occlusion [18]. The key for such patients

is raised suspicion by anesthesiologists and surgeons, with

continuous assessment of their whole body for clinical signs

of allergic reaction.

A possible algorithm for treating perioperative KS is shown

in Fig.2. When its anaphylactic component is present, all aller-

gic triggers should be removed, epinephrine, glucocorticoids

and antihistamines should be administered in combination to

high ﬂow oxygen and ﬂuid resuscitation [19]. When its coro-

nary syndrome component is present, a cardiology review and

administration of nitroglycerine, double antiplatelet medica-

tion (clopidogrel and acetylsalicylic acid) and calcium chan-

nel blockers (diltiazem, verapamil) is advised [20]. Primary

percutaneous coronary intervention (PCI) and ICU monitoring

are usually indicated Fig. (2).

In our case, patent blue V dye has triggered KS. Several

allergic reactions against patent blue V have been reported

in the literature, the incidence of which varies between 0.06

and 2.7%, with a mean value of 0.71%. Patent blue V allergic

reactions could vary from simple cutaneous manifestations to

cardiac arrest. Fortunately, the reported risk of severe allergic

reactions, that required vasopressors administration or surgery

interruption, remained extremely low and barely reached 0.1%

[21]. In addition, methylene blue has been proposed as a poten-

tial alternative to patent blue V, due to its comparable eﬃcacy

in SLN identiﬁcation, its lower cost and its decreased allergic

stimulation (below 0.5%). However, the possibility for cross

reactivity between these two dyes still exists [22]. Moreover,

super paramagnetic iron oxide (SPIO) nanoparticles and indo-

cyanine green ﬂuorescence (ICG) have demonstrated adequate

eﬃciency in SLN mapping in combination to a radio-isotope,

but their safety has still to be proved [23, 24]. Finally, the uti-

lization of a radio-isotope alone without a blue dye is another

proposed option that showed comparable SLN identiﬁcation

rates, but required advanced surgical experience [25]. Nev-

ertheless, patent blue V has never been reported as a trigger

for KS.

Conclusion

KS is a combination of ACS and anaphylactic reaction that

rarely happens in the operating room. Diagnosis demands

raised suspicion by anesthesiologists and surgeons, when they

are facing an intraoperative shock without a clear cause, which

does not respond to usual therapeutic protocols. Multiple trig-

gers have been reported up to date and our case identiﬁed pat-

ent blue V for sentinel lymph node biopsy as a new one.

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Table1 Kounis syndrome in the operating room

Date; Study Surgery Cause Type LVEF ECG Treatment Outcome Allergies Onset ACS Onset

anaphy-

laxis

Before skin incision

2013; Sanchez Rotator cuﬀ

arthroscopy

Rocuro-

nium ± Cefa-

zoline

I N/A ST elevation in front

and bottom of

heart

Nitroglycerine, clopidogrel,

acetylsalicylic acid

Methylprednisolone, dex-

chlorpheniramine, raniti-

dine, ephedrine

Primary PCI

Discharged No Yes Yes

2013; Shah Urologic Gelofusine II Normal ST elevations in 3

leads, pulseless

electrical activ-

ity and p-wave

asystole

Metaraminol, epinephrine,

atropine, norepinephrine

CTCA

Discharged Penicillin

Anti-tetanus

serum

Yes Yes

2015; Ates TURP Midazolam I Normal ST depression on

anterior deriva-

tions

Acetylsalicylic acid, LMWH,

atorvastatin, ranitidine

Antihistamines and corticos-

teroids

Primary PCI

Discharged No Yes No

2016; Lerner Lipoma (local

anesthesia)

Bupiv-

acaine ± lido-

caine

I 70% ST elevation in

inferior leads, ven-

tricular ﬁbrillation

and cardiac arrest

Deﬁbrillations, epinephrine,

amiodarone

Primary PCI

Discharged Insect stings

and oxytetra-

cycline

Yes Yes

2017; Sakamoto LAP ileocecal

excision

Rocuronium I N/A ST elevation Adrenaline, noradrenaline,

atropine, amiodarone

Steroids and antihistamines

Primary PCI

Discharged N/A Yes Yes

2018; Vasquez Foot Fracture Fentanyl ± bupiv-

acaine

I Diastolic

dysfunc-

tion

Signs of ischemia Ephedrine, dexamethasone,

salbutamol, epinephrine

Aspirin, clopidogrel, atorv-

astatin

Primary PCI

Cardio-respiratory

arrest

N/A No Yes

After skin incision

2012; Takenaka Varicose vein

stripping

Latex I Normal ST elevation Ephedrine, phenylephrine and

noradrenaline, adrenaline

Nitroglycerin, noradrenaline,

diltiazem

Discharged No Yes No

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N/A non-available, LVEF left ventricular ejection fraction, ECG electrocardiogram, LAP laparoscopic, ACS acute coronary syndrome, TURP transurethral prostatectomy, TURB transurethral

resection of bladder tumor, CTCA computerized tomography coronary angiography, LMWH low molecular weight heparin, PCI percutaneous coronary intervention

Table1 (continued)

Date; Study Surgery Cause Type LVEF ECG Treatment Outcome Allergies Onset ACS Onset

anaphy-

laxis

2013; Marcoux Hernia repair Latex II 57% Third-degree

AV-block and ST-

elevations

Ephedrine, glycopyrrolate,

epinephrine, salbutamol,

norepinephrine

Clopidogrel and acetylsali-

cylic acid

Primary PCI

Coronary re-

stenosis after

4months

No Yes No

2017; Tornero Spinal surgery Succinylated

gelatin

I Lateral wall

motion

abnor-

malities

ST depression in the

left-sided leads

Ephedrine, epinephrine,

hydrocortisone, sugamma-

dex, dexamethasone

Heparin, amiodarone

Primary PCI

Discharged No No Yes

2019; Sato TURB and

LAP nephro-

ureterectomy

Cefazolin I N/A ST in lead II of the

ECG decreased

Nitroglycerin and nicorandil

Corticosteroids and chlorphe-

niramine

CTCA

Discharged No Yes No

2020; Our case Breast surgery Patent blue V I 40% ST depressions in

leads II and III

Dimetindene, corticosteroids,

norepinephrine

Clopidogrel, acetylsalicylic

acid

Primary PCI

Discharged No No Yes

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Funding None to disclose for all authors.

Compliance with ethical standards

Conflict of interest The authors report no conﬂict of interest.

Informal consent For this type of study formal consent is not required.

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