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\title{Amiodarone triggered Kounis syndrome complicated by refractory cardiac
arrest rescued with VA-ECMO.}



\author[1]{Marc Soriano}%
\author[1]{Alessandro Sionis}%
\author[1]{Enrique Rodríguez Font}%
\author[1]{Ana Bonet}%
\author[1]{Lorena Soto}%
\author[1]{Manel Tauron}%
\author[1]{David Belmar}%
\author[1]{Sabiñe Arakama}%
\author[1]{Josep Mayol}%
\author[1]{Laura Rodríguez}%
\affil[1]{Hospital de la Santa Creu i Sant Pau}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\textbf{Abstract:} A patient with atrial fibrillation admitted for an
elective electrical cardioversion. He was given an amiodarone bolus that
triggered Kounis syndrome with cardiac arrest (CA) and refractory shock
needing mechanical support with ECMO and refractory hypoxemia that
improved with inhaled nitric oxide. Allergy to amiodarone was later
confirmed.\emph{Introduction}

Atrial fibrillation is the most common supraventricular arrhythmia. Some
studies revealed benefits in maintaining sinus rhythm in patients with
AF, especially in young patients (1). Electrical cardioversion is an
option when pharmacological cardioversion fails.

Kounis syndrome (2) is a rare disease that consists of an allergic
coronary syndrome, it usually presents as an ST-segment elevation acute
coronary syndrome. It requires emergent coronary angiography with
intracoronary vasodilators infusion and angioplasty if required. We
present an unusual form of Kounis Syndrome triggered by endovenous
amiodarone that underwent with cardiorespiratory arrest and refractory
shock due to the vasospasm. In this situation mechanical circulatory
support with ECMO was necessary to ensure tissue perfusion.
Specifically, in the in-hospital cardiac arrest, ECMO implantation is an
expanding therapy and is showing promising results.

\emph{}

\emph{History of presentation}

A 60-years-old man with a previous history of persistent atrial
fibrillation (AF) treated with oral amiodarone was admitted for an
elective electrical cardioversion. A 200 J shock, under sedation with
propofol and midazolam, was ineffective and the decision was made to
administer a 300 mg bolus of intravenous amiodarone. Immediately after,
the patient presented an extensive skin rash associated with pruritus
that was shortly followed by cardiac arrest secondary to pulseless
electrical activity. Advanced cardiopulmonary resuscitation (CPR) was
started but the patient persisted in cardiac arrest. ST-segment
elevation was observed on the monitor so the patient was transferred to
the cathlab for emergent coronary angiography. A left main coronary
artery spasm was observed (figure 1) and complete reversal of spasm was
achieved after 5 bolus of intracoronary nitroglycerin. After 19 minutes
of advanced CPR with administration of 8 mg of adrenaline, 200 mg of
hydrocortisone and 5 mg of dexchlorpheniramine recovery of spontaneous
circulation was achieved. Echocardiography revealed biventricular severe
dysfunction (video 1). The patient remained in refractory shock despite
of high doses of vasoactive drugs so VA-ECMO and intra-aortic balloon
pump (IABP) were implanted.

\emph{Past medical history}

The patient had a history of arterial hypertension, dyslipidemia and
sleep apnea-hypoapnea syndrome (SAHS) in treatment with CPAP. Paroxysmal
AF was diagnosticated five years ago undergoing electrical cardioversion
with premature recurrence. Dronedarone was initially used as an
antiarrhythmic drug, but after the recurrence of AF was changed to
amiodarone. Echocardiography showed left atrial enlargement with
preserved left ventricular function without valvulopathies.

Despite the treatment with amiodarone the patient persisted in AF so a
new electrical cardioversion was programmed followed by pulmonary vein
isolation.

\emph{Differential diagnosis}

Anaphylactic shock, cardiac arrest due to acute myocardial infarction,
coronary artery embolism or Kounis syndrome, respiratory arrest due to
hypoxemia.

\emph{Investigations}

Non-significant coronary lesions on the coronary angiography and absence
of regional wall motion abnormalities rule out the ischaemic cardiogenic
shock and coronary embolism.

No evidence of hypoxemia on initial blood gases and normal oxygen
saturation at the beginning of the case exclude hypoxemic cause.

The sudden presentation after drug administration accompanied by
erythema and pruritus led to the diagnosis of anaphylaxis. Coronary
angiography showed coronary vasospasm and a tentative diagnosis of
Kounis syndrome probably due to amiodarone was made. This was confirmed
later through determination of blood tryptase and later with positive
allergy tests for amiodarone.

\emph{Management}

The patient was admitted to the intensive cardiac care unit due to
refractory shock requiring mechanical circulatory support with VA-ECMO
and IABP.

High flow ECMO (3.7-4L) and aggressive fluid resuscitation were needed
in the first few hours to keep the patient well perfused. Stress
steroids were also given. After 48-72 hours the patient presented
progressive hemodynamic improvement until VA-ECMO support could be
weaning after five days. Biventricular function was completely
recovered.

Another problem during admission was severe respiratory failure. Deep
sedation, muscular relaxation, high fraction of oxygen in inspired air
(FiO2) and high requirement of positive end-expiratory pressure was
needed to achieve normoxemia. There was no response to empiric
antibiotic therapy and aggressive negative fluid balance. Suspecting
diffuse pulmonary vasoconstriction with ventilation-perfusion mismatch,
inhaled nitric oxide (NO) was started. An excellent response was
achieved with a rapid improvement of oxygenation allowing to reduce the
FiO2 requirements. A bronchoscopy was performed, isolating a
methicillin-resistant staphylococcus aureus in the cultures with no
evidence of complicated pneumonia in the CT scan. After seven days of
target antibiotics the patient remained apyrexial without other signs of
infection so treatment was suspended with good evolution.

Neurologically, the patient evolved without sequelae.

To confirm the diagnosis of allergic reaction, tryptase levels were
determined at the beginning and 24 hours later. Finally allergy tests
were performed resulting positive for amiodarone and confirming the
diagnosis.

One year after the event the patient is asymptomatic with functional
class-I of NYHA, persisting in AF controlled with beta-blocker treatment
and anticoagulated with a direct oral anticoagulant

\emph{Discussion}

The Kounis syndrome was first describe in 1991 and, as has been
described, it consists in a vasospasm due to allergic reaction. In these
cases, treatment with adrenaline is controversial because of the
eventual worsening of ischemia, vasospasm and increase in the QT
segment. However, in our case it was necessary considering the situation
of cardiorespiratory arrest. Vasodilator agents should be contemplated
as specific treatment. In our case, intracoronary nitroglycerin was
administered (4).

In our case, the most probable trigger of the Kounis syndrome was the
intravenous administration of amiodarone. To diagnose anaphylaxis, in
addition to pruritus and skin lesions after the drug administration,
determination of serum tryptase during the acute phase with subsequent
normalization is useful (figure 2). Mast cells are the main inflammatory
cells in the allergic reaction. Its degranulation produces the release
of inflammatory and vasoactive molecules. Tryptase determination is the
main marker of mast cell activity with a 73\% sensitivity and 98\%
specificity (5).

Some drugs have been associated with Kounis syndrome but as far as we
know from published evidence, this is the first case with amiodarone.
However, there are some cases of anaphylactic shock with intravenous
amiodarone in patients who already take it orally, especially in cases
of allergy to iodine (6).

The use of VA-ECMO has been previously described in the setting of
anaphylactic shock, with few cases being described. This case supports
the usefulness of ECMO in refractory shock requiring circulatory support
(7).

Another remarkable point to highlight in this case is the usefulness of
NO in refractory hypoxemia in a patient with VA-ECMO once initial
treatment has failed (deep sedation, pharmacological relaxation and
optimized ventilation). In our case it was effective and prevented
further aggressive treatments such as pronation or conversion to
VAV-ECMO. NO would act as a pulmonary vasodilator, reducing the reflex
vasoconstriction that occurs due to hypoxia, improving the pulmonary
ventilation/perfusion ratio. And although studies have not shown a
reduction in mortality, they have shown a significant improvement of
refractory hypoxemia. (8) (9).

Therefore, it is an interesting case, since on one hand, it shows an
infrequent cause of cardiorespiratory arrest such as coronary vasospasm
due to anaphylactic shock. And on the other hand, it highlights the
usefulness of circulatory support with ECMO in the scenario of
cardiorespiratory arrest.

\emph{}

\emph{Conclusions}

\emph{Authorship}

MS, AS, LR: involved in the writing of the article, design and
conceptualization. ER, AB, MT, LS, SA, JM, DB: involved in
conceptualization and methodology of the article. All authors approve
the final version of the case report for submission to the Clinical Case
Reports.

\emph{}

\emph{References}

(1).Dudink E, Erkuner O, Berg J, et al. The influence of progression of
atrial fibrillation on quality of life: a report from the Euro Heart
Survey. Europace 2018;20:929-934.

(2).Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis,
diagnosis and therapeutic management. Clin Chem Lab Med 2016;54:1545-59.

(3).Nikolaidis LA, Kounis NG, Grandman AH - Allergic angina and allergic
myocardial infarction: a new twist on an old syndrome. Can J Cardiol
2002;18:508-11.

(4).Alblaihed L, Huis In't Veld MA. Allergic Acute Coronary
Syndrome-Kounis Syndrome. Emerg Med Clin North Am. 2022;40(1):69-78.

(5).Muraro A, Worm M, Alviani C, et al. European Academy of Allergy and
Clinical Immunology, Food Allergy, Anaphylaxis Guidelines Group. EAACI
guidelines: Anaphylaxis (2021 update). Allergy. 2022;77(2):357-377.

(6).Batool A, Batool K, Habib H, et al. Anaphylactic Shock as a Rare
Side Effect of Intravenous Amiodarone. Cureus. 2022;14(1):211-18.

(7).Le HY, Tien ND, Son PN, et al. Extracorporeal membrane oxygenation
support in refractory anaphylactic shock after bee stings: A case
report. Perfusion. 2022;0(0):1-3.

(8).Shin TG, Jo IJ, Sim MS, et al. Two-year survival and neurological
outcome of in-hospital cardiac arrest patients rescued by extracorporeal
cardiopulmonary resuscitation. Int J Cardiol. 2013;168(4):3424-30.\selectlanguage{english}
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